A 3D-QSAR Analysis of CDK2 Inhibitors Using FMO Calculations and PLS Regression

• Published in: Chemical & pharmaceutical bulletin Vol. 67; no. 6; pp. 546 - 555
• Main Authors: Yoshida, Tomoki, Hirono, Shuichi
• Format: Journal Article
• Language: English; Japanese
• Published: Japan The Pharmaceutical Society of Japan 01.06.2019; Pharmaceutical Society of Japan; Japan Science and Technology Agency
• Subjects: Amino acids; Binding energy; Binding Sites; Biological activity; Coordination compounds; Cyclin-dependent kinase 2; Cyclin-Dependent Kinase 2 - antagonists & inhibitors; fragment molecular orbital; Inhibitors; Least-Squares Analysis; Ligands; Molecular Docking Simulation; Molecular orbitals; partial least squares; Protein Binding; Protein Kinase Inhibitors - chemistry; Protein Structure, Tertiary; Proteins; protein–ligand interaction; Quantitative Structure-Activity Relationship; Regression analysis; Structure-activity relationships; Thermodynamics; Three dimensional models; partial least squares; protein–ligand interaction; fragment molecular orbital
• ISSN: 0009-2363; 1347-5223
• DOI: 10.1248/cpb.c18-00990

We report a three-dimensional quantitative structure–activity relationship (3D-QSAR) analysis of CDK2 inhibitors using fragment molecular orbital (FMO) calculations and partial least squares (PLS) regression. In our analysis, fragment binding energies of individual amino acids and fragment binding energy of a single ligand in a protein–ligand complex are evaluated by FMO calculations and used as descriptors in PLS regression to estimate biological activities of the ligands. The analysis was applied to the system of CDK2 protein and its inhibitors and the effectiveness of the method was tested. Application of the 3D-QSAR model demonstrated that it offered good predictive ability and was able to predict not only biological activity of ligands but also identify important amino acid residues which could be targeted in order to improve ligand activity.