INSILICO DRUG DESIGN AND MOLECULAR DOCKING STUDIES OF NOVEL COUMARIN DERIVATIVES AS ANTI-CANCER AGENTS

Simpi Mehta; Seema R Pathak

doi:10.22159/ajpcr.2017.v10i4.16826

Authors

Simpi Mehta Department of chemistry, Amity School of Applied Sciences, Amity University Gurgaon, India
Seema R Pathak

DOI:

https://doi.org/10.22159/ajpcr.2017.v10i4.16826

Abstract

Objective: Cancer is the major worldwide problem. It arises due to uncontrolled growth of cells. In the present study a series of novel coumarin derivatives were designed and computationallyoptimized to investigate the interaction between designed ligands and 10 pdb files of five selected proteins. The objective here was to analyse in silico anticancerous activityÂ of designed ligands to reduce cost and time for getting novel anticancerous drug with minimum side effects.

Methods: Docking studies were performed to find outmaximum interaction between designed ligandsÂ and Â selected five proteins Â using Schrondinger software Maestro. Capecitabin has been used as reference compound. Structures of selected proteins were downloaded from protein data bank.

Results: All the designed ligands showed mild to excellent binding with proteins.Most of the ligands exhibited better interaction Â compared to reference compoundcapacitabin with all pdb files. Some of Â designed ligands amongst (1-7) showed excellent docking score with Â all pdb files(2v5z, 2v60, 2v61) ofAmine oxidase.Â

Conclusion: All the designed ligands were docked with ten pdb files of five different proteins and it was found that out of seven designed ligand, ligand 4 showed best binding (docking score -10.139 ) withÂ pdb 2v5z of protein Amine oxidase. Docked ligand cavity of ligand 4 showed Â important hydrophobic/non polar residues such asIle199,Ile316,Trp119,Phe168,Ile198,Cys172,Tyr188,Tyr398,Tyr435,Phe343,Tyr60,Leu328,Leu171 and showed pi-pi interaction with Tyr326.Further wet lab studies are continued in our laboratory to Â confirm and find out efficiency and activity of target compounds.

Keywords: Docking, Mono Amine Oxidase, Coumarin derivatives, Anticancerous activity, binding energy, Ramachandran Plot, Hydrophobic residue.

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Author Biography

Simpi Mehta, Department of chemistry, Amity School of Applied Sciences, Amity University Gurgaon, India

Head,

Department of Chemistry,

Amity School of Applied Sciences

Amity University, Gorgoan, Haryana,India

References

Gupta M, Dahiya J, Marwaha RK, Dureja H. Therapies in cancer treatment: An overview. Int J Pharm Pharm Sci 2015;7(4):1-9.

Sloane D. Cancer epidemiology in the United States: Racial, social, and economic factors. Methods Mol Biol 2009;471:65-83.

Klenkar J, Molnar M. Natural and synthetic coumarins as potential anticancer agents. J Chem Pharm Res 2015;7(7):1223-38.

Ostrov DA, HernÃ¡ndez Prada JA, Corsino PE, Finton KA, Le N, Rowe TC. Discovery of novel DNA gyrase inhibitors by high-throughput virtual screening. Antimicrob Agents Chemother 2007;51(10):3688-98.

Kostova I. Coumarins as inhibitors of HIV reverse transcriptase. Curr HIV Res 2006;4(3):347-63.

Shih JC, Chen K, Ridd MJ. Monoamine oxidase: From genes to behavior. Annu Rev Neurosci 1999;22:197-217.

True L, Coleman I, Hawley S, Huang CY, Gifford D, Coleman R, et al. A molecular correlate to the Gleason grading system for prostate adenocarcinoma. Proc Natl Acad Sci U S A 2006;103(29):10991-6.

Ishar MP, Singh G, Singh S, Sreenivasan KK, Singh G. Design, synthesis, and evaluation of novel 6-chloro-/fluorochromone derivatives as potential topoisomerase inhibitor anticancer agents. Bioorg Med Chem Lett 2006;16:1366-70.

Nioi P, Hayes JD. Contribution of NAD(P)H: Quinone oxidoreductase 1 to protection against carcinogenesis, and regulation of its gene by the Nrf2 basic-region leucine zipper and the arylhydrocarbon receptor. Mutat Res 2004;555(1-2):149-71.

Nolan KA, Doncaster JR, Dunstan MS, Scott KA, Frenkel AD, Siegel D, et al. Synthesis and biological evaluation of coumarin-based inhibitors of NAD(P)H: Quinone oxidoreductase-1 (NQO1). J Med Chem 2009;52:7142-56.

Normanno N, De Luca A, Bianco C, Strizzi L, Mancino M, Maiello MR, et al. Epidermal growth factor receptor (EGFR) signaling in cancer. Eur J Cancer 2006;366(1):2-16.

Normanno N, De Luca A, Bianco C, Strizzi L, Mancino M, Maiello MR, et al. Epidermal growth factor receptor (EGFR) signaling in cancer. Gene 2006;366(1):2-16.

Patil RB, Sawant SD, Reddy KV, Shirsat M. Synthesis, docking studies and evaluation of antioxidant activity of some chromenone derivatives. Res J Pharm Biol Chem Sci 2015;6(2):381-91.

Caro AA, Cederbaum AI. Oxidative stress, toxicology, and pharmacology of CYP2E1. Annu Rev Pharmacol Toxicol 2004;44:27-42.

Oyama T, Sugio K, Isse T, Matsumoto A, Nose N, Uramoto H, et al. Expression of cytochrome P450 in non-small cell lung cancer. Front Biosci 2008;13:5787-93.

Rodriguez-Antona C, Ingelman-Sundberg M. Cytochrome P450 pharmacogenetics and cancer. Oncogene 2006;25(11):1679-91.

Yano JK, Hsu MH, Griffin KJ, Stout CD, Johnson EF. Structures of human microsomal cytochrome P450 2A6 complexed with coumarin and methoxsalen. Nat Struct Mol Biol 2005;12(9):822-3.

Patents: Furo-coumarinsulfonamides as Protein Kinase C Inhibitors. Available from: http://www.google.com/patents/US5216014.

Marshall ME, Butler K, Hermansen D. Structural modification of coumarin for increased anti-coagulation potency. Prostate 1990;17:95-108.

Sashidhara KV, Kumar A, Kumar M, Sarkar J, Sinha S. Synthesis and in vitro evaluation of novel coumarin-chalcone hybrids as potential anticancer agents. Bioorg Med Chem Lett 2010;20(24):7205-11.

Ganugapati J, Swarna S. Molecular docking studies of antidiabetic activity of cinnamon compounds. Asian J Pharm Clin Res 2014;7(2):1-4.

Fadilah F, Arsianti A, Kusumardi K, Tedjo A. Molecular docking studies of analogues of antimycin A3 as caspases inhibitors of apoptosis in colorectal cancer. Asian J Pharm Clin Res 2016;9(3):350-2.

Tiwary BK, Pathak RK, Pradhan K, Nanda AK, Bothra AK, Chakraborty R. Evaluation of drug candidature of some quinazoline-4-(3h)-ones as inhibitor of human dihydrofolatereductase enzyme: Molecular docking and in silico studies. Int J Pharm Pharm Sci 2014;6(2):393-400.

Gupta P, Rai N, Gautam P. Anticancer drugs as potential inhibitors of acrab-tolc of multidrug resistant Escherichla coli: As in silico molecular modeling and docking study. Asian J Pharm Clin Res 2015;8(1):351-8.

Sabitha K, Kodous A, Rajkumar T. Computational analysis of mutations in really interesting new gene finger domain and BRCA1 C terminus domain of breast cancer susceptibility gene. Asian J Pharm Clin Res 2016;9(3):96-102.