Open Access

Cheminformatics studies to analyze the therapeutic potential of phytochemicals from Rhazya stricta

  • Abdullah Y. Obaid1,
  • Sreedhara Voleti2,
  • Roop Singh Bora3, 4,
  • Nahid H. Hajrah3,
  • Abdulkader M. Shaikh Omer5,
  • Jamal S. M. Sabir3 and
  • Kulvinder Singh Saini3, 4Email author
Chemistry Central Journal201711:11

DOI: 10.1186/s13065-017-0240-1

Received: 30 May 2016

Accepted: 11 January 2017

Published: 30 January 2017

Abstract

Rhazya stricta is a unique medicinal plant source for many indole alkaloids, non-alkaloids, flavonoids, triterpenes and other unknown molecules with tremendous potential for therapeutic applications against many diseases. In the present article, we generated computational data on predictive properties and activity across two key therapeutic areas of cancer and obesity, and corresponding cheminformatics studies were carried out to examine druggable properties of these alkaloids. Computed physiochemical properties of the 78 indole alkaloids from R. stricta plant using industry-standard scientific molecular modeling software and their predictive anti-cancer activities from reliable web-source technologies indicate their plausible therapeutic applications. Their predictive ADME properties are further indicative of their drug-like-ness. We believe that the top-ranked molecules with anti-cancer activity are clearly amenable to chemical modifications for creating potent, safe and efficacious compounds with the feasibility of generating new chemical entities after pre-clinical and clinical studies.

Keywords

Rhazya stricta Alkaloids Physiochemical properties Druggability Anticancer molecules Anti-obesity molecules

Background

Rhazya stricta Decsne (Apocynaceae family), a traditional herbal medicinal plant from Western and South Asia, has been shown to have multiple pharmacological effects due to the presence of over 100 alkaloids [13]. The chemical constituents of this plant (R. stricta) may possess biological activities of antifungal, antimicrobial, antioxidant, CNS, hypertension, metabolic, and inflammatory disorders. Rhazimine, an alkaloid isolated from R. stricta leaves, was shown to affect arachidonic acid metabolism in human blood [4]. This alkaloid was shown to be a dual and selective inhibitor of platelet activating factor (PAF)-induced platelet aggregation and arachidonic acid metabolism. Other effects of the lyophilized extract of R. stricta include an antispasmodic effect in rat muscles [5]. In another study, antioxidant effects were observed at higher doses, and it reduced the hepatic and renal concentrations of glutathione (GSH) and increased the ascorbic acid levels, whereas the degree of lipid peroxidation was reduced [6]. A recent study has shown that the basic alkaloid fraction from R. stricta significantly induces one of the chemopreventive enzyme-Nqo 1, through an Nrf 2-dependent mechanism, thereby establishing its role as an anti-tumor agent [7]. In another pharmacological study, the biochemical parameters including blood lipid profile concentrations, liver enzyme activities and kidney functions were analyzed in rats [8]. It was also found that aqueous extract of R. stricta and indole alkaloids caused a significant increase in serum adiponectin levels and resulted in significant improvements in insulin resistance [9]. In another follow up study, we observed indole-alkaloids of R. stricta improved not only the lipid profile and liver function but also led to improvements in the insulin levels in rats, most likely via modulating insulin resistance [10]. Indole-alkaloids of R. stricta had been reported to have anticancer properties [11]. Other studies by our departmental colleagues showed that alkaloid extract of R. stricta leaves inhibited proliferation, colony formation and anchorage-independent growth in various cancer cell lines such as colon cancer, breast cancer and lung cancer [1214].

Understanding the chemical structure, physiochemical, and chemical-informatic properties of these natural product compounds will give clues for further modifications required in their structures responsible for their biological activities. Even though, there have been about 100 chemical entities of indole-based alkaloid constituents of R. stricta which have been reported but their chemical structures are yet to be clustered and identified, and moreover the pharmacological application of any one of these constituents towards human health is yet to be identified. Understanding qualitative correlation of structures to their chemical druggability, IP potential, and their applicability towards a therapeutic area would be worth exploring prior to pre-clinical studies. Availability of this plant (R. stricta), thus its phytochemical constituents largely in Arabian and South Asian region makes it worth studying through computational, synthetic, and biological view point. Indole based alkaloids such as vinblastine and vincristine are well known for their anti-cancer properties. From systematically generated informatics data analysis, one would be able to evaluate the physiochemical properties of the potential therapeutic compounds. These promising molecules which have “desirable pharmacophores” may provide obvious extension to a better targeted therapeutic benefit. Conventional drugs obey set of rules such as Lipinski’s Rule-of-Five (RO5) [15], wherein all orally administered molecules need to have certain physiochemical properties. Calculation of these cheminformatic properties has thus become essential for all projects of new drug discovery which go through oral route of administration. Along with RO5, the new molecules also have to adhere to certain parameters which yield favorable ADMET outcome of an oral drug. We further evaluated these molecules for therapeutic activity, including anticancer, anti-obesity, anti-inflammatory, and anti-bacterial properties. Although these predictions are indicative only, the value of predictions in various target classes and therapeutic areas would be very useful for future experimental studies. Moreover, their metabolic fate with key enzymes such as P450’s is also predicted for probable drug–drug and drug-target (P450) interactions (reviewed in [16, 17]).

Methods

For prediction of various therapeutic potential of these molecules, commercially and publicly available technologies as below were utilized.
  1. a.

    PharmaExpert (http://www.pharmaexpert.ru)—PASS [18]

     
  2. b.

    Superpred (http://prediction.charite.de)—Predictive Targets [19]

     
  3. c.

    SwissTargetPrediction (http://www.swisstargetprediction.ch)—Predictive Target [20]

     
  4. d.

    CDRUG (http://bsb.kiz.ac.cn/CDRUG)—Anti-cancer activity [21]

     
Schrodinger [22], a scientific software that predicts drug-like properties and liabilities (viz. HERG and CNS), and ACD/Labs [23] for physiochemical and cheminformatics studies were utilized. Details of the molecules, names, structures were obtained from the literature, commercial sources, and knowledge-based web sources. Tables 1 and 2 gives the details of these molecules together with their 2D SMILES notation, respectively.
Table 1

Chemical structures and names of Rhazya stricta compounds

Table 2

SMILES codes for Rhazya stricta compounds

MOL ID

Name

SMILES code

M1

Akummidine

COC(=O)C1(CO)C2CC3=C([NH]C4=C3C=CC=C4)C5CC1\C(CN25)=C/C

M2

Antirhine

OCC(C=C)C1CCN2CCC3=C([NH]C4=C3C=CC=C4)C2C1

M3

3-Epi-antirhine

OCC(C=C)C1CCN2CCC3=C([NH]C4=C3C=CC=C4)C2C1

M4

Aspidosespermidine

CCC12CCCN3CCC4(C(CC1)NC5=C4C=CC=C5)C23

M5

Condylocarpine

COC(=O)C1=C2NC3=CC=CC=C3C24CCN5CCC1\C(=C\C)C45

M6

Dihydrocorynantheol

CCC1CN2CCC3=C([NH]C4=CC=CC=C34)C2CC1CCO

M7

Eburnamenine

CCC12CCCN3CCC4=C(C13)[N](C=C2)C5=CC=CC=C45

M8

Eburnamine

CCC12CCCN3CCC4C(C13)[N](C(O)C2)C5=CC=CC=C45

M9

Eburnamonine

CCC12CCCN3CCC4=C(C13)[N](C(=O)C2)C5=CC=CC=C45

M10

Geissoschizine

COC(=O)\C(=C/O)C\1CC2N(CCC3=C2[NH]C4=CC=CC=C34)CC1=C\C

M11

Isositsirikine

COC(=O)C(CO)C\1CC2N(CCC3=C2[NH]C4=CC=CC=C34)CC1=C/C

M12

16-Epi-Z-isositsirikine

COC(=O)C(CO)C\1CC2N(CCC3=C2[NH]C4=CC=CC=C34)CC1=C\C

M13

Leuconalm

CCC12CCCN3C(=O)C=C(C4=CC=CC=C4NC(=O)CC1)C23O

M14

Rhazinliam

CCC12CCC[N]3C=CC(=C13)C4=CC=CC=C4NC(=O)CC2

M15

Tetrahydrosecamine

CCC1CCCN(CCC2=C([NH]C3=CC=CC=C23)C4(CCC(C(=O)OC)C5=C(CCN6CCCC(CC)C6)C7=C

C=CC=C7[N]45)C(=O)OC)C1

M16

Presecamine

CCC1=CCCN(CCC2=C([NH]C3=CC=CC=C23)OC(=O)C4CCC(=C5N(C)C6=C C=CC=C6C45C

CN7CCC=C(CC)C7)C(=O)OC)C1

M17

Sewarine

COC(=O)C1=C2NC3=C(C=C(O)C=C3)C24CCN5C\C(=C\C)C1CC45

M18

Stemmadenine

C\C=C1/CN2CCC1C(C(=O)OCO)C3=C(CC2)C4=CC=CC=C4[N]3C

M19

Strictamine

COC(=O)C1C\2CC3N(CCC14C3=NC5=CC=CC=C45)CC2=C\C

M20

Strictosamide

OCC1OC(OC2OC=C3C(CC4N(CCC5=C4[NH]C6=CC=CC=C56)C3=O)C2C=C)C(O)C(O)C1O

M21

Strictosidine

COC(=O)C1=COC(OC2OC(CO)C(O)C(O)C2O)C(C=C)C1CC3NCCC4=C3[NH]C5=CC=CC=C45

M22

Taberonine

CCC12CC(=C3NC4=CC=CC=C4C35CCN(CC=C1)C25)C(=O)OC

M23

Tetrahydrlstonine

COC(=O)C1=COC(C)C2CN3CCC4=C([NH]C5=CC=CC=C45)C3CC12

M24

Vallesiachotamine

COC(=O)C1=CN2CCC3=C([NH]C4=CC=CC=C34)C2CC1\C(=C/C)C=O

M25

Aspidospermoise

CCC12CCCN3CCC4(C(CC1)N(C5OC(O)C(=O)C(O)C5O)C6=CC=CC=C46)C23

M26

Bhimbrine

COC(=O)C(CO)C\1CC2N(CCC3=C2[NH]C4=C3C=CC=C4)CC1=C/C

M27

Bhimbrine N-oxide

COC(=O)C(CO)C\1CC2C3=C(CC[N+]2([O-])CC1=C/C)C4=C([NH]3)C=CC=C4

M28

Rhazimine

COC(=O)C12C(CC3(C=NC4=CC=CC=C34)C1=O)N5CCC2\C(C5)=C/C

M29

Rhazimanine

COC(=O)C(CO)C\1CC2N(CCC3=C2[NH]C4=CC=CC=C34)CC1=C\C

M30

Rhazicine

COC(=O)C12C(CC3(C(O)NC4=CC=CC=C34)C1=O)N5CCC2\C(C5)=C\C

M31

Leepacine

COC(=O)C12C3CC4(C(NC5=CC=CC=C45)C6CC1\C(CN36)=C/C)C2=O

M32

2-Methoxy 1-2,dihydrorhazamine

COC1NC2=CC=CC=C2C13CC4N5CCC(\C(C5)=C/C)C4(C(=O)OC)C3=O

M33

HR-1

C\C=C1\C[N+]2([O-])CCC3=C(C2CC1(O)COC(C)=O)[N](C)C4=CC=CC=C34

M34

Vincanicine

COC1=CC=C2C(=C1)NC3=C(C=O)C\4CC5N(CCC235)CC4=C\C

M35

Rhazinaline

COC(=O)C1(C=O)C\2CC3N(CCC14C3=NC5=CC=CC=C45)CC2=C/C

M36

Beta-sitosterol

CCC(CCC(C)C1CCC2C3CC=C4CC(O)CCC4(C)C3CCC12C)C(C)C

M37

Ursolic acid

CC1CCC2(CCC3(C)C(=CCC4C5(C)CCC(O)C(C)(C)C5CCC34C)C2C1C)C(O)=O

M38

Stigmasterol

CCC(\C=C\C(C)C1CCC2C3CC=C4CC(O)CCC4(C)C3CCC12C)C(C)C

M39

Olenaolic acid

CC1(C)CCC2(CCC3(C)C(=CCC4C5(C)CCC(O)C(C)(C)C5CCC34C)C2C1)C(O)=O

M40

Rhazidigenine (rhazidine)

CCC12CCCN(CCC3(O)C(=NC4=CC=CC=C34)CC1)C2

M41

N-methylleuconolam

CCC12CCCN3C(=O)C=C(C4=CC=CC=C4N(C)C(=O)CC1)C23O

M42

(+)-Quebranchamine

CCC12CCCN(CCC3=C(CC1)[NH]C4=CC=CC=C34)C2

M43

Polyneuridine

COC(=O)C1(C=O)C2CC3=C([NH]C4=CC=CC=C34)C5CC1\C(CN25)=C\C

M44

(+)-Vincadiformine

CCC12CCCN3CCC4(C13)C(=C(C2)C(=O)OC)NC5=CC=CC=C45

M45

(−)-Vincadiformine

CCC12CCCN3CCC4(C13)C(=C(C2)C(=O)OC)NC5=CC=CC=C45

M46

Secamine

CCC1=CCCN(CCC2=C([NH]C3=C2C=CC=C3)C4(CCC(C(=O)OC)C5=C (CCN6CCC=C(CC)

C6)C7=CC=CC=C7[N]45)C(=O)OC)C1

M47

Vincadine

CCC12CCCN(CCC3=C([NH]C4=CC=CC=C34)C(C1)C(=O)OC)C2

M48

Bis-strictidine

CCC1=C2C3CC4(CCN2CCC1)C5C=CC=CC5 N=C4C6CC7(CCN8CCCC(=C68)

CC)C3=NC9=C7C=CC=C9

M49

3,14-Dehydrorhazigine

CCC1=CN(CCC1)CCC2C(=NC3=C2C=CC=C3)C4CCC(=C5NC6=C(C=CC=C6) C45C

CN7CC(=CC=C7)CC)C(=O)OC

M50

16-Hydrorhazisidine

CCC1=CCCN(CCC2=C3C(CC(C(O)[N]3C4=C2C=CC=C4)C5=C(CCN6CCCC(=C6)CC)

C7=C([NH]5)C=CC=C7)C(=O)OC)C1

M51

Rhazisidine

CCC1=CCCN(CCC2=C3C(CC4C([N]3C5=C2C=CC=C5)C6=C(CC)C=C CN6C

CC7=C4[NH]C8=C7C=CC=C8)C(=O)OC)C1

M52

Isorhazicine

COC(=O)C12C(CC3(C(O)NC4=C3C=CC=C4)C1=O)N5CCC2\C(C5)=C\C

M53

Rhazigine

CCC1=CCCN(CCC2=C([NH]C3=C2C=CC=C3)C4CCC(=C5NC6=C(C=CC=C6) C45C

CN7CCC=C(CC)C7)C(=O)OC)C1

M54

Strictisidine

COC(=O)C12C3CC4(C1=O)C(=NC5=C4C=CC=C5)C6CC2\C(CN36)=C\C

M55

Strictamine-N-oxide

COC(=O)C1C\2CC3C4=NC5=CC=CC=C5C14CC[N +]3([O-])CC2=C/C

M56

Strictigine

CCC1=C2CCN(CCC23C(=NC4=CC=CC=C34)C=C)C1

M57

Strictine

COC(=O)C1C2CC3 N(CCC4=C3[N]1C5=CC=CC=C45)C=C2C(C)=O

M58

Stricticine

COC(=O)C1=C2NC3=CC=CC=C3C24CCN5CC6(OC6C)C1CC45

M59

Strictalamine

C\C=C1/CN2CCC34C(C=O)C1CC2C3=NC5=CC=CC=C45

M60

1,2-Dehydroaspidospermine

CCC12CCCN3CCC4(C13)C(=NC5=CC=CC=C45)CC2

M61

Tetrahydrosecodine

CCC1CCCN(CCC2=C([NH]C3=CC=CC=C23)C(C)C(=O)OC)C1

M62

Dihydrosecodine

CCC1=CCCN(CCC2=C([NH]C3=CC=CC=C23)C(C)C(=O)OC)C1

M63

Dihydrosecamine

CCC1CCCN(CCC2=C([NH]C3=C2C=CC=C3)C4(CCC(C(=O)OC)C5=C (CCN6CC

C=C(CC)C6)C7=CC=CC=C7[N]45)C(=O)OC)C1

M64

Dihydropresecamine

CCC1CCCN(CCC2=C([NH]C3=CC=CC=C23)OC(=O)C4CCC(=C5 N© C6=CC=C

C=C6C45CCN7CCC=C(CC)C7)C(=O)OC)C1

M65

Tetrahydropresecamine

CCC1CCCN(CCC2=C([NH]C3=CC=CC=C23)OC(=O)C4CCC(=C5 N© C6=CC=C

C=C6C45CCN7CCCC(CC)C7)C(=O)OC)C1

M66

Rhazinol

C\C=C1\CN2CCC34C(CO)C1CC2C3=NC5=CC=CC=C45

M67

Rhazimol

COC(=O)C1(CO)C\2CC3N(CCC14C3=NC5=CC=CC=C45)CC2=C/C

M68

Rhazidigenine-N-oxide

CCC12CCC[N+]([O-])(CCC3(O)C(=NC4=CC=CC=C34)CC1)C2

M69

(−)-16R,21R-Omethyleburmanine

CCC12CCCN3CCC4=C(C13)[N](C(C2)OC)C5=CC=CC=C45

M70

Decarbomethoxy-15,20,16,17-tetrahydrosecodine

CCC1CCCN(CCC2=C(CC)[NH]C3=CC=CC=C23)C1

M71

1,2-Dehydroaspidospermidine-N-oxide

CCC12CCC[N+]3([O–])CCC4(C13)C(=NC5=CC=CC=C45)CC2

M72

Rhazizine

COC(=O)C12OCN3C(O1)C4(CCN5C\C(=C\C)C2CC45)C6=CC=CC=C36

M73

15-Hydroxyvincadifformine

CCC12CC(=C3NC4=CC=CC=C4C35CCN(CCC1O)C25)C(=O)OC

M74

Dihydroburnamenine

CCC12CCCN3CCC4=C(C13)[N](CC2)C5=CC=CC=C45

M75

16s,16′-Decarboxytetrahydrosecamine

CCC1CCCN(CCC2=C([NH]C3=C2C=CC=C3)C4CCC(C(=O)OC)C5=C

(CCN6CCCC(CC)C6)C7=C(C=CC=C7)[N]45)C1

M76

Nor-C-fluorocuraine

C\C=C1\CN2CCC34C2CC1C(=C3NC5=CC=CC=C45)C=O

M77

Strictibine

COC(=O)C1=CC=C2NC3=CC=CC=C3C12

Results and discussion

Physiochemical and cheminformatic studies

ACD/Laboratories informatics modules generated physiochemical and cheminformatics data of R. stricta indole and non-indole alkaloids. For all the selected 78 molecules in this study, it was observed that less than 20% of the molecules are having molecular weights >450, while most molecules range around 300–350, indicating their viability for additional medicinal chemistry amenable nature. Most of these molecules are also moderately to highly soluble—mainly due to the high value of pKa (leading to solubility at neutral pH). Additionally, many of these indole/non-indole molecules are also less lipophilic (~75% of them have logP ~3 to 4). Alkaloids that violate Lipinski’s Rule-of-5 are either due to molecular weight or logP, are tetrahydrosecamine; presecamine; beta-sitosterol; ursolic acid; stigmasterol; oleanolic acid; secamine; bis-strictidine; 3,14-dehydrorhazigine; 16-hydroxyrhazisidine; rhazisidine; rhazigine; dihydrosecamine; dihydropresecamine; tetrahydropresecamine; decarbomethoxy-15,17-tetrahydrosecodine;16s,16′-decarboxytetrahydro-secamine. Figures 1 and 2 give the plots of molecular weight and LogP (lipophilicity) of individual compounds, accordingly. Since most of the molecules have a basic nitrogen and sometimes, may be more than one, leading to a larger pKa at physiological pH—thus leading most molecules are highly to moderately soluble at physiological pH. Very few compounds and non-indole alkaloids have no basic nitrogen leading to highly insoluble compounds in water at physiological pH. As the acidity goes up (leading towards pH 1), most compounds become largely soluble. A qualitative and quantitative (computational) estimate of solubility of these compounds are given in Tables 3 and 4, respectively.
Fig. 1

Variation of Molecular weight of compounds of Rhazya stricta

Fig. 2

Variation of LogP of compounds of Rhazya stricta

Table 3

Qualitative assessment of Rhazya stricta compounds with respect to Lipinski’s Rule-of-5 and solubility

ID

Name

LogP

MW

HBD

HBA

#RotB

Rings

Rule-of-5

Leadlike

Solubility

1

Akummidine

Optimal

Good

Good

Good

Good

Bad

Good

Good

Soluble

2

Antirhine

Optimal

Good

Good

Good

Good

Good

Good

Good

Soluble

3

3-epi-Antirhine

Optimal

Good

Good

Good

Good

Good

Good

Good

Soluble

4

Aspidosespermidine

Optimal

Good

Good

Good

Good

Bad

Good

Good

Soluble

5

Condylocarpine

Optimal

Good

Good

Good

Good

Bad

Good

Good

Soluble

6

Dihydrocorynantheol

Optimal

Good

Good

Good

Good

Good

Good

Good

Soluble

7

Eburnamenine

Lipophilic

Good

Good

Good

Good

Bad

Good

Moderate

Soluble

8

Eburnamine

Optimal

Good

Good

Good

Good

Bad

Good

Good

Soluble

9

Eburnamonine

Optimal

Good

Good

Good

Good

Bad

Good

Good

Soluble

10

Geissoschizine

Optimal

Good

Good

Good

Good

Good

Good

Good

Insoluble

11

Isositsirikine

Optimal

Good

Good

Good

Good

Good

Good

Good

Soluble

12

16-Epi-Z-isositsirikine

Optimal

Good

Good

Good

Good

Good

Good

Good

Soluble

13

Leuconalm

Optimal

Good

Good

Good

Good

Good

Good

Good

Soluble

14

Rhazinliam

Lipophilic

Good

Good

Good

Good

Good

Good

Moderate

Highly insoluble

15

Tetrahydrosecamine

Very lipophilic

Bad

Good

Good

Bad

Bad

Bad

Bad

Soluble

16

Presecamine

Very lipophilic

Bad

Good

Good

Bad

Bad

Bad

Bad

Soluble

17

Sewarine

Optimal

Good

Good

Good

Good

Bad

Good

Good

Soluble

18

Stemmadenine

Optimal

Good

Good

Good

Good

Bad

Good

Good

Soluble

19

Strictamine

Optimal

Good

Good

Good

Good

Bad

Good

Good

Insoluble

20

Strictosamide

Optimal

Moderate

Good

Good

Good

Bad

Good

Bad

Soluble

21

Strictosidine

Optimal

Bad

Bad

Bad

Good

Bad

Bad

Bad

Soluble

22

Taberonine

Optimal

Good

Good

Good

Good

Bad

Good

Good

Soluble

23

Tetrahydrlstonine

Optimal

Good

Good

Good

Good

Bad

Good

Good

Soluble

24

Vallesiachotamine

Optimal

Good

Good

Good

Good

Good

Good

Good

Highly insoluble

25

Aspidospermoise

Optimal

Good

Good

Good

Good

Bad

Good

Good

Soluble

26

Bhimbrine

Optimal

Good

Good

Good

Good

Good

Good

Good

Soluble

27

Bhimbrine N-oxide

Optimal

Good

Good

Good

Good

Good

Good

Good

Soluble

28

Rhazimine

Optimal

Good

Good

Good

Good

Bad

Good

Good

Soluble

29

Rhazimanine

Optimal

Good

Good

Good

Good

Good

Good

Good

Soluble

30

Rhazicine

Optimal

Good

Good

Good

Good

Bad

Good

Good

Soluble

31

Leepacine

Optimal

Good

Good

Good

Good

Bad

Good

Good

Soluble

32

2-Methoxy,1-2,dihydro rhazamine

Optimal

Good

Good

Good

Good

Bad

Good

Good

Soluble

33

HR-1

Optimal

Good

Good

Good

Good

Good

Good

Good

Soluble

34

Vincanicine

Optimal

Good

Good

Good

Good

Bad

Good

Good

Soluble

35

Rhazinaline

Optimal

Good

Good

Good

Good

Bad

Good

Good

Insoluble

36

Beta-sitosterol

Very lipophilic

Lipophilic

Good

Good

Good

Good

Good

Moderate

Moderate

37

Ursolic acid

Very lipophilic

Lipophilic

Good

Good

Good

Good

Bad

Moderate

Highly insoluble

38

Stigmasterol

Lipophilic

Good

Good

Good

Good

Good

Moderate

Moderate

Insoluble

39

Olenaolic acid

Very lipop

Lipophilic

Good

Good

Good

Good

Bad

Moderate

Highly insoluble

40

Rhazidigenine (rhazidine)

Optimal

Optimal

Good

Good

Good

Good

Good

Good

Good

41

N-methylleuconolam

Optimal

Good

Good

Good

Good

Good

Good

Good

Soluble

42

(+)-Quebranchamine

Lipophilic

Good

Good

Good

Good

Good

Good

Moderate

Soluble

43

Polyneuridine

Optimal

Good

Good

Good

Good

Bad

Good

Good

Soluble

44

(+)-Vincadiformine

Optimal

Good

Good

Good

Good

Bad

Good

Good

Soluble

45

(−)-Vincadiformine

Optimal

Good

Good

Good

Good

Bad

Good

Good

Soluble

46

Secamine

Very

Lipop

Bad

Good

Good

Bad

Bad

Bad

Bad

47

Vincadine

Optimal

Good

Good

Good

Good

Good

Good

Good

Soluble

48

Bis-strictidine

Very lipop

Bad

Good

Good

Good

Bad

Bad

Bad

Insoluble

49

3,14-Dehydrorhazigine

Very lipop

Bad

Good

Good

Bad

Bad

Bad

Bad

Highly insoluble

50

16-Hydrorhazisidine

Very lipop

Bad

Good

Good

Bad

Bad

Bad

Bad

Soluble

51

Rhazisidine

Very lipop

Bad

Good

Good

Good

Bad

Bad

Bad

Insoluble

52

Isorhazicine

Optimal

Good

Good

Good

Good

Bad

Good

Good

Soluble

53

Rhazigine

Very lipop

Bad

Good

Good

Bad

Bad

Bad

Bad

Soluble

54

Strictisidine

Optimal

Good

Good

Good

Good

Bad

Good

Good

Soluble

55

Strictamine-N-oxide

Optimal

Good

Good

Good

Good

Bad

Good

Good

Soluble

56

Strictigine

Optimal

Good

Good

Good

Good

Bad

Good

Good

Soluble

57

Strictine

Optimal

Good

Good

Good

Good

Bad

Good

Good

Highly insoluble

58

Stricticine

Optimal

Good

Good

Good

Good

Bad

Good

Good

Soluble

59

Strictalamine

Optimal

Good

Good

Good

Good

Bad

Good

Good

Insoluble

60

1,2-Dehydro-aspidospermine

Optimal

Good

Good

Good

Good

Bad

Good

Good

Soluble

61

Tetrahydrosecodine

Lipophilichilic

Good

Good

Good

Good

Good

Good

Moderate

Soluble

62

Dihydrosecodine

Lipophilichilic

Good

Good

Good

Good

Good

Good

Moderate

Soluble

63

Dihydrosecamine

Very lipophilic

Bad

Good

Good

Bad

Bad

Bad

Bad

Soluble

64

Dihydropresecamine

Very lipophilic

Bad

Good

Good

Bad

Bad

Bad

Bad

Soluble

65

Tetrahydropresecamine

Very lipop

Bad

Good

Good

Bad

Bad

Bad

Bad

Soluble

66

Rhazinol

Optimal

Good

Good

Good

Good

Bad

Good

Good

Insoluble

67

Rhazimol

Optimal

Good

Good

Good

Good

Bad

Good

Good

Insoluble

68

Rhazidigenine-N-oxide

Optimal

Good

Good

Good

Good

Good

Good

Good

Soluble

69

(−)-16R,21R-Omethyleburmanine

Optimal

Good

Good

Good

Good

Bad

Good

Good

Soluble

70

Decarbomethoxy-15,20,16,17-tetrahydrosecodine

Very lipophilic

Good

Good

Good

Good

Good

Moderate

Moderate

Soluble

71

1,2-Dehydroaspidosper midine-N-oxide

Optimal

Good

Good

Good

Good

Bad

Good

Good

Soluble

72

Rhazizine

Optimal

Good

Good

Good

Good

Bad

Good

Good

Soluble

73

15-Hydroxyvincadiffor mine

Optimal

Good

Good

Good

Good

Bad

Good

Good

Soluble

74

Dihydroburnamenine

Lipophilic

Good

Good

Good

Good

Bad

Good

Moderate

Soluble

75

16s,16′-Decarboxytetra hydrosecamine

Very lipop

Bad

Good

Good

Bad

Bad

Bad

Bad

Soluble

76

Nor-C-fluorocuraine

Optimal

Good

Good

Good

Good

Bad

Good

Good

Soluble

77

Strictibine

Optimal

Good

Good

Good

Good

Good

Good

Good

Insoluble

LogP partition-coefficient, MW molecular weight, HBD hydrogen bond donor, HBA hydrogen bond acceptors, #RotB number of rotatable bonds, Rings # of ideally acceptable rings, Rule-of-5 Lipinski’s rule of five, Leadlike leadlikeness, Solubility solubility classification

Table 4

Predicted solubility and pKa (acid and base) of various Rhazya stricta compounds

ID

Name

Solubility

LogSW/LogSw

LogSw/pH

pKa (acid)

pKa (base)

1

Akuammidine

Soluble

−3.32

8.85

14.79

6.88

2

Antirhine

Soluble

−4.08

9.49

14.72

9.24

3

3-Epi-antirhine

Soluble

−4.08

9.49

14.72

9.24

4

Aspidosespermidine

Soluble

−2.34

10.82

 

9.94

5

Condylocarpine

Soluble

−3.13

9.36

 

7.98

6

Dihydrocorynantheol

Soluble

−4.04

9.57

15.08

9.37

7

Eburnamenine

Soluble

−4.6

8.92

 

8.61

8

Eburnamine

Soluble

−4.39

9.15

14.3

 

9

Eburnamonine

Soluble

−4.4

8.82

 

8.13

10

Geissoschizine

Insoluble

−3.64

6.59

4.73

8.25

11

Isositsirikine

Soluble

−4.1

9.16

14.29

8.49

12

16-Epi-Z-isositsirikine

Soluble

−4.1

9.16

14.29

8.49

13

leuconolam

Soluble

−1.83

6.71

11.76

0.36

14

Rhazinilam

Highly insoluble

−4.47

7

 

1.21

15

Tetrahydrosecamine

Soluble

−3.67

8.07

17.43

9.4

16

Presecamine

Soluble

−5.27

8.48

15.79

8.54

17

Sewarine

Soluble

−2.98

9.17

11.08

1.95

18

Stemmadenine

Soluble

−3.63

9.21

11.84

8.08

19

Strictamine

Insoluble

−4.47

7.7

 

5.74

20

Strictosamide

Soluble

−3.26

7

12.79

−1.64

21

Strictosidine

Soluble

−2.73

10.83

12.81

10.62

22

Tabersonine

Soluble

−2.99

9.25

 

7.64

23

Tetrahydroalstonine

Soluble

−4.4

8.89

18.03

8.27

24

Vallesiachotamine

Highly insoluble

−5.21

7.45

17.46

6.08

25

Aspidospermiose

Soluble

−0.19

9.81

10.11

9.88

26

Bhimberine

Soluble

−4.1

9.16

14.29

8.49

27

Bhimbhrine N-oxide

Soluble

0.4

9.66

14.2

5.17

28

Rhazimine

Soluble

−2.89

8.9

 

6.51

29

Rhazimanine

Soluble

−4.1

9.16

14.29

8.49

30

Rhazicine

Soluble

−1.6

8.94

11.3

6.36

31

Leepacine

Soluble

−1.84

9.43

 

6.69

32

2-Methoxy-1,2-dihydrorhazimine

Soluble

−2.18

9.15

 

6.3

33

HR-1

Soluble

0.43

8.55

12.69

4.6

34

Vincanicine

Soluble

−2.67

9.67

 

8.16

35

Rhazinaline

Insoluble

−4.14

7.47

 

5.03

36

Beta-sitosterol

Highly insoluble

−7.6

7

15.03

 

37

Ursolic acid

Highly insoluble

−6

6.01

15.18

 

38

Stigmasterol

Highly insoluble

−7.52

7

15.03

 

39

Oleanolic acid

Highly insoluble

−6.02

6.04

15.18

 

40

Rhazidigenine

Soluble

−3.2

9.92

12.43

8.82

41

N-methylleuconolam

Soluble

−1.52

6.55

11.62

0.09

42

(+)-Quebrachamine

Soluble

−4.15

9.55

17.84

9.74

43

Polyneuridine

Soluble

−3.2

8.46

17.19

6.11

44

(+)-Vincadiformine

Soluble

−3.06

10.04

 

9.33

45

(−)-Vincadifformine

Soluble

−3.06

10.04

 

9.33

46

Secamine

Soluble

−5.12

8.22

17.34

8.71

47

Vincadine

Soluble

−4.23

9.28

16.98

9.11

48

Bis-strictidine

Insoluble

−6.11

7.79

 

7.57

49

3,14-Dehydrorhazigine

Highly insoluble

−5.89

8.12

 

10.62

50

16-Hydrorhazisidine

Soluble

−5.05

8.28

13.98

10.8

51

Rhazisidine

Insoluble

−5.56

8.2

17.47

8.76

52

Isorhazicine

Soluble

−1.6

8.94

11.3

6.36

53

Rhazigine

Soluble

−4.44

7.7

17.45

8.89

54

Strictisidine

Soluble

−2.18

8.18

 

4.27

55

Strictamine-N-oxide

Soluble

−0.67

8.73

 

4.17

56

Strictigine

Soluble

−4.07

8.83

 

7.71

57

Strictine

Highly insoluble

−4.79

7.36

 

5.41

58

Stricticine

Soluble

−3.68

9.33

 

8.43

59

Strictalamine

Insoluble

−3.94

8.04

 

5.87

60

1,2-Dehydroaspidospermidine(eburenine)

Soluble

−2.84

10.23

 

9.38

61

Tetrahydrosecodine

Soluble

−3.85

9.67

16.75

9.33

62

Dihydrosecodine

Soluble

−3.84

9.44

16.66

8.73

63

Dihydrosecamine

Soluble

−4.61

8.3

17.43

9.4

64

Dihydropresecamine

Soluble

−4.78

8.28

15.88

9.16

65

Tetrahydropresecamine

Soluble

−3.89

8.23

15.88

9.65

66

Rhazinol

Insoluble

−4.1

8.25

14.53

6.3

67

Rhazimol

Insoluble

−4.24

7.67

14.53

5.45

68

Rhazidigenine-N-oxide

Soluble

0.5

8.35

11.98

49.2

69

(−)16R,21R-omethyleburnamine

Soluble

−4.93

8.73

 

8.66

70

Decarbomethoxy-15,20,16,17-tetrahydros

Soluble

−3.79

9.81

17.83

9.46

71

1-2-Dehydroasidospermidine-N-oxide

Soluble

−1.2

8.95

 

4.82

72

Rhazizine

Soluble

−2.61

9.2

 

7.31

73

15-Hydroxyvincadifformine

Soluble

−2.36

9.88

14.4

8.46

74

Dihydroeburnamenine

Soluble

−4.72

9.06

 

9.41

75

16s,16’-Decarboxytetra-hydrosecamine

Soluble

−3.5

7.88

17.43

9.4

76

Nor-C-fluorocurarine

Soluble

−2.4

9.8

 

8.14

77

Strictibine

Insoluble

−3.7

7

 

1.06

Solubility solubility classifications, LogSW/LogSw ratio of solubility in water vs. intrinsic solubility, LogSw/pH solubility in water at pH 7.0, pKa (acid) pKa in acidic pH, pKa(base) pKa in basic pH

QUIKPROP calculations

Predicted Quikprop properties for potential cardiac liabilities such as HERG, and CNS liabilities (Blood–Brain-Barrier) and drug-like nature of these molecules indicate that many of these molecules are well within the boundaries of accepted hit-, and lead-like nature. QuikProp calculations were performed using Schrodinger’s Maestro for various alkaloids of R. stricta. These predictions not only give Rule-of-5 data, but also predict the cardiotoxicity predictions (HERG) and CNS penetration potential (logBBB) properties. More importantly, it also gives the prediction regarding cell-permeability (Caco2). All these models are well validated in literature, and most of them perform well within the reproducible results for training datasets. Results indicate that many of the molecules have decent permeation through Caco2 cell lines (>300), while the polar surface area (PSA) is not too high (>120) for oral absorption. For HERG toxicity prediction, below −5 (i.e. −6, −7 etc.) is not considered to be safe. Hence, those molecules whose logHERG values are well below -5 (such as geissoschizine, presecamine, tetrahydrosecamine) may exhibit cardioliability. The human intestinal absorption is also predicted, and it appears for most molecules, these values are larger. Any %HIA prediction >90% is expected to be well absorbed, and their polar surface area (PSA) is also a direct correlation to it. Those molecules whose molecular weights are >500 exhibit rule-of-5 violation and this violation goes beyond 1 to a maximum of 3. Those molecules appear structurally much larger and like dimers. Table 5 gives computed Quikprop computed values of various alkaloids of R. stricta. Table 6 also indicates various other physiochemical parameters including surface tension, parachor etc. of R. stricta indole and non-indole analogs.
Table 5

Quikprop calculation (for physiochemical properties) of Rhazya stricta compounds

Title

Name

M.W

HBD

HBA

QP logP

QP logS

QP logHERG

QP Caco2

QP logBB

%HOA

PSA

RO5v

M1

Akummidine

352.432

1

5

3.2

−3.5

−5.1

410.4

0.1

93

63

0

M2

Antirhine

296.411

2

4

3.1

−3.3

−5.6

583.1

0.1

95

40

0

M3

3-Epi-antirhine

296.411

2

4

3.1

−3.3

−5.6

583.1

0.1

95

40

0

M4

Aspidosespermidine

282.428

1

3

2.8

−1.9

−5.2

382.4

1.1

90

18

0

M5

Condylocarpine

322.406

0

3

4

−4.5

−5.5

735.5

0.4

100

48

0

M6

Dihydrocorynantheol

298.427

2

4

3.2

−3.6

−5.7

521.2

0.1

95

40

0

M7

Eburnamenine

278.396

0

2

4.1

−3.7

−5.2

2375.6

0.9

100

7

0

M8

Eburnamine

296.411

1

4

3.2

−3.1

−4.9

1159.1

0.5

100

27

0

M9

Eburnamonine

294.396

0

5

2.4

−2.1

−4.8

1051.6

0.6

95

32

0

M10

Geissoschizine

352.432

1

6

3

−4.4

−6.2

202.7

−0.4

86

79

0

M11

Isositsirikine

354.448

1

5

3.6

−3.9

−5.5

348.3

−0.1

94

68

0

M12

16-Epi-Z-isositsirikine

354.448

1

5

3.7

−4.6

−6.1

305.6

−0.2

93

71

0

M13

Leuconalm

326.394

2

6

2

−3.3

−3.7

600.6

−0.6

88

82

0

M14

Rhazinliam

294.396

1

3

4.1

−4.6

−4.2

3342.3

0.1

100

36

0

M15

Tetrahydrosecamine

680.929

0

7

8.5

−8.1

−8.1

198.9

0.2

92

75

2

M16

Presecamine

676.897

0

8

7.5

−5.7

−7.1

134.1

0

83

79

2

M17

Sewarine

338.405

1

4

3.3

−4.1

−5.3

305.7

0

91

69

0

M18

Stemmadenine

354.448

0

5

3.3

−3.4

−5.2

363.8

0

92

57

0

M19

Strictamine

322.406

0

6

2.4

−2.3

−4.7

624.1

0.4

91

47

0

M20

Strictosamide

498.532

5

15

0.6

−4

−5.9

94.5

−2.1

66

147

0

M21

Strictosidine

530.574

6

15

0.5

−2.6

−6.4

34.7

−1.7

19

164

3

M22

Taberonine

336.433

0

3

4

−4.1

−5.3

617.2

0.3

100

51

0

M23

Tetrahydrlstonine

352.432

1

6

3.2

−4.3

−6.1

573.5

0.3

95

59

0

M24

Vallesiachotamine

350.416

1

6

3.4

−5

−5.1

932

−0.6

100

81

0

M25

Aspidospermoise

428.527

3

12

0.2

−1.3

−5.9

16.8

−0.4

50

102

0

M26

Bhimbrine

354.448

1

5

3.6

−3.9

−5.5

370.7

−0.1

94

69

0

M27

Bhimbrine N-oxide

370.447

1

6

3.7

−3.2

−5.1

917.7

−0.7

100

79

0

M28

Rhazimine

350.416

0

8

2.4

−3.5

−6.7

333.6

0

86

67

0

M29

Rhazimanine

354.448

1

5

3.7

−4.6

−6.1

305.6

−0.2

93

71

0

M30

Rhazicine

368.432

0

7

1.6

−1

−5.5

56.9

0.3

68

88

0

M31

Leepacine

350.416

1

7

1.6

−1.7

−5.9

103.1

0.6

72

74

0

M32

2-Methoxy 1-2,dihydrorhazamine

382.458

0

8

1.8

−1.1

−5.7

113.2

0.6

74

72

0

M33

HR-1

370.447

1

6

3.8

−3.3

−5

1346.8

−0.5

100

70

0

M34

Vincanicine

322.406

0

4

3.1

−3.1

−4.7

454.4

0.2

93

62

0

M35

Rhazinaline

350.416

0

8

1.5

−1.3

−4.7

337

0.1

81

68

0

M36

beta-Sitosterol

414.713

1

2

7.5

−8.2

−4.4

4119.2

−0.2

100

21

1

M37

Ursolic acid

456.707

2

4

6.1

−6.8

−1.7

304.5

−0.4

94

60

1

M38

Stigmasterol

412.698

1

2

7.4

−8.1

−4.3

4119.2

−0.2

100

21

1

M39

Olenaolic acid

456.707

2

4

6.2

−7

−1.8

306

−0.4

95

60

1

M40

Rhazidigenine (rhazidine)

298.427

1

4

3.1

−3.1

−4.8

849.1

0.4

100

34

0

M41

N-methylleuconolam

340.421

1

7

2.4

−3.4

−3.8

1336.6

−0.3

100

66

0

M42

(+)-Quebranchamine

282.428

1

2

4.1

−4

−5

1678.5

0.7

100

15

0

M43

Polyneuridine

350.416

1

6

2.4

−3.1

−5

299.1

0

85

75

0

M44

(+)-Vincadiformine

338.449

0

3

4.1

−4.3

−5.2

655.8

0.3

100

49

0

M45

(−)-Vincadiformine

338.449

0

3

4.1

−4.3

−5.2

713

0.3

100

49

0

M46

Secamine

676.897

0

7

8.6

−8.3

−8.5

200.4

0.2

92

76

2

M47

Vincadine

340.464

0

3

4.6

−5.4

−6

637.6

0.2

100

46

0

M48

Bis-strictidine

560.824

2

3

7.9

−7.7

−5.8

1941.9

0.7

100

24

2

M51

Rhazisidine

614.829

1

5

8.8

−9.3

−7.6

1208.3

0.2

100

50

2

M52

Isorhazicine

368.432

0

7

1.6

−1.1

−5.7

49

0.2

66

88

0

M53

Rhazigine

618.861

1

5

8.9

−9.2

−8.6

153.6

0.1

92

65

2

M54

Strictisidine

348.401

0

8

1.5

−1.7

−5.1

270.9

0

79

74

0

M55

Strictamine-N-oxide

338.405

0

7

2.3

−0.9

−3.8

1371.3

−0.2

97

58

0

M56

Strictigine

278.396

0

4

3.1

−2.5

−4.7

1380.1

0.6

100

19

0

M57

Strictine

336.39

0

6

3.1

−3.3

−4.1

2156.2

−0.2

100

59

0

M58

Stricticine

338.405

0

5

2.9

−2.8

−4.9

836.2

0.5

96

65

0

M59

Strictalamine

292.38

0

6

1.6

−1.7

−4.7

602.9

0.4

86

50

0

M60

1,2-Dehydro-aspido-spermine

280.412

0

4

3.2

−2.7

−4.6

1558

0.7

100

15

0

M61

Tetrahydrosecodine

342.48

0

3

5

−5.1

−5.9

687.8

0

100

50

0

M62

Dihydrosecodine

340.464

0

3

5

−5.5

−6.5

632.6

−0.1

100

51

0

M63

Dihydrosecamine

678.913

0

7

8.6

−8

−8.1

214.4

0.2

93

75

2

M64

Dihydropresecamine

678.913

0

8

7.8

−6

−7

155.8

0.1

86

78

2

M65

Tetrahydropresecamine

680.929

0

8

7.8

−6.5

−7.3

144.9

0

85

80

2

M66

Rhazinol

294.396

1

5

1.2

−1.8

−4.6

581

0.3

83

40

0

M67

Rhazimol

352.432

0

6

2.4

−2

−4.8

572.5

0.2

90

60

0

M68

Rhazidigenine-N-oxide

314.427

1

5

3.1

−1.9

−4

1964.2

−0.2

100

46

0

M69

(−)-16R,21R-Omethyleburmanine

310.438

0

4

3.3

−3.3

−4.9

2470.6

−0.7

100

13

0

M70

Decarbomethoxy-15,20,16,17-tetrahydrosecodine

284.444

1

2

4.7

−4.6

−5.8

1672.7

0.5

100

18

0

M71

1,2-Dehydro-aspidospermidine-N-oxide

296.411

0

5

3.1

−1.2

−3.5

4109.3

0.2

100

29

0

M72

Rhazizine

368.432

0

7

2.5

−2.1

−4.5

1005.1

0.6

95

53

0

M73

15-Hydroxy-vincadifformine

354.448

1

5

3.2

−3.8

−5.3

302.4

−0.1

90

67

0

M74

Dihydroburnamenine

280.412

0

2

3.9

−3.6

−4.8

2470.6

0

100

5

0

M75

16s,16’-Decarboxy-tetrahydrosecamine

622.892

1

6

7.6

−6.1

−6.8

295.2

0.5

90

45

2

M76

Nor-C-fluorocuraine

292.38

0

3

2.8

−2.3

−3.8

512

0.4

92

52

0

M77

Strictibine

213.235

1

2

2.5

−3.3

−4.7

1789.3

−0.2

100

49

0

MW molecular weight, HBD hydrogen bond donors, HBA hydrogen bond acceptors, QPlogP predicted octanol/water partition coefficient, QPlogS predicted aqueous solubility, QPlogHERG predicted IC50 value for blockage of HERG K+ channels, QPCaco2 predicted Caco-2 cell permeability, QPlogBB predicted brain/blood partition coefficient, %HOA percentage of human oral absorption, PSA polar surface area, RO5v number of violations of Lipinski’s Rule of Five

Table 6

Surface related and ring-related properties of Rhazya stricta compounds

ID

Name

CR

NR

NOR

HetR

#R

Para

Ind.Ref

Sur.Ten

Density

Polar.

1

Akuammidine

0.81

0.08

0.19

0.19

6

743.43

1.68

65.34

1.35

39.32

2

Antirhine

0.86

0.09

0.14

0.14

4

676.25

1.65

56.53

1.2

35.76

3

3-Epi-antirhine

0.86

0.09

0.14

0.14

4

676.25

1.65

56.53

1.2

35.76

4

Aspidosespermidine

0.9

0.1

0.1

0.1

5

647.87

1.63

50.04

1.16

34.2

5

Condylocarpine

0.83

0.08

0.17

0.17

5

681.18

1.66

56.36

1.3

36.43

6

Dihydrocorynantheol

0.86

0.09

0.14

0.14

4

687.1

1.64

55.86

1.19

35.85

7

Eburnamenine

0.9

0.1

0.1

0.1

5

589.57

1.7

49.78

1.25

33.94

8

Eburnamine

0.86

0.09

0.14

0.14

5

595.24

1.72

54.34

1.35

34.28

9

Eburnamonine

0.86

0.09

0.14

0.14

5

595.24

1.72

54.34

1.34

34.28

10

Geissoschizine

0.81

0.08

0.19

0.19

4

762.54

1.66

61.38

1.29

40.01

11

Isositsirikine

0.81

0.08

0.19

0.19

4

776.63

1.64

59.3

1.27

40.13

12

16-Epi-Z-isositsirikine

0.81

0.08

0.19

0.19

4

776.63

1.64

59.3

1.27

40.13

13

Leuconolam

0.79

0.08

0.21

0.21

4

692.66

1.65

63.34

1.33

35.61

14

Rhazinilam

0.86

0.09

0.14

0.14

4

635.67

1.65

47.86

1.22

34.93

15

Tetrahydrosecamine

0.84

0.08

0.16

0.16

7

1449.04

1.63

46.81

1.23

78.28

16

Presecamine

0.84

0.08

0.16

0.16

7

1516.34

1.65

60.13

1.24

78.73

17

Sewarine

0.8

0.08

0.2

0.2

5

696.4

1.69

64.76

1.38

37.04

18

Stemmadenine

0.81

0.08

0.19

0.19

5

729.69

1.64

47.88

1.28

39.55

19

Strictamine

0.83

0.08

0.17

0.17

5

631.14

1.71

52.17

1.37

36.23

20

Strictosamide

0.72

0.06

0.28

0.28

6

986.67

1.72

84.28

1.53

50.75

21

Strictosidine

0.71

0.05

0.29

0.29

5

1078.5

1.66

74.07

1.44

54

22

Tabersonine

0.84

0.08

0.16

0.16

5

723.31

1.65

55.72

1.27

38.37

23

Tetrahydroalstonine

0.81

0.08

0.19

0.19

5

748.43

1.66

58.69

1.3

39.39

24

Vallesiachotamine

0.81

0.08

0.19

0.19

4

754.43

1.65

59.07

1.29

39.54

25

Aspidospermiose

0.77

0.06

0.23

0.23

6

885.22

1.68

74

1.42

45.19

26

Bhimberine

0.81

0.08

0.19

0.19

4

776.63

1.64

59.3

1.27

40.13

27

Bhimbhrine N-oxide

0.78

0.07

0.22

0.22

4

    

 45.12

28

Rhazimine

0.81

0.08

0.19

0.19

6

690.3

1.69

54.96

1.38

38.6

29

Rhazimanine

0.81

0.08

0.19

0.19

4

776.63

1.64

59.3

1.27

40.13

30

Rhazicine

0.78

0.07

0.22

0.22

6

757.54

1.66

64.83

1.38

39.13

31

Leepacine

0.81

0.08

0.19

0.19

7

709

1.68

63.18

1.39

37.7

32

2-Methoxy-1,2-dihydrorhazimine

0.79

0.07

0.21

0.21

6

800.93

1.63

56.72

1.31

41.05

33

HR-1

0.78

0.07

0.22

0.22

4

     

34

Vincanicine

0.83

0.08

0.17

0.17

5

683.12

1.66

57.29

1.3

36.52

35

Rhazinaline

0.81

0.08

0.19

0.19

5

690.3

1.69

54.96

1.38

38.6

36

Beta-sitosterol

0.97

0

0.03

0.03

4

1051.02

1.52

37.64

0.98

51.22

37

Ursolic acid

0.91

0

0.09

0.09

5

1076.71

1.56

45

1.1

52.93

38

Stigmasterol

0.97

0

0.03

0.03

4

1038.63

1.53

38.25

0.99

51.19

39

Oleanolic acid

0.91

0

0.09

0.09

5

1077.07

1.56

45.41

1.1

52.95

40

Rhazidigenine

0.86

0.09

0.14

0.14

4

650.55

1.64

48.09

1.21

35.15

41

N-methylleuconolam

0.8

0.08

0.2

0.2

4

730.79

1.65

61.9

1.31

37.53

42

(+)-Quebrachamine

0.9

0.1

0.1

0.1

4

672.49

1.62

50.29

1.12

35.27

43

Polyneuridine

0.81

0.08

0.19

0.19

6

735.31

1.67

62.83

1.34

38.85

44

(+)-Vincadiformine

0.84

0.08

0.16

0.16

5

735.7

1.63

53.98

1.25

38.4

45

(-)-Vincadifformine

0.84

0.08

0.16

0.16

5

735.7

1.63

53.98

1.25

38.4

46

Secamine

0.84

0.08

0.16

0.16

7

1449.04

1.63

46.81

1.22

78.28

47

Vincadine

0.84

0.08

0.16

0.16

4

776.11

1.61

52.34

1.18

39.67

48

Bis-strictidine

0.9

0.1

0.1

0.1

9

1150.88

1.73

52.95

1.31

67.18

49

3,14-Dehydrorhazigine

0.87

0.09

0.13

0.13

7

1340.13

1.64

46.53

1.2

73.46

50

16-Hydrorhazisidine

0.85

0.09

0.15

0.15

7

1345.28

1.65

48.02

1.24

73.94

51

Rhazisidine

0.87

0.09

0.13

0.13

8

1284.82

1.68

49.12

1.27

72.59

52

Isorhazicine

0.78

0.07

0.22

0.22

6

757.54

1.66

64.83

1.38

39.13

53

Rhazigine

0.87

0.09

0.13

0.13

7

1412.62

1.65

58.36

1.21

74.23

54

Strictisidine

0.81

0.08

0.19

0.19

7

635.5

1.78

63.63

1.55

37.59

55

Strictamine-N-oxide

0.8

0.08

0.2

0.2

5

     

56

Strictigine

0.9

0.1

0.1

0.1

5

622.49

1.63

42.69

1.14

34.52

57

Strictine

0.8

0.08

0.2

0.2

5

636.29

1.73

55.79

1.44

36.71

58

Stricticine

0.8

0.08

0.2

0.2

6

682.41

1.68

61.46

1.39

36.43

59

Strictalamine

0.86

0.09

0.14

0.14

5

580.88

1.74

55.15

1.37

33.92

60

1,2-Dehydroaspidospermidine

0.9

0.1

0.1

0.1

5

590.09

1.7

50.6

1.27

33.8

61

Tetrahydrosecodine

0.84

0.08

0.16

0.16

3

807.26

1.56

42.67

1.08

40.69

62

Dihydrosecodine

0.84

0.08

0.16

0.16

3

793.18

1.58

44.47

1.11

40.53

63

Dihydrosecamine

0.84

0.08

0.16

0.16

7

1449.04

1.63

46.81

1.23

78.28

64

Dihydropresecamine

0.84

0.08

0.16

0.16

7

1530.43

1.64

59.1

1.23

78.84

65

Tetrahydropresecamine

0.84

0.08

0.16

0.16

7

1544.52

1.63

58.11

1.22

78.96

66

Rhazinol

0.86

0.09

0.14

0.14

5

580.88

1.74

55.15

1.38

33.92

67

Rhazimol

0.81

0.08

0.19

0.19

5

690.3

1.69

54.96

1.39

38.6

68

Rhazidigenine-N-oxide

0.83

0.09

0.17

0.17

4

     

69

(-)16R,21R-omethyleburnamine

0.87

0.09

0.13

0.13

5

639.83

1.67

47.55

1.27

36.25

70

Decarbomethoxy-15,20,16,17-tetrahydros

0.9

0.1

0.1

0.1

3

703.65

1.57

40.68

1.02

36.31

71

1-2-Dehydroasidospermidine-N-oxide

0.86

0.09

0.14

0.14

5

     

72

Rhazizine

0.78

0.07

0.22

0.22

6

744.62

1.67

62.43

1.39

39.14

73

15-Hydroxyvincadifformine

0.81

0.08

0.19

0.19

5

750.68

1.65

60.33

1.32

39

74

Dihydroeburnamenine

0.9

0.1

0.1

0.1

5

589.57

1.7

49.78

1.26

33.94

75

16s,16′-Decarboxytetra-hydrosecamine

0.87

0.09

0.13

0.13

7

1339.61

1.64

46.2

1.21

73.6

76

Nor-C-fluorocurarine

0.86

0.09

0.14

0.14

5

624.5

1.68

57.83

1.29

33.99

77

Strictibine

0.81

0.06

0.19

0.19

3

442.8

1.65

51.74

1.29

23.76

Ind Ref refractive index, Para parachor, Sur ten surface tension, Polar polarizability, #R number of rings, CR ratio of carbons, NR ratio of nitrogens, NOR ratio of oxygens, HetR ratio of heteroatoms

Predicted therapeutic area applications

PASS—prediction of activity spectra for substances

This web-based predictive server from Way2Drug, has variety of annotators of substances for their probability of active or inactive towards few targets. Out of all services and products of them, we utilized PASS method of predictions. More than 100 activities are predicted with their probability of activities and in-activities. Some of them include kinase inhibitors, GPCR antagonists, and some specific targets like adrenergic receptors, and their kinase inhibitors. We considered the probability of active (Pa) >0.3 (i.e. >30%), and should be greater than probability of inactive (Pi). Given these conditions, we observed many alkaloids have indicated Pa >0.8 in certain conditions (such as, anthrine has predicted Pa at 90% towards β-adrenergic receptor kinase inhibitor, 5-HTA release stimulant). Majority of them also is predicted to be substrate to CYP3A4 and CYP2D6 indicating their metabolic instability (Pa ~ 0.5, 0.4, respectively). Several such predictions for all 78 alkaloids has been computed—leaving predictions to be validated, experimentally. Similarly, dihydrocorynantheol and corynantheol were also predicted to be 5-HT release stimulants, and have been projected to be chemosensitizers. Eburnamenine is predicted to be a Nootropic agent at 90% Pa, while eburnamine is predicted to be a CNS (anti-depressant and mood disorder management agent at >96% Pa). Strictosidine is predicted to be an antiprotozoal at 86% Pa, β-sitosterol is anti-hypercholesterolemic agent with Pa ~98%, rhazidigenine (rhazidine) is an antidyskinetic at 60% Pa, secamine is a H1F1A expression inhibitor at 83% Pa (but a non-pharmaceutically acceptable molecule due to high MW and many RO5 violations). A similar observations is also made for 16-hydrorhazisidine (72% Pa for H1F1A expression inhibitor). Strictamine is predicted to be gluconate 2-dehydrogenase acceptor with 70% Pa, and 1,2-dehydroaspidospermine (which is a small molecule) has been predicted to be analeptic with 77% Pa. Dihydrosecamine is predicted to be a H1F1A expression inhibitor with 77% Pa, and rhazidigenine-N-oxide is predicted to be a cognition disorder agent with 64% Pa. Decarbomethoxy-15,20,16,17-tetrahydrosecodine is a small molecule with ~70% Pa for antidyskinetic and antineuronic agent, 1,2-dehydrospidospermidine-N-oxide is predicted to be 87% as analeptic.

Anticancer activity through CDRUG

This set of predictions using the structures and SMILES codes of the alkaloids, annotates the anti-cancer activity by predicting “Mean logGI50”. Most molecules that have Mean LogGI50 values lower than −5 are considered to have anti-cancer activity. It is interesting to know that all the molecules of R. stricta alkaloids (indole/non-indole) have predicted mean logGI50 values ranging between −4.95 and −6.50—indicating they all may have anti-cancer activities. There are about 10 compounds that have predicted logGI50 values less than −6, which indicate strong anti-cancer activity. Table 7 shows the predicted mean LogGI50 values of all the compounds considered in the present study.
Table 7

Predicted mean LogGI50 of Rhazya stricta compounds whose values lower than −6.0 are highlighted in italics may exhibit anti-cancer activity

MOL ID

Name

Mean LogGI50 CDRUG

M1

Akummidine

−5.408

M2

Antirhine

−5.408

M3

3-Epi-antirhine

−5.408

M4

Aspidosespermidine

−5.726

M5

Condylocarpine

−5.726

M6

Dihydrocorynantheol

−5.408

M7

Eburnamenine

−5.096

M8

Eburnamine

−5.096

M9

Eburnamonine

−5.096

M10

Geissoschizine

−5.048

M11

Isositsirikine

−5.408

M12

16-Epi-Z-isositsirikine

−5.408

M13

Leuconalm

−5.154

M14

Rhazinliam

−5.096

M15

Tetrahydrosecamine

−4.975

M16

Presecamine

−5.726

M17

Sewarine

−5.726

M18

Stemmadenine

−5.408

M19

Strictamine

−5.726

M20

Strictosamide

−5.256

M21

Strictosidine

−5.937

M22

Taberonine

−5.726

M23

Tetrahydrlstonine

−5.408

M24

Vallesiachotamine

−5.408

M25

Aspidospermoise

−5.726

M26

Bhimbrine

−5.408

M27

Bhimbrine N-oxide

−5.408

M28

Rhazimine

−5.726

M29

Rhazimanine

−5.408

M30

Rhazicine

−5.726

M31

Leepacine

−5.726

M32

2-Methoxy 1-2,dihydrorhazamine

−5.726

M33

HR-1

−5.096

M34

Vincanicine

−5.726

M35

Rhazinaline

−5.726

M36

Beta-sitosterol

−5.918

M37

Ursolic acid

−5.124

M38

Stigmasterol

−5.918

M39

Olenaolic acid

−5.124

M40

Rhazidigenine (rhazidine)

6.327

M41

N-methylleuconolam

−5.154

M42

(+)-Quebranchamine

−5.861

M43

Polyneuridine

−5.408

M44

(+)-Vincadiformine

−5.726

M45

(−)-Vincadiformine

−5.726

M46

Secamine

6.298

M47

Vincadine

−5.486

M48

Bis-strictidine

−5.409

M49

3,14-Dehydrorhazigine

−5.726

M50

16-Hydrorhazisidine

6.298

M51

Rhazisidine

−5.406

M52

Isorhazicine

−5.726

M53

Rhazigine

−5.726

M54

Strictisidine

−5.726

M55

Strictamine-N-oxide

−5.726

M56

Strictigine

−5.726

M57

Strictine

−5.096

M58

Stricticine

−5.726

M59

Strictalamine

6.327

M60

1,2-Dehydroaspidospermine

6.327

M61

Tetrahydrosecodine

−5.783

M62

Dihydrosecodine

−5.408

M63

Dihydrosecamine

6.298

M64

Dihydropresecamine

−5.726

M65

Tetrahydropresecamine

−5.726

M66

Rhazinol

−5.726

M67

Rhazimol

−5.726

M68

Rhazidigenine-N-oxide

6.327

M69

(−)-16R,21R-Omethyleburmanine

−5.096

M70

Decarbomethoxy-15,20,16,17-tetrahydrosecodine

6.471

M71

1,2-Dehydroaspidospermidine-N-oxide

6.327

M72

Rhazizine

−4.878

M73

15-Hydroxyvincadifformine

−5.726

M74

Dihydroburnamenine

−5.096

M75

16s,16′-Decarboxytetrahydrosecamine

−4.975

M76

Nor-C-fluorocuraine

−5.726

M77

Strictibine

−5.785

SuperPred—predicted target interactions

From this server studies on R. stricta alkaloids, we observed that many of these molecules may interact with CYP2D6 or CYP3A4 as substrates. The indication of these results mean that their target may be unknown, but they do modify the drug metabolism, and affect drug–drug interactions.

SwissTarget prediction

While predictions from this web-server may suggest each molecule have certain target activity, they almost correlate well with the PASS server prediction—which gives additional probability of prediction for each molecule to be active or inactive against the target of interest.

Overall from the calculated cheminformatics studies and web-server predictions, we understand that few molecules like anthrine, condylocarpine, dihydrocorynantheol etc. have predicted GIC50 values in sub µM concentrations, while they also have predicted drug–drug activity towards CYP3A4, and CYP2D6 enzymes. Most molecules turnout to be modulators of membrane receptor ligands while some have predicted cholinesterase, CNS (5HT2x), adenosine (A2A/A2B) activity. Moreover, all molecules have predicted activity towards certain targets (Pa > 30%).

Conclusions

Table 8 indicates the top 10-best naturally occurring indole alkaloids of R. stricta that were predicted to be having decent anti-cancer activity and other good physiochemical properties together with cheminformatics properties—these molecules are antirhine, 3-epi-antirhine, condylocarpine, eburnamine, eburnamonine, taberonine, ursolic acid, stigmasterol, olenaolic acid, (+)-vincadiformine, (−)-vincadiformine, (−)-16R,21R-omethyleburmanine, 15-hydroxy-vincadifformine, and dihydroburnamenine.
Table 8

Key details of top molecules with predicted targets for anti-cancer and anti-obesity, probable rule-of-5, predicted LogGI50 with predicted H-, and p values

SI. No

Mol. name

Mol. wt

Predicted

LogG150/H-/p val

Target

RO5 violations

Liability

Comment

Anti-cancer

Anti-obesity

Druggability

Hepatic

HERG, renal issues

M2

Antirhine

296.411

−5.41/0.39/0.05

5HT2A,BC

Good

CYP2D6

None predicted

M3

3-Epi-antirhine

296.411

−5.41/0.39/0.05

5HT2A,B

Good

CYP2D6

None predicted

M5

Condylocarpine

322.406

−5.73/0.42/0.03

Negative

Good

None

None predicted

M8

Eburnamine

296.411

−5.10/0.74/0.01

5HT2A,BC

Good

2D6,3A4

None predicted

M9

Eburnamonine

294.396

−5.10/1.00/0.01

5HT2A,BC

Good

2D6,3A4

None predicted

M22

Taberonine

336.433

−5.73/0.67/0.01

Negative

Good

None

None predicted

M37

Ursolic acid

456.707

−5.12/1.00/0.00

Negative

Moderate (LogP)

None

Highly hydrophobic

M38

Stigmasterol

412.698

−5.92/0.93/0.04

Negative

Moderate (LogP)

CYP17A1

Highly hydrophobic

M39

Olenaolic acid

456.707

−5.12/0.71/0.07

Negative

Moderate (LogP)

None

Highly hydrophobic

M44

(+)-Vincadiformine

338.449

−5.73/0.56/0.02

5HT3A

Good

None

None predicted

M45

(−)-Vincadiformine

338.449

−5.73/0.56/0.02

5HT3A

Good

None

None predicted

M69

(−)-16R,21R-Omethyleburma nine

310.438

−5.10/0.55/0.02

5HT2A,BC

Good

CYP2D6

None predicted

M73

15-Hydroxy-vincadifformine

354.448

−5.73/0.56/0.02

5HT2A,BC

Good

None

None predicted

M74

Dihydroburnamenine

280.412

−5.10/0.63/0.01

Negative

Good

2D6,3A4

None predicted

Declarations

Authors’ contribution

AYO, SV, RSB were involved in generation of computational data on predictive properties of various Rhazya stricta’s alkaloids; NHH and AMSO participated in data acquisition. SV, JSMS and KSS were involved in overall research planning & supervision, data analysis and manuscript writing. All authors read and approved the final manuscript.

Acknowledgements

The authors gratefully acknowledge the financial support from KAU Vice President for Educational Affairs Prof. Dr. Abdulrahman O Alyoubi, The Deanship of Scientific Research (DSR) at King Abdulaziz University (KAU), Jeddah, Saudi Arabia, represented by the Unit of Strategic Technologies Research through the Project number (D 008/431) for the Project entitled: “Identification and Isolation of Salt and Heat-Tolerance Genes of R. stricta and Detection of Metabolites and their Therapeutic Effects via Cheminformatics”.

Competing interests

The authors declare that they have no competing interests.

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
Department of Chemistry, Faculty of Science, King Abdulaziz University
(2)
Indras Pvt. Ltd
(3)
Biotechnology Research Group, Department of Biological Sciences, Faculty of Science, King Abdulaziz University
(4)
Department of Biotechnology, Eternal University
(5)
Department of Biological Sciences, Faculty of Science, King Abdulaziz University

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Copyright

© The Author(s) 2017