caa a22 4500 467938717 CHVBK 20180406153005.0 cr unu---uuuuu 170328e20060601xx s 000 0 eng 10.1007/s10822-006-9051-5 doi (NATIONALLICENCE)springer-10.1007/s10822-006-9051-5 Comparative residue interaction analysis (CoRIA): a 3D-QSAR approach to explore the binding contributions of active site residues with ligands [Elektronische Daten] [Prasanna Datar, Santosh Khedkar, Alpeshkumar Malde, Evans Coutinho] A novel approach termed comparative residue-interaction analysis (CoRIA), emphasizing the trends and principles of QSAR in a ligand-receptor environment has been developed to analyze and predict the binding affinity of enzyme inhibitors. To test this new approach, a training set of 36 COX-2 inhibitors belonging to nine families was selected. The putative binding (bioactive) conformations of inhibitors in the COX-2 active site were searched using the program DOCK. The docked configurations were further refined by a combination of Monte Carlo and simulated annealing methods with the Affinity program. The non-bonded interaction energies of the inhibitors with the individual amino acid residues in the active site were then computed. These interaction energies, plus specific terms describing the thermodynamics of ligand-enzyme binding, were correlated to the biological activity with G/PLS. The various QSAR models obtained were validated internally by cross validation and boot strapping, and externally using a test set of 13 molecules. The QSAR models developed on the CoRIA formalism were robust with good r 2, q 2 and r pred 2 values. The major highlights of the method are: adaptation of the QSAR formalism in a receptor setting to answer both the type (qualitative) and the extent (quantitative) of ligand-receptor binding, and use of descriptors that account for the complete thermodynamics of the ligand-receptor binding. The CoRIA approach can be used to identify crucial interactions of inhibitors with the enzyme at the residue level, which can be gainfully exploited in optimizing the inhibitory activity of ligands. Furthermore, it can be used with advantage to guide point mutation studies. As regards the COX-2 dataset, the CoRIA approach shows that improving Coulombic interaction with Pro528 and reducing van der Waals interaction with Tyr385 will improve the binding affinity of inhibitors. Springer Science+Business Media B.V., 2006 CoRIA nationallicence COX-2 nationallicence Docking nationallicence G/PLS statistics nationallicence Simulations nationallicence QSAR nationallicence Datar Prasanna Department of Pharmaceutical Chemistry, Bombay College of Pharmacy, Kalina, Santacruz (E), 400 098, Mumbai, India aut Khedkar Santosh Department of Pharmaceutical Chemistry, Bombay College of Pharmacy, Kalina, Santacruz (E), 400 098, Mumbai, India aut Malde Alpeshkumar Department of Pharmaceutical Chemistry, Bombay College of Pharmacy, Kalina, Santacruz (E), 400 098, Mumbai, India aut Coutinho Evans Department of Pharmaceutical Chemistry, Bombay College of Pharmacy, Kalina, Santacruz (E), 400 098, Mumbai, India aut Journal of Computer-Aided Molecular Design Kluwer Academic Publishers 20/6(2006-06-01), 343-360 0920-654X 20:6<343 2006 20 10822 https://doi.org/10.1007/s10822-006-9051-5 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s10822-006-9051-5 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Datar Prasanna Department of Pharmaceutical Chemistry, Bombay College of Pharmacy, Kalina, Santacruz (E), 400 098, Mumbai, India aut NATIONALLICENCE 700 1- Khedkar Santosh Department of Pharmaceutical Chemistry, Bombay College of Pharmacy, Kalina, Santacruz (E), 400 098, Mumbai, India aut NATIONALLICENCE 700 1- Malde Alpeshkumar Department of Pharmaceutical Chemistry, Bombay College of Pharmacy, Kalina, Santacruz (E), 400 098, Mumbai, India aut NATIONALLICENCE 700 1- Coutinho Evans Department of Pharmaceutical Chemistry, Bombay College of Pharmacy, Kalina, Santacruz (E), 400 098, Mumbai, India aut NATIONALLICENCE 773 0- Journal of Computer-Aided Molecular Design Kluwer Academic Publishers 20/6(2006-06-01), 343-360 0920-654X 20:6<343 2006 20 10822 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer