Studies On Design Of Dual Target Kinase Inhibitors And Dissociation Pathway Of Type â…¡ Inhibitor

Constituting about1.7%of all human genes,518different human protein kinasescan be categorized into about20groups based on structural similarities, and they areinvolved in a variety of important signal transduction and other cellular processes, suchas metabolism, transcription, apoptosis, differentiation, cell cycle progression,cytoskeletal rearrangement, cell movement, etc. The overexpress of protein kinase isrelated to many diseases, such as cancers, hypertension, Parkinson, inflammatory andautoimmune diseases. A large number of kinase inhibitors have been in clinical trials oreven pushed into market, and furthermore, the kinase-related basic research has madesignificant progress.Highly selective drug candidates against an individual target may be not quiteefficacious for many complicated diseases, and they are possibly more prone to drugresistance. The performance of molecular docking to search dual-target inhibitors forfour kinase pairs was evaluated. First, the representative structures for each kinase targetwere chosen by structural clustering of available crystal structures and used as thetemplate for molecular docking to distinguish inhibitors from non-inhibitors. The resultsillustrate that docking-based virtual screening has good capability to distinguish knowninhibitors from individual targets. Then, the performance of molecular docking toidentify dual-target kinase inhibitors for four kinase pairs was evaluated. The analysesshow that molecular docking can successfully filtering out most non-inhibitors andpredicted dual inhibitors well for two kinase pairs, but high false-positive rate leads tolow enrichment of true dual-target inhibitors in the final list. Umbrella sampling and MM/GBSA were employed to explore the possibledissociation pathway of the type II inhibitor from the binding pocket of p38MAPkinase. First, conventional molecular dynamics (CMD) simulations were performed toequilibrate the systems. Then, umbrella sampling was employed to pull the type IIinhibitor out of the binding pocket, and the WHAM technique was used to generatePMF. Finally, MM/GBSA was utilized to judge whether the type II inhibitor was outsideof the binding pocket and balanced. The results demonstrate that the most favorablepathway for the inhibitor/p38MAP kinase dissociation is the allosteric-pocket-channelrather than the ATP-pocket channel. Despite the fact that the value of the binding freeenergy calculated by MM/GBSA is much larger than the experimental data, it is also agood method to judge whether the inhibitor is outside of the pocket or not by comparingthe ΔΔGs of two pocket channel systems. Thus, combining the umbrella sampling andMM/GBSA is an effective method to analyze the entry/exit pathway.