Insight into crucial inhibitor–enzyme interaction of arylamides as novel direct inhibitors of the enoyl ACP reductase (InhA) from Mycobacterium tuberculosis: computer-aided molecular design

The enoyl ACP reductase enzyme (InhA) involved in the type II fatty acid biosynthesis pathway of Mycobacterium tuberculosis is an attractive target enzyme for antitubercular drug development. Arylamide derivatives are a novel class of InhA inhibitors used to overcome the drug-resistance problem of isoniazid, the frontline drug for tuberculosis treatment. Their remarkable property of inhibiting the InhA enzyme directly without requiring any coenzyme, makes them especially appropriate for the design of new antibacterials. In order to find a sound binding conformation for the different arylamide analogs, molecular docking experiments were performed with subsequent QSAR investigations. The X-ray conformation of one arylamide within its cocrystallized complex with InhA was used as a starting conformation for the docking experiments. The results thus obtained are perfectly consistent (rmsd = 0.73 Å) with the results from X-ray analysis. A thorough investigation of the arylamide binding modes with InhA provided ample information about structural requirements for appropriate inhibitor–enzyme interactions. Three different QSAR models were established using two three-dimensional (CoMFA and CoMSIA) and one two-dimensional (HQSAR) techniques. With statistically ensured models, the QSAR results obtained had high correlation coefficients between molecular structure properties of 28 arylamide derivatives and their biological activity. Molecular fragment contributions to the biological activity of arylamides could be obtained from the HQSAR model. Finally, a graphic interpretation designed in different contour maps provided coincident information about the ligand–receptor interaction thus offering guidelines for syntheses of novel analogs with enhanced biological activity.

MONATSHEFTE FÜR CHEMIE / CHEMICAL MONTHLY

DOI: 10.1007/s00706-010-0359-4