Design, Docking, In silico ADME Prediction of Novel 2-substituted-5-
hydroxy-1-(1-methyl-3-morpholinopropyl)-1H-indole-3-carboxamide Derivatives
for Estrogen Receptor Alfa in AF-2 Domain for Effective Anticancer
Treatment

Sandip   Narayan   Wagh; Vivekanand   Arvind   Chatpalliwar

doi:10.2174/1570180819666220613091348

Abstract

Aim: The present work has been designed to discover some novel 2-substituted -5-hydroxy-1- (1-methyl-3-morpholinopropyl)-1H-indole-3-carboxamide derivatives and their screening through computational molecular docking.

Background: The present manuscript describes designing novel 2-substituted-5-hydroxy-1-(1-methyl-3- morpholinopropyl)-1H-indole-3-carboxamide derivatives as specific ERα modulators, discusses the selection criteria for 1ERR, several interactions between the ligand and the amino acid residues that would probably elicit fruitful modulation of the receptor. Accordingly, a ligand was observed to yield a G Score of -10. 390, which was considered close and comparable with the standard ligand Raloxifene (-11.869).

Objective: Synthesize a few indole -3-carboxamide derivatives and test their ability to modulate ER-α through human cell line cultures for breast cancer. The present manuscript describes the designing of novel 2-substituted -5-hydroxy-1-(1-methyl-3-morpholinopropyl)-1H-indole-3-carboxamide derivatives as specific ERα modulators, discusses the selection criteria for 1ERR, several interactions between the ligand and the amino acid residues that would probably elicit fruitful modulation of the ER-alpha in the treatment of breast cancer.

Methods: This work involved designing a few 2-substituted-5-hydroxy-1-(1-methyl-3- morpholinopropyl)-1H-indole-3-carboxamide derivatives and their virtual screening for receptor modulation by carrying molecular docking studies to determine the binding interactions for best-fit conformations in AF-2 binding site of the ERα receptor, and ADME predictions by Quick Prop Tools. Those ligands that displayed satisfactory docking were selected for further studies. These revealed all-important functional groups that interact with active amino acid residues in the targeted cavity, substantiating their presence in molecules to elicit the desired response whence tested in vitro.

Results: Based on the docking studies of the designed derivatives, ligands BD59, BD60, BD65, BD58, BD64 BD61, BD54, BD32, BD48 and BD45 have shown better binding energy than the rest and were comparable with the interactions shown by the standard, Raloxifene. The observed results lamented the presence of a substitution at the C-2 position of indole scaffold, either straight or branched with terminal atom containing non-bonding electrons (halo/-NH₂). Accordingly, ligand BD59 carrying chlorobenzene chain (G Score= -10.390), whereas BD60 carrying flurobenzene chain (G Score = -10.204), whereas BD65 carrying methylbenzene chain (G Score = -9.863) were found to interact suitably with the active amino acid residues in the targeted cavity that are reported to be involved in interaction with the standard.

Conclusion: From the present results, we conclude that designed derivatives have the potential to modulate ERα receptors effectively, which can be synthesized and tested for their effectiveness, in vitro and in vivo against breast cancer.

Keywords: Docking, breast cancer, estrogen receptor α, 5-hydroxymorpholinopropylindole derivatives, SERM, raloxifene, Quick Prop.

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DOI https://dx.doi.org/10.2174/1570180819666220613091348	Print ISSN 1570-1808
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Letters in Drug Design & Discovery

Design, Docking, In silico ADME Prediction of Novel 2-substituted-5- hydroxy-1-(1-methyl-3-morpholinopropyl)-1H-indole-3-carboxamide Derivatives for Estrogen Receptor Alfa in AF-2 Domain for Effective Anticancer Treatment

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