Development of efficient docking strategies and structure-activity relationship study of the c-Met type II inhibitors

Abstract

Graphical AbstractTOC c-Met is a tyrosine kinase and an important therapeutic target for anticancer drugs. In present study, we systematically investigated the influence of a range of parameters on the correlation between experimental and calculated binding energies of type II c-Met inhibitors. Results from this study will form the basis for establishing an efficient computational docking approach for c-Met type II inhibitors design. Highlights• Testing a set of influences to the ranking ability of the docking program in MOE.• Structure-activity relationship study of c-Met type II inhibitors.• Establishing an efficient computational docking approach for c-Met type II inhibitors design.ABSTRACT： c-Met is a transmembrane receptor tyrosine kinase and an important therapeutic target for anticancer drugs. In the present study, we systematically investigated the influence of a range of parameters on the correlation between experimental and calculated binding free energies of type II c-Met inhibitors. We especially focused on evaluating the impact of different force fields, binding energy calculation methods, docking protocols, conformation sampling strategies, and conformations of the binding site captured in several crystallographic structures. Our results suggest that the force fields, the protein flexibility, and the selected conformation of the binding site substantially influence the correlation coefficient, while the sampling strategies and ensemble docking only mildly affect the prediction accuracy. Structure-activity relationship study suggests that the structural determinants to the high binding affinity of the type II inhibitors originate from its overall linear shape, hydrophobicity, and two conserved hydrogen bonds. Results from this study will form the basis for establishing an efficient computational docking approach for c-Met type II inhibitors design.

Osimertinib and Cabozantinib Combinatorial Therapy in an EGFR -Mutant Lung Adenocarcinoma Patient with Multiple MET Secondary-Site Mutations after Resistance to Crizotinib

“…[1][2][3][4] Type II inhibitors, such as cabozantinib, bind to an inactive conformation of MET, inhibiting a broader array of kinase targets. 5 A limited number of studies have reported MET inhibitor-associated resistance. In this study, we have described a patient with EGFR-mutant lung adenocarcinoma clinically benefitting from combinatorial therapy of osimertinib and cabozantinib after simultaneous development of four MET mutations upon crizotinib treatment.…”

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

“…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.…”

Design, Synthesis, and Biological Evaluation of Pyridineamide Derivatives Containing a 1,2,3-Triazole Fragment as Type II c-Met Inhibitors

“…c-Met inhibitors are classified as type I and type II inhibitors according to the binding mode of inhibitors with c-Met. Usually, c-Met inhibitors of type I are single-target inhibitors that bind to the hinge region of the ATP pocket, and c-Met inhibitors of type II are multitarget inhibitors that bind to the hinge region and an extra hydrophobic pocket [8,9]. With the development of biology and pharmacology, the intracellular mechanisms have been elucidated, and research in small molecule inhibitors has made significant progress.…”