Identification of Phytochemicals Targeting c-Met Kinase Domain using Consensus Docking and Molecular Dynamics Simulation Studies

Abstract

c-Met receptor tyrosine kinase is a proto-oncogene whose aberrant activation is attributed to a lower rate of survival in most cancers. Natural product-derived inhibitors known as "fourth generation inhibitors" constitute more than 60% of anticancer drugs. Furthermore, consensus docking approach has recently been introduced to augment docking accuracy and reduce false positives during a virtual screening. In order to obtain novel small-molecule Met inhibitors, consensus docking approach was performed using Autodock Vina and Autodock 4.2 to virtual screen Naturally Occurring Plant-based Anti-cancer Compound-Activity-Target database against active and inactive conformation of c-Met kinase domain structure. Two hit molecules that were in line with drug-likeness criteria, desired docking score, and binding pose were subjected to molecular dynamics simulations to elucidate intermolecular contacts in protein-ligand complexes. Analysis of molecular dynamics simulations and molecular mechanics Poisson-Boltzmann surface area studies showed that ZINC08234189 is a plausible inhibitor for the active state of c-Met, whereas ZINC03871891 may be more effective toward active c-Met kinase domain compared to the inactive form due to higher binding energy. Our analysis showed that both the hit molecules formed hydrogen bonds with key residues of the hinge region (P1158, M1160) in the active form, which is a hallmark of kinase domain inhibitors. Considering the pivotal role of HGF/c-Met signaling in carcinogenesis, our results propose ZINC08234189 and ZINC03871891 as the therapeutic options to surmount Met-dependent cancers.

Large-Scale Virtual Screening Against the MET Kinase Domain Identifies a New Putative Inhibitor Type

“…Molecular docking, molecular dynamics, and virtual screening approaches can now be efficiently used for the design of new inhibitors of the MET kinase domain [27,56,[76][77][78][79][80]. From all these approaches, new potent compounds were obtained and more highlights revealed about MET kinase domain conformational behavior.…”

“…We reasoned that it should be taken into account for designing drugs with improved efficiency and selectivity profiles [25,26]. To be efficient, the molecular docking engines embedded within the virtual screening approaches must be adapted to handle such flexibility [27,28]. In the present work, we used the ensemble-docking strategy-previously recognized for its efficiency in drug design [29]-and show the benefit of an investigation using a large ensemble-docking on MET.…”

MicroRNA‑200a suppresses migration and invasion and enhances the radiosensitivity of NSCLC cells by inhibiting the HGF/c‑Met signaling pathway

“…In recent years, an increasing number of studies have demonstrated that several inhibitors can specifically target HGF/c-Met in various types of cancer (38,39). Several c-Met inhibitors are currently under clinical studies (40,41). In addition, HGF analogues, anti-HGF humanized antibodies and c-Met induced receptor antibodies directed against the c-Met extracellular domain are being used to prevent HGF-specific binding and activation of c-Met (42,43).…”

Key Topics in Molecular Docking for Drug Design

“…Other reported strategies for achieving scoring function consensus are sequential docking [117,118], linear regression [119], rank-by-rank, rank-by-number, rank-by-vote [86,107,120] and standard deviation consensus [121]. Combinations of consensus docking strategies and ligand-based approaches have also been suggested [122,123].…”