title: Molecular docking and 3D QSAR studies of Chk2 inhibitors.
abstract: Isothiazole-carboxamidines are potent ATP competitive checkpoint kinases (Chk2) inhibitors. Three-dimensional quantitative structure-activity relationship models were developed using comparative molecular field analysis and comparative molecular similarity indices analysis. The study was performed using three different geometrical methods. In geometrical method-1, molecules were fully optimized by PM3 Hamiltonian and aligned using common substructure. This alignment was subsequently used for Ligand-based comparative molecular field analysis and comparative molecular similarity indices analysis. In receptor-guided analyses, the receptor coordinates were obtained from public domine (PDB 2cn8). The molecule-7 was docked into receptor protein using FlexX and two plausible binding modes were identified. These modes were used as templates for geometrical method-2 and 3. These methods were used for 3D QSAR. The geometrical method-3-based comparative molecular field analysis (q(2) = 0.75, r(2) = 0.87 and r(2) (predict) = 0.81) and comparative molecular similarity indices analysis (q(2) = 0.90, r(2) = 0.96 and r(2) (predict) = 0.75) gave better result. The steric, hydrophobic and hydrogen bond donor fields effects significantly contribute to activity. In this way, the receptor-guided study presents a more detailed understanding about chk2 active site interactions. The study indicated some modifications to the active molecule which might be valuable to improve the activity.
authors.affiliation: Computational Science Center, Future Fusion Technology Division, Korea Institute of Science and Technology, PO Box 131, Seoul 130-650, South Korea.
authors.forename: Fahran Ahmad
authors.initials: FA
authors.lastname: Pasha
authors.forename: Muhammad
authors.initials: M
authors.lastname: Muddassar
authors.forename: Seung
authors.initials: S
authors.lastname: Joo Cho
mesh_terms: D064447:Checkpoint Kinase 2; D003198:Computer Simulation; D008958:Models, Molecular; D015233:Models, Statistical; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D021281:Quantitative Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D064447:Checkpoint Kinase 2; D017346:Protein Serine-Threonine Kinases