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Letters in Drug Design & Discovery

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ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

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Research Article

A Rational Approach to Anticancer Drug Design: 2D and 3D- QSAR, Molecular Docking and Prediction of ADME Properties using Silico Studies of Thymidine Phosphorylase Inhibitors

Author(s): Vaibhav V. Raut*, Shashikant V. Bhandari, Shital M. Patil and Aniket P. Sarkate

Volume 20, Issue 2, 2023

Published on: 14 June, 2022

Page: [153 - 166] Pages: 14

DOI: 10.2174/1570180819666220215115633

Price: $65

Abstract

Background: Cancer is the most prevalent disease seen nowadays. Thymidine phosphorylase (TP) is an angiogenic enzyme that is overexpressed in many solid tumors. Over the years, Thymidine phosphorylase has emerged as a novel target for anticancer drug development as an inhibitor.

Objective: To design novel oxadiazole-isatin pharmacophore-containing molecules and explore their structural requirements related to the anticancer activity.

Methods: Pharmacophore optimisation was carried out for oxadiazole-isatin hybrid molecules using molecular modeling studies (2D and 3D QSAR). Further, the new chemical entities were designed using the combilib tool of V life software. To have a better understanding of the binding interactions, the newly designed molecules were docked. To achieve a drug-like pharmacokinetic profile, molecules were also tested for ADME prediction.

Results: Two-Dimensional Quantitative Structure-Activity Relationship (2D-QSAR) model was generated using the multiple regression method with r2 = 0.84 and q2 = 0.76. Three-Dimensional Quantitative Structure-Activity Relationship (3D-QSAR) model was obtained by simulated annealing k nearest near (SA kNN) method with q2 = 0.8099. Molecular docking studies showed promising results. Compound 5 was found to be with the best dock score and the best fit to the active site pocket of the thymidylate phosphorylase enzyme. The compounds have notable absorption, distribution, metabolism, and excretion (ADME) properties that can be predicted to assure a drug-like pharmacokinetic profile.

Conclusion: One of the most successful and fast-increasing methodologies is molecular modeling. It not only aids in the prediction of specific target compounds but also aids in the cost reduction of valuable substances. The successful use of molecular modeling was done in this study, with caution taken to avoid any chance co-relation. Optimised pharmacophore was obtained and new chemical entities were designed. Docking studies revealed that Compound 5 has shown better H-bond interaction with Lys 221 and Thr 151 with bond distances 2.0 Α° and 1.8 Α° which is the most active molecule. ADME tests discovered that the majority of the newly designed compounds were within a reasonable range as required in a druglike pharmacokinetic profile. Molecules 2, 4, 5, 6 can be considered as a lead for future synthesis and biological screening.

Keywords: Phosphorylase inhibitions, structure-activity relationship, oxadiazole-isatin hybrid, docking, ADME, anticancer.

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[1]
Hanf, V.; Kreienberg, R. Corpus Uteri.Die Gynakologie; Kaufmann, M.; Costa, S.D.; Scharl, A., Eds.; Springer: Berlin, Heidelberg, 2003, pp. 399-438.
[http://dx.doi.org/10.1007/978-3-662-11496-4_24]
[2]
Akiyama, S.; Furukawa, T.; Sumizawa, T.; Takebayashi, Y.; Nakajima, Y.; Shimaoka, S.; Haraguchi, M. The role of thymidine phosphorylase, an angiogenic enzyme, in tumor progression. Cancer Sci., 2004, 95(11), 851-857.
[http://dx.doi.org/10.1111/j.1349-7006.2004.tb02193.x] [PMID: 15546501]
[3]
Balzarini, J.; Gamboa, A.E.; Esnouf, R.; Liekens, S.; Neyts, J.; De Clercq, E.; Camarasa, M.J.; Pérez-Pérez, M.J. 7-Deazaxanthine, a novel prototype inhibitor of thymidine phosphorylase. FEBS Lett., 1998, 438(1-2), 91-95.
[http://dx.doi.org/10.1016/S0014-5793(98)01271-X] [PMID: 9821965]
[4]
Gbaj, A.; Edwards, P.N.; Reigan, P.; Freeman, S.; Jaffar, M.; Douglas, K.T. Thymidine phosphorylase from Escherichia coli: tight-binding inhibitors as enzyme active-site titrants. J. Enzyme Inhib. Med. Chem., 2006, 21(1), 69-73.
[http://dx.doi.org/10.1080/14756360500424010] [PMID: 16570508]
[5]
Langen, P.; Etzold, G.; Bärwolff, D.; Preussel, B. Inhibition of thymidine phosphorylase by 6-aminothymine and derivatives of 6-aminouracil. Biochem. Pharmacol., 1967, 16(9), 1833-1837.
[http://dx.doi.org/10.1016/0006-2952(67)90260-2] [PMID: 6053224]
[6]
Casanova, E.; Herna, A. 5′-O-tritylinosine and analogues as allosteric inhibitors of human thymidine phosphorylase. J. Med. Chem., 2006, 49(18), 5562-5570.
[7]
Glomb, T.; Szymankiewicz, K.; Świątek, P. Anti-cancer activity of derivatives of 1,3,4-oxadiazole. Molecules, 2018, 23(12), 1-16.
[http://dx.doi.org/10.3390/molecules23123361] [PMID: 30567416]
[8]
Mullican, M.D.; Wilson, M.W.; Connor, D.T.; Kostlan, C.R.; Schrier, D.J.; Dyer, R.D. Design of 5-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3,4-thiadiazoles, -1,3,4-oxadiazoles, and -1,2,4-triazoles as orally-active, nonulcerogenic antiinflammatory agents. J. Med. Chem., 1993, 36(8), 1090-1099.
[http://dx.doi.org/10.1021/jm00060a017] [PMID: 8478906]
[9]
Lai, H.; Dou, D.; Aravapalli, S.; Teramoto, T.; Lushington, G.H.; Mwania, T.M.; Alliston, K.R.; Eichhorn, D.M.; Padmanabhan, R.; Groutas, W.C. Design, synthesis and characterization of novel 1,2-benzisothiazol-3(2H)-one and 1,3,4-oxadiazole hybrid derivatives: potent inhibitors of Dengue and West Nile virus NS2B/NS3 proteases. Bioorg. Med. Chem., 2013, 21(1), 102-113.
[http://dx.doi.org/10.1016/j.bmc.2012.10.058] [PMID: 23211969]
[10]
Gan, X.; Hu, D.; Chen, Z.; Wang, Y.; Song, B. Synthesis and antiviral evaluation of novel 1,3,4-oxadiazole/thiadiazole-chalcone conjugates. Bioorg. Med. Chem. Lett., 2017, 27(18), 4298-4301.
[http://dx.doi.org/10.1016/j.bmcl.2017.08.038] [PMID: 28838690]
[11]
Zhang, Z.M.; Zhang, X.W.; Zhao, Z.Z.; Yan, R.; Xu, R.; Gong, H.B.; Zhu, H.L. Synthesis, biological evaluation and molecular docking studies of 1,3,4-oxadiazole derivatives as potential immunosuppressive agents. Bioorg. Med. Chem., 2012, 20(10), 3359-3367.
[http://dx.doi.org/10.1016/j.bmc.2012.03.064] [PMID: 22520630]
[12]
Ibrahim, H.S.; Abou-Seri, S.M.; Tanc, M.; Elaasser, M.M.; Abdel-Aziz, H.A.; Supuran, C.T. Isatin-pyrazole benzenesulfonamide hybrids potently inhibit tumor-associated carbonic anhydrase isoforms IX and XII. Eur. J. Med. Chem., 2015, 103, 583-593.
[http://dx.doi.org/10.1016/j.ejmech.2015.09.021] [PMID: 26408817]
[13]
Rohini, R.; Reddy, P. M.; Shanker, K.; Kanthaiah, K.; Ravinder, V.; Hu, A. Synthesis of Mono, Bis-2-(2-Arylideneaminophenyl) Indole Azome- Thines as Potential Antimicrobial Agents., 2011, 34(7), 1077-1084.
[14]
Verma, M.; Pandeya, S.N.; Singh, K.N.; Stables, J.P. Anticonvulsant activity of Schiff bases of isatin derivatives. Acta Pharm., 2004, 54(1), 49-56.
[PMID: 15050044]
[15]
Sridhar, S.K.; Ramesh, A. Synthesis and pharmacological activities of hydrazones schiff and mannich bases of isatin derivatives. Biol. Pharm. Bull., 2001, 24(10), 1149-1152.
[16]
Patel, H.M.; Noolvi, M.N.; Sharma, P. Quantitative structure–activity relationship (QSAR) studies as strategic approach in drug discovery. Med. Chem. Res., 2014, 23, 4991-5007.
[17]
Khan, P.M.; Roy, K. Current approaches for choosing feature selection and learning algorithms in quantitative structure-activity relationships (QSAR). Expert Opin. Drug Discov., 2018, 13(12), 1075-1089.
[http://dx.doi.org/10.1080/17460441.2018.1542428] [PMID: 30372648]
[18]
Javid, M.T.; Rahim, F.; Taha, M.; Nawaz, M.; Wadood, A.; Ali, M.; Mosaddik, A.; Shah, S.A.A.; Farooq, R.K. Synthesis, SAR elucidations and molecular docking study of newly designed isatin based oxadiazole analogs as potent inhibitors of thymidine phosphorylase. Bioorg. Chem., 2018, 79(February), 323-333.
[http://dx.doi.org/10.1016/j.bioorg.2018.05.011] [PMID: 29803079]
[19]
Halgren, T.A. Molecular geometries and vibrational frequencies for MMFF94 *. J. Comput. Chem., 2000, 17(1 996), 553-586.
[20]
Sharma, M.C.; Kohli, D.V. Insight into the structural requirement of substituted quinazolinone biphenyl acylsulfonamides derivatives as angiotensin II AT 1 receptor antagonist: 2D and 3D QSAR approach. J. Saudi Chem. Soc., 2014, 18(1), 35-45.
[http://dx.doi.org/10.1016/j.jscs.2011.05.011]
[21]
Cramer, R.D.; Patterson, D.E.; Bunce, J.D. Comparative molecular field analysis (CoMFA). 1. Effect of shape on binding of steroids to carrier proteins. J. Am. Chem. Soc., 1988, 110(18), 5959-5967.
[http://dx.doi.org/10.1021/ja00226a005] [PMID: 22148765]
[22]
Crystal structure of human thymidine phosphorylase in complex with a small molecule inhibitor. Available from: https://www.rcsb.org/structure/1UOU Accessed on 5th November 2021.
[23]
Pawar, V.; Lokwani, D.; Bhandari, S.; Mitra, D.; Sabde, S.; Bothara, K.; Madgulkar, A. Design of potential reverse transcriptase inhibitor containing Isatin nucleus using molecular modeling studies. Bioorg. Med. Chem., 2010, 18(9), 3198-3211.
[http://dx.doi.org/10.1016/j.bmc.2010.03.030] [PMID: 20381364]

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