Classical MD and metadynamics simulations on back-pocket binders of CDK2 and VEGFR2: a guidepost to design novel small-molecule dual inhibitors

Abstract

Cyclin-Dependent Kinase 2 (CDK2) and Vascular-Endothelial Growth Factor Receptor 2 (VEGFR2) are promising targets for the design of novel inhibitors in anticancer therapeutics. In a recent work, our group designed a set of potential dual inhibitors predicted to occupy an allosteric back pocket near the active site of both enzymes, but their dynamic and unbinding behavior was unclear. Here, we used molecular dynamics (MD) and metadynamics (meta-D) simulations to study two of these virtual candidates (herein called IQ2 and IQ3). Their binding mode was predicted to be similar to that observed in LQ5 and BAX, well-known back-pocket binders of CDK2 and VEGFR2, respectively, including H-bonding with critical residues such as Leu83/Cys113 and Asp145/Asp190 (but excepting H-bonding with Glu51/Glu111) in CDK2/VEGFR2, correspondingly. Likewise, while LQ5 and BAX unbound through the allosteric channel as expected for type-IIA inhibitors, IQ2 and IQ3 unbound via the ATP channel (except for CDK2-IQ2) as expected for type-I½A inhibitors. Interestingly, a C-C single/double bond difference between IQ2/IQ3, respectively, resulted associated with differences in the AS/T loop flexibility observed for CDK2. These insights will help developing scaffold modifications during an optimization stage, serving as a starting point to develop dual kinase inhibitors in challenging biological targets with a promising anticancer potential.

Communicated by Ramaswamy H. Sarma

Keywords:

• Molecular dynamics simulations
• metadynamics
• back-pocket binders
• dual inhibitors
• protein kinases

Acknowledgements

We acknowledge funds from the Colombian Ministry of Science, Technology and Innovation MINCIENCIAS Grant No. 727. Also, we thank funding sources from Universidad de los Andes under Educational Loan Program for Doctoral Students (Vice-Rectory of Research and Creation) and the Doctoral Studies Support Program of the Faculty of Engineering.

Disclosure statement

No potential conflict of interest was reported by the authors.

Data availability

The raw data supporting the conclusions of this manuscript will be made available by the authors, without undue reservation, to any qualified researcher.

Additional information

Funding

Colombian Ministry of Science, Technology and Innovation – MINCIENCIAS.