Molecular docking and 3D QSAR studies of Chk2 inhibitors.
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.
Pasha
Fahran Ahmad
FA
Computational Science Center, Future Fusion Technology Division, Korea Institute of Science and Technology, PO Box 131, Seoul 130-650, South Korea.
Muddassar
Muhammad
M
Joo Cho
Seung
S
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
D047428:Protein Kinase Inhibitors; D064447:Checkpoint Kinase 2; D017346:Protein Serine-Threonine Kinases