Identification of Small Molecule-Based Inhibitor of Estrogen Receptor: A Computational Approach

Abstract

Breast cancer is the prevailing type of cancer impacting women worldwide. Estrogen receptor (positive) breast tumors constitute approximately 75% of the total breast cancer cases. Virtual screening of 200 small organic molecule-based ligands against estrogen receptor alpha (ERα) was performed using AutoDock Vina. The molecules were ranked according to their binding affinity values, and their interactions with the residues of the active site were thoroughly examined. Computational prediction of the ADMET properties was also performed to understand the pharmacokinetic (PK) properties of the screened molecules. L10 exhibited the highest binding affinity. (-12.311 kcal/mol), which was higher than the FDA-approved drug Afimoxifene (-10.46 kcal/mol). DFT studies with L10 revealed favorable structural and electronic properties augmenting the drug-like nature of the molecule. The apo-protein and the protein-ligand complex corresponding to L10 were subsequently subjected to 100ns all-atom MD simulation using GROMACS with CHARMM 36 force field. Analysis of the simulation trajectory indicated reasonably high stability of the corresponding protein-ligand complex. Thus, our current study shows that L10 can be a potentially strong inhibitor of the estrogen receptor alpha (ERα), and hence it may be studied further for developing drugs against breast cancer.