Molecular docking, MM/GBSA and 3D-QSAR studies on EGFR inhibitors

Epidermal growth factor receptor (EGFR) is the first growth factor receptor proposed as a target for cancer therapy. Molecular modeling protocols like molecular docking, molecular mechanics/generalized born surface area (MM/GBSA) calculations and three dimensional-quantitative structure activity relationship (3D-QSAR) studies were performed on 45 molecules to understand the structural requirements for EGFR tyrosine kinase inhibitors. Conformation for all the molecules obtained from molecular docking were used as is for 3D-QSAR analysis. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) models were obtained by performing partial least square analysis on 35 training molecules and these models were validated using 10 test moleucles. The models showed good statistical results in terms of r 2 , q ^2_loo and r ^2_pred values. Information rendered from 3D-QSAR model and sitemap analysis was used to optimize lead molecule to design prospective inhibitors. Improvement in EGFR binding affinity can be achieved by substitutional modification on phenyl ring attached to alkynyl group with bulkier hydrogen bond donor and acceptor substituents that can increase favourable interaction with the receptor. Graphical Abstract Epidermal growth factor receptor (EGFR) is the first growth factor receptor proposed as a target for cancer therapy. An integrated computational protocol using molecular docking and 3DQSAR were performed using the CoMFA and CoMSIA methods. Derived models showed good statistical reliability that is evident from their r 2 , q 2 loo values. Information obtained from 3DQSAR model was applied for optimization of lead molecule and to design novel potential inhibitors.