Comparative Analysis of Various Electrostatic Potentials on Docking Precision Against Cyclin‐Dependent Kinase 2 Protein: A Multiple Docking Approach

Abstract

The fundamental of molecular modeling is the interaction and binding to form a complex, because it explains the action of most drugs to a receptor active site. In the present study, different semiempirical (RM1, AM1, PM3, MNDO) and ab initio (HF, DFT) charge models were investigated for their performance in prediction of docking pose against CDK2 proteins with their respective inhibitor. Further, multiple docking approaches and Prime/MM-GBSA calculations were applied to predict the binding mode with respective charge model against CDK2 inhibitors. A reliable docking result was obtained using RRD, which showed significance improvement on ligand binding poses and docking score accuracy to the IFD. The combined use of RRD and Prime/MM-GBSA method could give a high correlation between the predicted binding free energy and experimental biological activity. The preliminary results point out that AM1 could be a precious charge model for design of new drugs with enhanced success rate. As a very similar result was also found for a different system of the protein-ligand binding, the suggested scoring function based on AM1 method seems to be applicable in drug design. The results from this study can provide insights into highest success rate for design of potent and selective CDK2 inhibitors.

A highly efficient sorbitol dehydrogenase from Gluconobacter oxydans G624 and improvement of its stability through immobilization

“…The bond orders, length, and angle were fixed and minimized with the Optimized Potentials for Liquid Simulations (OPLS-2005) force field as described previously 45 . After the protein and ligand structure was minimized and setup for the molecular modeling calculations through GLIDE grid generation, the grid was generated for both proteins 46 . Sitemap v3.6 was used to identify the five highest ranked potential binding sites for the prepared structures of GoSLDH and PfMDH using high accuracy and a restrictive hydrophobicity definition 47 .…”

Ligand-Binding Affinity Estimates Supported by Quantum-Mechanical Methods

“…Several reviews have been published on related subjects. − It is not trivial to delimit the subject, because essentially all MM force fields are partly based on QM parameters and nearly all computational studies of ligand binding involve some QM calculations, e.g., to obtain the atomic charges of the ligand. Therefore, we have restricted the review to studies that present estimates of Δ G bind involving explicit QM components, i.e., excluding papers only devoted to the structure of the RL complex or involving QM only to obtain parameters in the MM force field (e.g., quantum-polarized ligand docking and other methods to obtain system-specific QM charges ,− ). We also omit ligand-based (3D) quantitative structure–activity relationship (QSAR) methods, − QM studies of drug metabolism, or approaches to study enzyme mechanisms and reaction energies. ,− Moreover, the review is focused on method developments, i.e., papers with at least a partial focus on the methods.…”

Targeting the cyclin-binding groove site to inhibit the catalytic activity of CDK2/cyclin A complex using p27KIP1-derived peptidomimetic inhibitors

“…The notable results from MM-GBSA rescoring approach could be a more attractive alternative to the free energy perturbation (FEP) and thermodynamic integration (TI) methodologies for rank ordering. It can be as accurate approach to handle more structurally dissimilar ligands and more diverse set of pharmaceutically relevant targets, and structure-based lead optimization against CDK2 at a fraction of the computational cost [52][53][54]. Along with them, the MM-GBSA method is using a single minimized protein-ligand complex instead of ensembles of snapshots from MD trajectories.…”

“…Along with them, the MM-GBSA method is using a single minimized protein-ligand complex instead of ensembles of snapshots from MD trajectories. Therefore, it became an efficient method to refine and rescore docking screening results [52,54]. , and 17 have shared the same binding pocket, although they showed a difference in shape and electrostatic potential (Fig.…”