Insilico Docking Study of Isoxazole Indole Linked Resorcinol Derivatives as Promising Selective Estrogen Receptor Modulators & Anticancer Drugs

Abstract

A series of 9 compounds with isoxazole-indole-γ-resorcylic acid scaffold, segregated into B1 & A1 series, wherein, B1 comprises compounds:1,3,4,5, & 9 and A1comprises compounds: 2,6,7, & 8 , on the basis of variable substituents at the indole , resorcinol and isoxazole end of the scaffold as in Fig. 1, were designed and docked with human estrogen receptor:1ERRα. The binding affinity (BA) and the interacting amino acids compared with reference selective estrogen receptor modulators (SERMs) such as Raloxifene, Estradiol, Bazedoxifene, Bisphenol, Genistein, Daidzein, Ormiloxifene,Tamoxifen,6-hydroxy-naphthalen-2yl-benzo(D)-isoxazol-6-ol(1)(WAY-397) using PyRx software and their ADME properties predicted with SWISS ADME online tool. Significant similarities and minor differences in the binding pattern between the key interacting aminoacids such as Arg 394,Glu 353, Asp 351, Leu 346, Leu 525, Trp 383,Phe 404 ,Ala 350, Leu 387, Met 421 responsible for ER agonist/antagonist activity found in the binding cavity of a 1 Errα -Bazedoxifene/1 Errα -raloxifene/1 Errα -estradiol docked complex AND 1 Errα -isoxazole-indole- resorcinol docked complex indicate their promising potential to serve as potent ER agonists in bone or ER antagonists against breast cancer and other cancer diseases. The Compounds with Highest BA is of the order: BA (A1series)>B1 series & BA(6)=BA(8)>BA(7)>BA(2)>BA(9)=BA(1)>BA(3)>BA(4)=BA(5)

Key Words

Molecular docking - Estrogen receptor - isoxazole indole resorcinol - SERM

Publication History

Received: 30 May 2022

Accepted: 27 June 2022

Article published online:
11 August 2022

• References

• 1 Brzozowski AM, Pike ACW, Dauter Z. et al. Molecular basis of agonism and antagonism in the oestrogen receptor. Nature 1997; 389: 753-758
• 2 Musa MA, Khan MO, Cooperwood JS. “Medicinal chemistry and emerging strategies applied to the development of selective estrogen receptor modulators (SERMs)”. Current Medicinal Chemistry 2007; 14: 1249-1261
• 3 “Raloxifene Hydrochloride Monograph for Professionals”. Drugs.com. American Society of Health-System Pharmacists. Retrieved 22 March 2019
• 4 Goldstein SR. “A pharmacological review of selective oestrogen receptor modulators”. Human Reproduction Update 2000; 6: 212-224
• 5 Weatherman RV, Clegg NJ, Clegg NJ. “Differential SERM activation of the estrogen receptors (ERα and ERβ) at AP-1 sites”. Chemistry & Biology 2001; 8: 427-436
• 6 Escande A, Pillon A, Servant N. et al. “Evaluation of ligand selectivity using reporter cell lines stably expressing estrogen receptor alpha or beta”. Biochem. Pharmacol 2006; 71: 1459-1469
• 7 “DUAVEE^® (conjugated estrogens/bazedoxifene) tablets for oral use” (PDF). U.S. Food and Drug Administration. October 2013
• 8 Osteoporosis drug stops growth of breast cancer cells, even in resistant tumors”. Duke University Medical Center. June 15, 2013
• 9 Kung AW, Chu EY, Xu L. “Bazedoxifene: a new selective estrogen receptor modulator for the treatment of postmenopausal osteoporosis”. Expert Opinion on Pharmacotherapy 2009; 10: 1377-1385
• 10 Miller CP. “SERMs: evolutionary chemistry, revolutionary biology”. Current Pharmaceutical Design 2002; 8: 2089-2111
• 11 Palacios S. “Endometrial Effects of SERMs”. In Sanchez AC, Calaf i Alsina J, Dueñas-Díez J (eds.). Selective estrogen receptor modulators a new brand of multitarget drugs (1st ed.). Berlin: Springer; pp 2006: 282-283
• 12 Muchtaridi M, Yusuf M, Diantini A. et al. Potential activity of fevicordin-a from phaleria macrocarpa(Scheff) boerl. Seeds as estrogen receptor antagonist based on cytotoxicity and molecular modelling studies. Int. J. Mol. Sci. 2014; 15: 7225-7249
• 13 Jensen EV, Jordan VC. “The estrogen receptor: a model for molecular medicine”. Clinical Cancer Research 2003; 9: 1980-1989
• 14 Jordan VC. “Antiestrogens and selective estrogen receptor modulators as multifunctional medicines. 2. Clinical considerations and new agents”. Journal of Medicinal Chemistry 2003; 46: 1081-1111
• 15 Lewis-Wambi JS, Kim H, Curpan R. et al. The Selective Estrogen Receptor Modulator Bazedoxifene Inhibits Hormone-Independent Breast Cancer Cell Growth and Down-Regulates Estrogen Receptor and Cyclin D1. , Mol Pharmacol 2011; 80: 610-620
• 16 Manas ES, Unwalla RJ, Xu ZB. et al. Structure-based design of estrogen receptor_ selective ligands. J Am Chem Soc 2004; 126: 15106-15119
• 17 Wen-Ming Li, Xiao-Bo Li, Su-Xia Sun. et al. Agonist and antagonist recognition studies for oestrogen receptor by molecular dynamics simulation. Molecular Simulation 2013; 39: 228-233