CDK HIV-1 Integrase protease HAT GPCR Retniblastoma


  Cyclin-dependent kinases (CDKs) belong to the family of serine/threonine kinases that play a key role in the regulation and increasingly being identified as important target for therapeutic intervention in cancer. Crystallography has revealed that the ATP-binding site of CDK2 can accommodate a number of diverse molecular frameworks, exploiting various sites of interaction. Basically, we have been exploring ways of optimizing lead compounds against CDK2. We have made an effort to find out potential and explore the putative binding modes with various series of CDK2 inhibitors by using homology modeling, multiple docking (RRD, IFD and QPLD) with different semi-empirical and ab intio charge model, free energy calculation and molecular dynamics simulation studies. In another stage of the results are evaluated through combined QM/MM interaction energy, and subsequently the best candidates are re-evaluated through calculation of some quantum chemical descriptors (MESP, HOMO/LUMO etc.) to successfully rank the novel CDK2 inhibitors. Examples include the HOMO and LUMO plot of active compound (up) and least-active compound (down), respectively of CDK2 inhibitor.
  Targeting the hydrophobic binding pocket of cyclin binding groove site of CDK2/cyclin A complex is an alternative approach in anti-cancer therapeutics. Currently available ATP inhibitors of CDK2 exhibiting higher toxicity and lack the specificity. Blocking the substrate recruitment site of cyclin binding groove gives the specific inhibition of CDK2 and induces the apoptosis. Designing of peptidomimetics inhibitors derived from cyclin recognizing motif region of various CIP/KIP family inhibitors and substrate activator proteins could specifically bind with cyclin binding groove. Implementation of REPLACE (REplacement with Partial Ligand Alternatives through Computational Enrichment) strategy can generate the peptidomimetic of protein‚ąíprotein interactions. The significant antitumor effects obtained through these peptidomimetics studies provides strong impetus for further drug development with the aim of obtaining more drug like small molecule inhibitors. In silico validation and screening of peptidomimetics as an effective strategy for converting peptidic compounds to more pharmaceutically relevant compounds.