Molecular modelling study on pyrrolo[2,3-b]pyridine derivatives as c-Met kinase inhibitors: a combined approach using molecular docking, 3D-QSAR modelling and molecular dynamics simulation

Abstract

Mesenchymal-epithelial transition factor (c-Met), also known as hepatocyte growth factor receptor (HGFR) is a unique member of receptor tyrosine kinase (RTKs) family. Dysregulation of c-Met/HGF signalling pathway is validated in a variety of human proliferative diseases. Therefore, targeting c-Met has become a promising strategy in anti-proliferative drug discovery. In this work, an integrated computational approaches were performed on 67 c-Met inhibitors to explore the structural requirements for their activity. Molecular docking was performed to elucidate their binding mode in c-Met active site. Subsequently, 3D-QSAR models were constructed using comparative molecular filed analysis (CoMFA q² = 0.692, r² = 0.912 and r² _pred = 0.897) and comparative molecular similarity indices analysis (CoMSIA q² = 0.751, r² = 0.946 and r² _pred = 0.944) techniques. The CoMSIA map analysis showed that hydrophobic contours play key role for inhibitory activity. According to docking and 3D-QSAR results, A total of 31 novel c-Met inhibitors with predicted improved activity were designed. A 100 ns molecular dynamics simulation and binding free energy calculations using the MM-PBSA method revealed the stability of the designed compound D12 inside the c-Met active site. In summary , the results of our study could provide significant insight for future design and development of novel c-Met kinase inhibitors.