A CoMFA study of COX-2 inhibitors with receptor based alignment

Datar, Prasanna A.; Coutinho, Evans C.

doi:10.1016/j.jmgm.2004.07.003

Cited by 23 publications

(15 citation statements)

References 34 publications

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“…The approach was tested on a diverse set of COX-2 inhibitors. The CoRIA models have a good correlation coefficient (r 2 ) and predictive power (q 2 ) compared to previously reported [62][63][64][65][66] 3D-QSAR models for COX-2 inhibitors.…”

Section: Discussionmentioning

confidence: 65%

“…Further, when the analysis is run using only the molecular descriptors (D), the r 2 obtained is~0.5 and the above mentioned terms are associated with very small coefficients. There are several QSAR models reported for COX-2 inhibitors in the literature [62][63][64][65][66]. The CoMFA model developed by Desiraju et al [62], where a limited set of 1,2-diarylimidazole derivatives were minimized with constraints and aligned to the X-ray conformation of SC-558, has a q 2 of 0.56 and a r pred 2 of 0.79 for the test set.…”

Section: Resultsmentioning

confidence: 99%

“…The r pred 2 is for large diverse test set in our study, which is limited to a structural class in each of three studies mentioned above. We had previously reported a CoMFA study of COX-2 inhibitors, using two strategies for generating conformations and alignment of the molecules; one based on 'template-forcing' on to SC-558, and other based on 'flexible docking' [65]. The CoMFA model based on 'template forcing' has a q 2 of 0.66 and an r pred 2 of 0.63, while the CoMFA model developed with 'flexible docking' has a q 2 of 0.73 and an r pred 2 of 0.76.…”

Section: Resultsmentioning

confidence: 99%

“…This result parallels the observation in the present CoRIA models, which suggests that it is important to decrease the van der Waals interactions particularly with residues Tyr385, Tyr115 and Arg433 to improve the activity. The training set used in the previous study [65] and the one in the present CoRIA study are not exactly the same. For comparison purposes, we have developed a CoMFA model using the present training set of 36 molecules.…”

Section: Resultsmentioning

confidence: 99%

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Comparative residue interaction analysis (CoRIA): a 3D-QSAR approach to explore the binding contributions of active site residues with ligands

Datar

Khedkar

Malde

et al. 2006

J Comput Aided Mol Des

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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.

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Section: Discussionmentioning

confidence: 65%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 2 more Smart Citations

Comparative residue interaction analysis (CoRIA): a 3D-QSAR approach to explore the binding contributions of active site residues with ligands

Datar

Khedkar

Malde

et al. 2006

J Comput Aided Mol Des

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“…This technique is often referred to as "receptor-based alignment" or "docking-based alignment" [15], and is known to produce better models than the standard procedure of atom-based alignment.…”

Section: Docking As a Methods Of Alignmentmentioning

confidence: 99%

De novo design of 7-aminocoumarin derivatives as novel falcipain-3 inhibitors

2011

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The availability of the crystal structure of falcipain-3, knowledge of the peptides carrying the 7-aminocoumarin moiety as falcipain-3 ligands/substrates, and a need for new antimalarial agents stimulated us to look at the possibility of finding some novel falcipain-3 inhibitors. In this paper, we report the effect of substitution at the 7-amino position of the coumarin nucleus on the inhibition of falcipain-3, which is a well-validated antimalarial target. The de novo drug design was assisted by QSAR studies that shed light on the binding patterns of known and the newly designed inhibitors, thus taking this discovery process to the next level.

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Preclinical Development Handbook

Gad¹

2007

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A CoMFA study of COX-2 inhibitors with receptor based alignment

Cited by 23 publications

References 34 publications

Comparative residue interaction analysis (CoRIA): a 3D-QSAR approach to explore the binding contributions of active site residues with ligands

Comparative residue interaction analysis (CoRIA): a 3D-QSAR approach to explore the binding contributions of active site residues with ligands

De novo design of 7-aminocoumarin derivatives as novel falcipain-3 inhibitors

Preclinical Development Handbook

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