OncoTargets and Therapy (May 2022)
Identification of 1,2,4-Oxadiazoles-Based Novel EGFR Inhibitors: Molecular Dynamics Simulation-Guided Identification and in vitro ADME Studies
Abstract
Vishal Unadkat,1,2 Shishir Rohit,1 Paranjay Parikh,3 Kaushal Patel,3 Vinod Sanna,4 Sanjay Singh2,5 1Kashiv Biosciences Pvt Ltd, Ahmedabad, 382210, Gujarat, India; 2Division of Biological & Life Sciences (Formerly Institute of Life Sciences), School of Arts & Sciences, Ahmedabad University, Ahmedabad, 380009, Gujarat, India; 3Department of Advanced Organic Chemistry, P.D. Patel Institute of Applied Sciences, Charotar University of Science and Technology, Changa, Gujarat, 388421, India; 4Piramal Pharma Solutions, Ahmedabad, 382213, Gujarat, India; 5National Institute of Animal Biotechnology, Hyderabad, 500032, Telangana, IndiaCorrespondence: Sanjay Singh, Division of Biological & Life Sciences (Formerly Institute of Life Sciences), School of Arts & Sciences, Ahmedabad University, Navaragnpura, Ahmedabad, 380009, Gujarat, India, Email [email protected]: In this work, we have identified heterocyclic derivatives with 1,2,4 oxadiazole scaffold mimicking the functions of tyrosine kinase inhibitors. Fourteen molecules that displayed the best fit were picked from the library of compounds and studied under in-silico and in-vitro conditions. Four compounds were selected for further cytotoxicity and ADME (Absorption, Distribution, Metabolism, Elimination) profiling showing IC50 (from 8– 13 μM) values against EGFR positive cancer cell line (MCF7).Methods: A molecular dynamics simulation study was performed to understand the correlation of non-covalent binding energies with biological activity. The drug-like properties of the selected four compounds (7a, 7b, 7e, and 7m) were evaluated by in-vitro ADME studies. Compounds 7a, 7b, and 7m were the active compounds in the molecular dynamics simulations study. Further, EGFR binding activity was confirmed with EGFRWT and EGFRT790M kinase assay using a luminescence-based method.Results: These compounds ( 7a, 7b, and 7m) showed activity against EGFRWT and mutant EGFRT790M, exhibiting IC50 values of 5) and showed high permeability (Papp 17 × 10− 6 cm/s). Lastly, all these compounds were moderately stable in liver microsomes at alkaline pH with a half-life of 30– 60 min, while at a highly acidic pH (2.0), the compounds were stable up to 15– 20 min.Conclusion: Overall, in-vitro ADME results of these molecules showed good drug-like properties, which are well correlated with the in-silico ADME data, making them ideal for developing an oral drug delivery formulation.Graphical Abstract: Keywords: 1,2,4-oxadiazoles, structure-based design, molecular dynamics, absorption, distribution, metabolism, excretion, anticancer
