ONIOM study of the nonbonding interaction of the 2PU inhibitor with the CDK2 and CDK4 cyclin‐dependant kinases

Abstract

ABSTRACT:We discuss in this article, the applicability of hybrid techniques [especially the our-own N-layered integrated molecular orbital and molecular mechanics (ONIOM) method] to weak chemical interactions in large systems, such as the interaction of cyclin-dependant kinases, CDK4, and CDK2, with a specific ligand (2PU) showing selectivity for CDK4. Our results show that the energies from the ONIOM calculations perfectly match our former molecular dynamics results, both for determining the amino acids which have strongest interactions with the ligand and for explaining the selectivity of 2PU towards CDK4, as compared with CDK2. We show that the ONIOM method is a good candidate for studying such interactions in large systems, even though there are still some technical and theoretical problems to solve. The calculation details will be presented together with the methodology we devised for using the ONIOM approach in such a context.

Interaction Mechanism of Flavonoids and α-Glucosidase: Experimental and Molecular Modelling Studies

“…Zeng et al (2016) investigated the binding modes of two isoflavones (daidzein and genistein) with trypsin using molecular docking methods [19]. Li et al (2009) clarified the interaction mechanism of the cyclin-dependent kinases (CDK2 and CDK4) and their inhibitor (2PU) based on ONIOM calculations [20]. In 2017, Lefebvre et al presented a new approach, the independent gradient model (IGM), which enabled the automatic identification and visualization of covalent and non-covalent interactions of atoms/fragments in the 3D real space using pro-molecular density [21].…”

Simulation with quantum mechanics/molecular mechanics for drug discovery

“…There are only a few works which report the testing of several QM area sizes in a study. For example, Li and F. Barbault & F. Maurel collaborators had tested this QM area size effect on the interaction energy of a CDK2 kinase inhibitor [72]. They found that a proper definition of the QM size is crucial and especially when charged amino-acids are encompassed in the QM area.…”