Computational study of non-catalytic T-loop pocket on CDK proteins for drug development**Project supported by the National Natural Science Foundation of China (Grant No. 11704140), the Natural Science Foundation of Hubei Province, China (Grant No. 2017CFB116), the Thousand Talents Plan (Grant No. 31103201603), and the Self-determined Research Funds of CCNU from the Colleges’ Basic Research and Operation of MOE 20205170045 to

Abstract

Cyclin-dependent kinases (CDKs) are critical to the cell cycle and many other biological processes, and as such, are considered as one of the promising targets for therapy against cancer and other diseases. Most pan-CDK inhibitors bind to the highly conserved catalytic ATP-binding pocket and therefore lack the specificity to prevent side effects. It is desirable to develop drugs targeting non-catalytic pockets for specificity towards individual CDKs. Here we performed a systematic analysis of non-catalytic pockets on CDKs and identified a region underneath the T-loop, which we term TL pocket, for potential inhibitor development. Specifically, we compared the TL pockets of human CDK2 and CDK7-homolog Pfmrk of Plasmodium falciparum, a malaria-causing parasite. Molecular dynamics simulations of several short peptides revealed that this less conserved TL pocket could be used to design potentially specific inhibitors against malaria disease.