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254 Virtual Screening of Anticancer Drugs

ID Finding Effect

Protein kinase C Catechin Inhibitory

effect

Anticancer Komori et al.

(1993)

1a25

Protein kinase C Camptothecin Inhibitor Induction of

apoptosis in

tumour

Martelli et al.

(1999);

Nieves-Neira

and

Pommier

(1999)

1a35 Topoisomerase I Camptothecin Inhibitor Anticancer Sinha et al.

(1995)

1agw FGF receptor 1 Catechin Inhibitor Anticancer Liang et al.

(1997)

1cpj Cathepsin B Catechin Activator Anticancer Ahmad et al.

(2000)

1crp C-H-ras p21

protein

Catechin Inhibition of

ras-

transformed

cells

Anticancer Chung et al.

(1999)

1dvi Calpain Camptothecin Inhibition of

calpain

activities

Induces

apoptosis in

leukemic

cells

Eymin et al.

(1997)

1jsu Cyclin-

dependent

kinase-2

Catechin Inhibitor Anticancer Liang et al.

(1997)

1mnc Neutrophil

collagenase

Catechin Collagenase

inhibitor

Inhibition of

metastasis

of cancerous

cells

Demeule et

al. (2000)

1p38 MAP kinase p38 Catechin Inhibition of

activation of

p38

mitogen-

activated

protein

kinase

Anticancer Chen et al.

(1999)

Note: * based on reference Chen and Ung, 2001 with minor modifications.

Table 15.5. Known and potential human and mammalian therapeutic targets/receptors. PDB

ID is the identification number of a protein in PDB database.

PDB Protein Phytomolecule Ex

erimental Thera

eutic References

Virtual Screening of Anticancer Drugs 255

Table 15.6. The library compounds favour the ‘Lipinski’s Rule of Five’ and showing good

docking interaction energy (in Kcal/mol).

PubChemID 1a25 1a35 1agw 1awn 1cdk 1mnc

CID_969516 -93.284

-110.886

-60.896

-79.784

-62.67

-92.725

CID_10595440 -96.161 -84.798 -66.114 -75.358 -61.336 -85.486

CID_24360 -68.579 -88.454 -56.159 -62.99 -73.825 -84.888

CID_442783 -58.505 -95.962 -68.764 -73.19 -58.485 -84.216

CID_9064 -62.434 -78.713 -56.782 -58.508 -78.106 -84.114

CID_5281767 -89.577 -109.977 -64.375 -61.402 -57.156 -82.609

CID_6398761 -78.512 -78.512

-78.512

CID_10923720 -73.704 -73.704 -73.704 -73.704 -73.704 -73.704

CID_4259412 -72.424 -72.424 -72.424 -72.424 -72.424 -72.424

CID_638034 -71.559 -71.559 -71.559 -71.559 -71.559 -71.559

CID_5057 -71.286 -71.286 -71.286 -71.286 -71.286 -71.286

CID_11000304 -70.201 -70.201 -70.201 -70.201 -70.201 -70.201

CID_65076 -69.511 -69.511 -69.511 -69.511 -69.511 -69.511

CID_9802152 -69.507 -69.507 -69.507 -69.507 -69.507 -69.507

CID_9931851 -69.423 -69.423 -69.423 -69.423 -69.423 -69.423

CID_11821800 -67.853 -67.853 -67.853 -67.853 -67.853 -67.853

CID_5311 -67.649 -67.649 -67.649 -67.649 -67.649 -67.649

CID_9830646 -67.317 -67.317 -67.317 -67.317 -67.317 -67.317

CID_5381733 -67.239 -67.239 -67.239 -67.239 -67.239 -67.239

CID_4018 -66.356 -66.356 -66.356 -66.356 -66.356 -66.356

Note: Docking results of only few leads and receptors are summarized here with

modification.

Besides, there are examples of well known drugs, which violate the Lipinski’s rule of five

but at the same time work well pharmacologically (Table 15.8). A detailed description and

pharmacological action of known drugs/bioactive compounds and 68 potential anticancer

leads, virtually screened after Rule of five and docking based studies, is given in Table

15.9. Also for comparison, three different set of compounds and their corresponding

docking energy (in kcal/mol) against each known anticancer receptor have been

summarized in Table 15.10, which revealed that curcumin derivatives showed best

interactions with most of the anticancer receptors, compared to other set compounds

(Figure 15.2).

Docking and QSPR based virtual screening of anticancer compound

All the targets showed minimum docking of -23.239 kcal/mol with ecabet (CID_3070413).

For targets 1a25, bioactive compound curcumin (CID_10666836) showed maximum

docking score of -97.054 kcal/mol. For receptors 1a35, 1awn, 1mnc, 1p38, 1rpa, 1ydt,

1yfo, 2gss and 7ice, curcumin (CID_969516) showed maximum docking scores for each.

For anticancer target 1a35 and 1awn maximum docking scores were -110.886 and -79.784

respectively, while for targets 1mnc, 1p38, 1rpa, 1ydt, 1yfo, 2gss and 7ice docking score

was similar i.e. -92.725 kcal/mol. For receptor 1agw, maxacalcitol (CID_6398761) showed

256 Virtual Screening of Anticancer Drugs

maximum docking score of -78.512 kcal/mol. For receptor 1awn, curcumin (CID_969516)

showed maximum docking score of -79.784 kcal/mol. For receptor 1cdk, 1cpj, 1crp, 1dvi

and 1jsu compound maxacalcitol (CID_6398761) showed maximum docking score of -

78.512 kcal/mol. For receptor 1p38, 1rpa, 1ydt, 1yfo, 2gss and 7ice compound

epigallocatechin gallate (CID_65064) showed maximum docking score of -119.166

kcal/mol.

(i) (ii)

(iii) (iv)

Figure 15.2. Best docked on Curcumin phytomolecule with anticancer known receptors (i, ii)

1a25, (iii) 1a35 and (iv) 1agw, with best docking score -97.054, -110.886 and -68.764

Kcal/mol respectively.

Details of docked compounds are as follows: Eighteen compounds did not show good

interaction energy with any anticancer receptors. These are: CID_11969852,

CID_1548910, CID_10607, CID_5280373, CID_5385555, CID_446925, CID_5319123,

CID_5978, CID_5316150, CID_5281235, CID_13342, CID_16219940, CID_122127,

CID_16197727, CID_634470, CID_68781, CID_3001662 and CID_10612216. For

receptor 1a25, compound curcumin (CID_10666836, LogP 2.517, solvent accessible

surface area 403.32 Å

, mol. formula C21H20O6, mol.wt. 368.385) showed maximum

docking score of -97.054 kcal/mol and minimum -23.239 kcal/mol by ecabet

(CID_3070413) with Anticarcinogenic, Anti-Infective, Anti-Ulcer, Protease Inhibitors

activity. For receptor 1a35, 1awn, 1mnc, 1p38, 1rpa, 1ydt, 1yfo, 2gss and 7ice compound

curcumin (CID_969516 Log P 2.479, solvent accessible surface area 383.405 Å

, mol.

formula C21H20O6 mol.wt. 368.385) showed maximum docking scores.

Virtual Screening of Anticancer Drugs 257

Table 15.7. Details of quantitative data of best fit compounds*, to be used for QSPR/QSAR model development.

Compound ID Log P SASA Polarity LRS SRS RC MR LUMO IP HOMO HF CME FC AC BC

CID_969516 2.479 383.405 42.632 6 6 2 103.424 -0.853 8.829 -8.829 -156.534 -34.719 0 47 48

CID_10595440 2.517 404.692 44.257 6 6 2 105.359 -1.07 8.804 -8.804 -155.602 -23.394 0 47 48

CID_24360 0.558 334.54 40.783 6 5 5 94.492 -1.586 9.103 -9.103 -89.015 -8.49 0 42 46

CID_442783 2.517 404.092 44.476 6 6 2 105.359 -1.092 8.782 -8.782 -156.042 -23.66 0 47 48

CID_9064 2.113 282.442 29.908 6 6 3 72.852 0.059 8.847 -8.847 -208.638 -12.187 0 35 37

CID_5281767 2.517 402.688 44.28 6 6 2 105.359 -1.085 8.793 -8.793 -155.908 -23.506 0 47 48

CID_6398761 2.984 443.462 50.537 6 5 3 123.828 -0.296 8.688 -8.688 -190.761 44.829 0 72 74

CID_10923720 1.962 272.515 29.338 6 6 3 70.823 -0.43 9.028 -9.028 -134.611 -6.208 0 30 32

CID_4259412 7.089 476.104 51.508 6 5 4 124.565 0.004 9.586 -9.586 -246.985 52.243 0 78 81

CID_638034 4.751 407.713 44.403 6 6 1 107.075 -0.541 8.42 -8.42 -68.454 4.413 0 56 56

CID_5057 4.751 407.212 44.332 6 6 1 107.075 -0.517 8.445 -8.445 -68.775 4.434 0 56 56

CID_11000304 1.962 270.146 29.398 6 6 3 70.823 -0.668 9.17 -9.17 -142.404 -10.93 0 30 32

CID_65076 7.089 474.076 51.404 6 5 4 124.565 0.056 9.532 -9.532 -246.884 52.74 0 78 81

CID_9802152 2.984 453.789 50.665 6 5 3 123.828 -0.218 8.717 -8.717 -191.477 40.306 0 72 74

Note: LogP: The octanol-water partition coefficient. Solvent accessible surf area (SASA): The molecular surface area accessible to a solvent molecule.

Polarizability (P): The molecule's average alpha polarizability. Smallest ring size (SRS): Information about rings present in the compound. Rings with more than

12 atoms are ignored. The number of atoms forming the smallest ring in the compound, or 0 if the compound contains no ring of size 12 or less. Ring count (RC):

The number of rings present in the compound. Rings with more than 12 atoms are ignored. The number of rings with 12 or fewer atoms (All= all aromatic, small, 5-

membered, 5-membered aromatic, 6-membered, 6-membered aromatic, large, large aromatic). Molar refractivity (MR): The molar refractivity of the compound.

LUMO energy: The energy gained when an electron is added to the lowest unoccupied molecular orbital (LUMO). Ionization potential (IP): The energy required

to remove an electron from a molecule in its ground state. HOMO energy: The energy required to remove an electron from the highest occupied molecular orbital

(HOMO). Heat of formation (HF): The energy released or used when a molecule is formed from elements in their standard states. Conformation minimum

energy (CME): Energy calculated for an optimized conformation of the compound. Formal Charge (FC): The net positive or negative charge on the molecule.

Atom count (AC): The number of atoms. Bond count (BC): The number of bonds. Weak and ionic bonds are ignored. * Results of only few compounds are

summarized in the table.

Table 15.8. Exceptionally some well known bioactive compounds showed violation of Lipinski’s rule of five.

Phyto-

molecule

Description PubChemID Mol.

Wt.

Log P Rule

of 5

violat

ion

Mol

Wt.

500

LogP

> 5

H-bond

donors

> 5

H-bond

acceptor

s > 10

Allicin antibacterial principle of

Allium sativum (garlic)

CID_65036 162.26

1.415 0 0 0 0 0

Catechin polyphenolic antioxidant

plant metabolites

(flavonoids); tea-plant

Camellia sinensis

CID_9064 290.27

2.113 0 0 0 0 0

Camptothecin An alkaloid isolated from

the stem wood of the

Chinese tree,

Camptotheca acuminata

CID_24360 348.35

0.558 0 0 0 0 0

Indole-3-

carbinol

occurs in edible

cruciferous vegetables

CID_3712 147.17

0.82 0 0 0 0 0

Epigallocatech

in gallate

antimutagen in green tea

(Camellia sinensis)

CID_65064 458.37

3.017 2 0 0 1 1

Phytoestrogen biochanin A; Plant

extracts and compounds,

primarily Isoflavones

CID_528037

284.26

1.994 0 0 0 0 0

Artemether quinghaosu derivative

(Artemisia annua)

SID_120130

SID_173966

298.37

3.331 0 0 0 0 0

Artemisinine sesquiterpene lactone

from Chinese medicinal

herb Artemisia annua

SID_210967

SID_498343

282.33

3.085 0 0 0 0 0

Curcumin Phytochemical of

CID_969516 368.38 2.479 0 0 0 0 0

258 Virtual Screening of Anticancer Drugs

Curcuma longa CID_528176

CID_442783

CID_106668

CID_105954

5 2.517 0 0 0 0 0

Menthol An alcohol produced from

mint oils (Mentha sp.) or

prepared synthetically

CID_16666

CID_1254

CID_165675

CID_19244

156.26

2.78 0 0 0 0 0

Vincristine Antitumour alkaloid

isolated from Vinca rosea

CID_5978 824.96

3.194 2 0.65 0 0 1

Podophyllotoxi

A lignan found in

Podophyllin resin from

the roots of Podophyllum

plants

CID_10607 414.41

1.408 0 0 0 0 0

Vinblastine Antitumour alkaloid

isolated from Vinca rosea

CID_13342 810.98

4.078 2 0.62

0 0 1

Table 15.9. Pharmacological action of potential anticancer leads virtually screened after QSPR, Lipinski’s Rule and docking

studies. PubChem ID in bold characters indicates reference anticancer phytomolecule, while shaded compounds indicate

diverse pharmacological action.

PubChem ID Potential Compound Description Pharmacological Action

CID_65036 Allicin Antibacterial principle of Allium sativum (garlic),

Free Radical Scavengers

Anticarcinogenic , Anti-

Infective, Antilipidaemic,

Antioxidants, Hypoglycemic

CID_24360 Camptothecin An alkaloid isolated from the stem wood of the

Chinese tree, Camptotheca acuminata. This

compound selectively inhibits the nuclear enzyme

DNA Topoisomerases Type I.

Anticarcinogenic ,

Antineoplastic, Phytogenic,

Enzyme Inhibitors

CID_9064 Catechin An antioxidant flavonoid, occurring especially in

wood

lants as both

(

)

-catechin and

(

)

Anticarcinogenic ,

Antioxidant

Virtual Screening of Anticancer Drugs 259

epicatechin (cis) forms.

CID_9685

CID_440623

2-hydroxyestrone Catechol estrogen which is a major metabolite of

estradiol in man and animals

Anticarcinogenic

CID_3071 3,3'-

diindolylmethane

Occurs in edible cruciferous vegetables; a

cytochrome P-450 antagonist; also downregulates

the pro-survival pathway in hormone independent

prostate cancer

Anticarcinogenic

CID_11617 Allyl sulfide Essence of garlic; inhibits CYP2E1 Anticarcinogenic,

Antioxidants

CID_10428109 Bexarotene A retinoid X receptor (RXR) selective agonist Anticarcinogenic

CID_11778794 Biochainin A Phytoestrogen Anticarcinogenic,

Phytoestrogens

CID_4259412 Cholesteryl sulfate Component of human seminal plasma and

spermatozoa

Anticarcinogenic, Serine

Proteinase Inhibitors

CID_5385552 Crocetin Increases oxygen diffusion in plasma Anticarcinogenic,

Antioxidants

CID_969516 Curcumin Curcuma longa Anticarcinogenic

CID_16590 Diallyl disulfide Major constituent of garlic oil Anticarcinogenic,

Antihypertensive,

Antineoplastic,

Spermatocidal,

Antimutagenic

CID_23663982 Ecabet Protease Inhibitors Anticarcinogenic, Anti-

Infective, Anti-Ulcer

CID_10923720 Genistein An isoflavonoid derived from soy products. It

inhibits PROTEIN-TYROSINE KINASE and

topoisomerase-II (DNA TOPOISOMERASES,

TYPE II); activity

Anticarcinogenic, Protein

Kinase Inhibitors,

Phytoestrogens

CID_3712 Indole-3-carbinol Occurs in edible cruciferous vegetables Anticarcinogenic

CID_3752 Irsogladine Radioprotective Anticarcinogenic, Anti-Ulcer,

Antineoplastic

CID_6398761 Maxacalcitol Dermatologic Anticarcinogenic,

Antineoplastic

CID_47318 Oltipraz Reverse Transcriptase Inhibitors Anticarcino

enic, Antiviral,

260 Virtual Screening of Anticancer Drugs

Schistosomicides,

CID_16741 Phenethyl

isothiocyanate

A dietary liver aldehyde dehydrogenase inhibitor;

also promotes urinary bladder carcinoma

Anticarcinogenic,

Carcinogens, Enzyme

Inhibitors

CID_72 Protocatechuic acid - Anticarcinogenic

CID_5056 Resveratrol Antineoplastic, Phytogenic, Antioxidants, Anticarcinogenic, Anti-

Inflammatory Non-Steroidal

CID_638034 Retinol acetate Enzyme Inhibitors, Platelet Aggregation Inhibitors,

Antimutagenic

Anticarcinogenic, Adjuvants,

Immunologic

CID_114835

CID_147004

Selenomethyl

selenocysteine

- Anticarcinogenic

CID_9830646 Squalamine From dogfish shark Squalus acanthias Anticarcinogenic, Anti-

Bacterial, Angiogenesis

Inhibitors

CID_5350 Sulforafan From Cardaria draba L. Anticarcinogenic

CID_10523508 Sulindac sulfone Inhibits K-ras-dependent cyclooxygenase-2;

sulfated analog of indomethacin

Anticarcinogenic,

Antineoplastic,

Cyclooxygenase Inhibitors

CID_5311 Vorinostat Inhibits histone deacetylase I and 3 Anticarcinogenic, Anti-

Inflammatory, Non-Steroidal,

Antineoplastic, Enzyme

Inhibitors

SID_210967 Artemisinin Sesquiterpene lactone from Chinese medicinal

herb Artemisia annua

Anti-Infective, Antimalarials

SID_12013078 Artemether Quinghaosu (Artemisia annua) derivative Antifungal, Antimalarials,

Antiprotozoal, Coccidiostats,

Schistosomicides

CID_1254 Menthol An alcohol produced from mint oils or prepared

synthetically

Antipruritics

Virtual Screening of Anticancer Drugs 261

Table 15.10. Docking based virtual screened bioactive library compounds.

Potential and known Human and Mammalian Anticancer Targets (PDB ID) with Docking PMF Score (kcal/mol)

Set Phytomolecule* PubChemI

Log P

1a25 1a35 1agw 1awn 1cdk 1cpj 1crp 1dvi 1jsu 1mnc

Allicin CID_65036 1.415 -43.037 -46.416 -37.286 -48.498 -56.023 -56.023 -56.023 -56.023 -56.023 -48.381

Catechin CID_9064 2.113 -62.434 -78.713 -56.782 -58.508 -78.106 -78.106 -78.106 -78.106 -78.106 -84.114

Reference

Camptothecin CID_24360 0.558 -68.579 -88.454 -56.159 -62.99 -73.825 -73.825 -73.825 -73.825 -73.825 -84.888

Indole-3-carbinol CID_3712 0.82 -42.206 -55.901 -43.368 -45.251 -58.694 -58.694 -58.694 -58.694 -58.694 -56.348

Epigallocatechin

gallate

CID_65064 3.017 -65.013 -100.77 -63.582 -54.635 -99.175 -99.175 -99.175 -99.175 -99.175 -119.166

Phytoestrogen CID_52803

1.994

183.896 172.614 204.157 195.431 193.097 193.097 193.097 193.097 193.097 163.819

Vincristine CID_5978 3.194

37283.7 35453.7

35519.6

35831.8

36248.8

48645.82

Podophyllotoxin CID_10607 1.408

122.043 95.506 133.323 159.248 120.838 120.838 120.838 120.838 120.838 102.247

Known

Vinblastine CID_13342 4.078

76808.1 76664.1

76710.0

76844.3

76681.2

77405.95

SID_12013

078

3.331 -27.854 -75.02 -34.746 -46.002 -63.802 -63.802 -63.802 -63.802 -63.802 -63.374 Artemether

SID_17396

662

3.331 -53.178 -76.233 -39.077 -45.211 -62.278 -62.278 -62.278 -62.278 -62.278 -62.944

SID_21096

3.085 -48.695 -66.867 -31.04 -36.533 -51.543 -51.543 -51.543 -51.543 -51.543 -65.439 Artemisinin

SID_49834

379

3.085 -49.188 -68.085 -31.227 -45.186 -51.642 -51.642 -51.642 -51.642 -51.642 -64.256

CID_96951

2.479 -93.284 -110.886 -60.896 -79.784 -62.67 -62.67 -62.67 -62.67 -62.67 -92.725

CID_52817

2.517 -89.577 -109.977 -64.375 -61.402 -57.156 -57.156 -57.156 -57.156 -57.156 -82.609

CID_44278

2.517 -58.505 -95.962 -68.764 -73.19 -58.485 -58.485 -58.485 -58.485 -58.485 -84.216

CID_10666

836

2.517 -97.054 -85.034 -67.547 -58.337 -56.308 -56.308 -56.308 -56.308 -56.308 -52.615

Curcumin

CID_10595

440

2.517 -96.161 -84.798 -66.114 -75.358 -61.336 -61.336 -61.336 -61.336 -61.336 -85.486

CID_16666 2.78 -36.111 -46.404 -25.399 -31.926 -49.708 -49.708 -49.708 -49.708 -49.708 -49.456

CID_1254 2.78 -35.34 -46.768 -29.303 -30.269 -50.201 -50.201 -50.201 -50.201 -50.201 -50.014

CID_16567

2.78 -35.378 -46.794 -29.295 -30.525 -49.038 -49.038 -49.038 -49.038 -49.038 -49.624

Diverse

Menthol

CID_19244 2.78 -35.988 -46.739 -29.331 -35.357 -49.006 -49.006 -49.006 -49.006 -49.006 -49.497

Note: Epigallocatechin gallate and Curcumin indicates best docking energies, while phytomolecules namely, Phytoestrogen, Vincristine, Podophyllotoxin and Vinblastine indicates poor

docking scores against all receptors which suggest that other targets might be responsible for their anticancer activities. * Results of few leads only.

262 Virtual Screening of Anticancer Drugs

Table 15.11. An anti-malarial QSAR model for the prediction of biological activity and dependable chemical descriptors.

Chemical

Sample

Name Mol. formula ( c)

)(D

)

(F) (H) (I) (K) (T) (AA) (AD)

CID_2719 Chloroq

uine

Cl 3

0.477 0.492 0.015

48 10.775 4.564 -0.34 38.819 2 6

CID_3159

Benzni

dazol

4.7

0.672 0.658 -0.014

31 61.863 6.212 -1.09 27.865 1 5

CID_4735 Pentam

idine

1.7

0.23 0.229 -0.001

49 -24.069 6.018 -0.863 40.795 2 6

CID_6437

380

Benflu

metol

NOCl

150

2.176 2.179 0.003

67 -5.975 3.107 -0.282 63.027 3 5

CID_4069

Mefloqu

ine

21.84

1.339 1.355 0.016

42 9.36 7.278 -0.532 33.722 2 6

CID_4993 Pyrimet

hamine

Cl 8.4

0.924 0.99 0.066

30 -8.437 1.985 -0.464 28.923 2 6

CID_8549 Quinine C

100.7

2.003 1.977 -0.026

48 16.247 1.861 -0.367 39.187 2 6

CID_6882

Artemis

inine

10.5

1.021 1 -0.021

42 32.503 6.073 -0.573 29.257 0 6

CID_4564

Artemet

her

3.43

0.535 0.551 0.016

47 37.278 1.952 -0.352 31.515 0 6

CID_5464

098

Artesun

ate

1.17

0.068 0.081 0.013

55 16.644 3.143 -0.757 38.091 0 6

CID_6540

Fansida

63.68 ? 1.804

65 -43.088 5.677 -1.491 59.356 4 6

Standard Error = 0.029061

Note: (c) = In vitro activity (IC

) nM, (D

) = Experimental log (IC

), = Predicted log (IC

), AE= Absolute error, F= Atom Count (all atoms), H=

Conformation Minimum Energy (kcal/mol), I= Dipole Moment (debye), K= Dielectric Energy (kcal/mol), T= Polarizability, AA= Ring Count

(aromatic 6 membered), AD= Size of Smallest Ring and ? = unknown activity

Virtual Screening of Anticancer Drugs 263