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.

Keywords: Binding free energy; Consensus docking; Molecular dynamics simulation; Natural products; c-Met inhibitor.

Fig. 1

Flowchart of the consensus docking procedure followed to choose hit compounds with c-Met kinase inhibitory activity

Fig. 2

Binding poses of the two hit molecules: a 1R0P in complex with ZINC08234189, and b 2RFS in complex with ZINC03871891. The N and C lobes of tyrosine kinase domain are shown in cyan and green, respectively. The predicted binding mode using Autodock 4.2 and Vina are displayed in blue and yellow stick representation, respectively. Key residues involved in interaction are represented in the stick format. The length of Hydrogen bonds colored as yellow dotted lines is indicated in Angstrom (color figure online)

Fig. 3

Pharmacophore features of the two hit molecules. a ZINC08234189 b ZINC03871891. Aromatic, hydrogen donor, hydrogen acceptor, and hydrophobic features are shown in violet, white, orange, and green spheres, respectively (color figure online)

Fig. 4

Root mean square deviation (RMSD) of the Cα atoms of the inactive (1R0P) and active (2RFS) conformation and ligand heavy atoms against the initial structure over 20 ns MD simulation. a 1R0P, b 2RFS, c RMSD of ligand backbone in complex with 1R0P, d RMSD of ligand backbone in complex with 2RFS

Fig. 5

Superimposed structures of c-Met inhibitors using Autodock Vina (green with a blue ligand) and MD-averaged structure of the last 5 ns (cyan with a yellow ligand) (color figure online)

Fig. 6

Root mean square fluctuations (RMSF) analysis of c-Met kinase domain residues in the presence and absence of hit molecules over 20 ns MD simulation period. a 1R0P, b 2RFS

Fig. 7

Radius of gyration of c-Met kinase domain in the presence and absence of hit molecules over 20 ns MD simulation period. a 1R0P, b 2RFS