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.

GRAPHICAL ABSTRACT

KEYWORDS:

• C-Met kinase
• 3D-QSAR
• molecular docking
• molecular dynamics simulation
• MM-PBSA

Acknowledgements

The authors gratefully acknowledge the Sheikh Bahaei National High Performance Computing Centre (SBNHPCC) for providing computing facilities and time. SBNHPCC is supported by scientific and technological department of presidential office and Isfahan University of Technology (IUT).

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by Isfahan University of Medical Sciences.