Title: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
Volume: 20
Issue: 8
Author(s): Sandip Narayan Wagh and Vivekanand Arvind Chatpalliwar*
Affiliation:
- Department of Pharmaceutical Chemistry, S.N.J.B’s S.S.D.J. College of Pharmacy, Neminagar, Chandwad, Nashik,
Maharashtra - 423 101, India
Keywords:
Docking, breast cancer, estrogen receptor α, 5-hydroxymorpholinopropylindole derivatives, SERM, raloxifene, Quick Prop.
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.
