Abstract
The goal of this work is the development of novel peptides with high efficacy of inhibiting activity of CDK6/CyclinD complex. The peptides were derived from primary sequence of P16 protein and its homologues. The interactions between CDK6 and P16/INK4a-derived peptides are studied with molecular dynamics simulation employing umbrella sampling method. The SASA implicit solvent model was used for simulation, which was accelerated using NVIDIA GPUs.
Highlights
Cyclin-dependent kinases (CDKs) play a major role in cell cycle regulation and cell division progression
The interactions between CDK6 and P16/INK4a-derived peptides are studied with molecular dynamics simulation employing umbrella sampling method
Many pathological processes including malignant tumors of various locations associated with abnormalities in cell division process are caused by defects in CyclinD-CDK4/6 complex functioning, which are conditioned by hyperexpression of CyclinD or CDK4/6, mutation of intracellular inhibitors or a number of other processes
Summary
Cyclin-dependent kinases (CDKs) play a major role in cell cycle regulation and cell division progression. The correct performance of various cyclin-dependent kinases secures the sequential progression of numerous metabolic processes required for cell division. The CyclinD-CDK4/6 complex activity is regulated by proteins of CKI (Cyclin-dependent kinase inhibitors) family. Numerous low-molecular CDK inhibitors are known [1] Their major disadvantage is low selectivity since they are mimicking ATP and are competing with it for binding sites, which are homologous in most kinases, the problem of cross-reactivity arises [2]. The combination of CPP technology with highly selective functional sequences derived from natural regulatory proteins appears to be a promising approach for development of targeted drugs. The CDK6 protein is used as drug target, and the tested peptides were derived from p16/INK4a protein sequence
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