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Role of Interactions and Volume Variation in Discriminating Active and Inactive Forms of Cyclin-Dependent Kinase-2 Inhibitor Complexes By:Saranya, N (Saranya, Nallusamy)[ 1 ] ; Selvaraj, S (Selvaraj, Samuel)[ 1 ] CHEMICAL BIOLOGY & DRUG DESIGN Volume: 78 Issue: 3 Pages: 361-369 DOI: 10.1111/j.1747-0285.2011.01145.x Published: SEP 2011 View Journal Information Abstract Molecular recognition process occurs through various non-bonded interactions in protein-ligand complexes. Analysis and visualization of interactions in a set of protein-ligand complexes provide insight for structure-based drug design. In the present study, we have made a comprehensive analysis on similarities and differences observed in hydrophobic interactions and hydrogen bond interactions of 170 X-ray crystal structures of active and inactive cyclin-dependent kinase-2 (CDK-2) ligand complexes obtained from the Protein Data Bank. We have also systematically analyzed variation of protein binding cavity volume (PCV) and ligand volume (LV) in CDK-2 ligand complexes. Hierarchical clustering of interaction patterns of CDK-2 ligands have been carried out in active and inactive forms. In PCV and LV analysis, PCV variation was observed to be high for inactive conformation and less for active conformation; the latter was found to bind ligands with higher volume. Further, correlation of interactions, PCV, and LV with the binding affinity was analyzed in active and inactive forms. Analysis of interactions and volume changes revealed the marked difference in CDK-2 active and inactive conformations. In conclusion, this study highlights the importance of considering inactive conformation in the docking and scoring methods to attain selectivity and potency. Keywords Author Keywords:Binding affinity; cluster analysis; cyclin-dependent kinase-2; hydrogen bond; hydrophobic interaction; inhibitors KeyWords Plus:SMALL-MOLECULE-BINDING; PROTEIN FLEXIBILITY; DRUG DESIGN; CRYSTAL-STRUCTURE; SCORING FUNCTION; CDK2 INHIBITORS; DOCKING; PREDICTION; SITES; MODES Author Information Reprint Address: Selvaraj, S (reprint author) Bharathidasan Univ, Dept Bioinformat, Sch Life Sci, Tiruchchirappalli 620024, Tamil Nadu, India. Addresses: [ 1 ] Bharathidasan Univ, Dept Bioinformat, Sch Life Sci, Tiruchchirappalli 620024, Tamil Nadu, India E-mail Addresses:[email protected] Funding Funding Agency Grant Number University Grants Commission, New Delhi View funding text Publisher WILEY-BLACKWELL, COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA Categories / Classification Research Areas:Biochemistry & Molecular Biology; Pharmacology & Pharmacy Web of Science Categories:Biochemistry & Molecular Biology; Chemistry, Medicinal Document Information Document Type:Article Language:English Accession Number: WOS:000294990900004 PubMed ID: 21599856 ISSN: 1747-0277 Other Information IDS Number: 821RA Cited References in Web of Science Core Collection: 47 Times Cited in Web of Science Core Collection: 0
