Discovery of new 2,4-diaminopyrimidines derivatives as EGFRT790M kinase inhibitors: a structure-based approach with DFT calculation, drug-likeness, ADME-toxicity properties evaluation and MD simulation

Abstract

AbstractCancer of the lung is known to be the principal cause of tumour-linked mortality worldwide. Non-small cell lung cancer (NSCLC) is the most common and lethal type of lung cancer with close to 2.0 million reported cases and a survival rate of not less than 20% at all stages in every 5 years of diagnosis. Despite the progress made in the treatment processes, there was no significant improvement in patients with NSCLC. As such, this research aims to design (utilizing a structure-based approach) potential EGFRT790M kinase inhibitors with their DFT calculations, Drug-likeness, ADME-Toxicity properties evaluation and MD simulation. A structure-based approach was employed to design potential EGFRT790M kinase inhibitors. The DFT calculations, Drug-likeness and ADME-Toxicity properties of the newly designed potential EGFRT790M kinase inhibitors were evaluated. MD simulation of the best newly designed compound was further studied. The virtual screening performed on the investigated EGFRT790M Kinase inhibitors has identified compound 8 with the highest mole dock score of − 136.377 kcal/mol as the best hit. The structure-based strategy was adopted to design six new compounds with better affinity (between − 138.255 to − 140.552 kcal/mol) towards the EGFRT790M Kinase enzyme (3IKA). The newly designed EGFR mutant inhibitors were seen to possess better mole dock scores than AZD9291 (− 118.872 kcal/mol). Based on the predicted drug-likeness and ADMET properties, the newly designed compounds are orally bioavailable with a bioavailability score of 0.55, can be synthesized easily in the wet lab (based on their synthetic accessibility score) and possess good pharmacokinetic profiles. The MD simulation performed at 150 ns provides insight into the stability of the S2D3 compound in the binding pocket of the 3IKA target protein. The total binding free energy calculation of the studied S2D3-3IKA complex suggested that van der Waals interactions and electrostatic interactions provided the general powerful force for the binding process. The designed compound S2D3 being stable with higher affinity and best pharmacokinetic properties is therefore recommended to be synthesized in the wet lab as potential NSCLC agents.