Elucidating drug-enzyme interactions and their structural basis for improving the affinity and potency of isoniazid and its derivatives based on computer modeling approaches.

The enoyl-ACP reductase enzyme (InhA) from M. tuberculosis is recognized as the primary target of isoniazid (INH), a first-line antibiotic for tuberculosis treatment. To identify the specific interactions of INH-NAD adduct and its derivative adducts in InhA binding pocket, molecular docking calculations and quantum chemical calculations were performed on a set of INH derivative adducts. Reliable binding modes of INH derivative adducts in the InhA pocket were established using the Autodock 3.05 program, which shows a good ability to reproduce the X-ray bound conformation with rmsd of less than 1.0 A. The interaction energies of the INH-NAD adduct and its derivative adducts with individual amino acids in the InhA binding pocket were computed based on quantum chemical calculations at the MP2/6-31G (d) level. The molecular docking and quantum chemical calculation results reveal that hydrogen bond interactions are the main interactions for adduct binding. To clearly delineate the linear relationship between structure and activity of these adducts, CoMFA and CoMSIA models were set up based on molecular docking alignment. The resulting CoMFA and CoMSIA models are in conformity with the best statistical qualities, in which r2cv is 0.67 and 0.74, respectively. Structural requirements of isoniazid derivatives that can be incorporated into the isoniazid framework to improve the activity have been identified through CoMFA and CoMSIA steric and electrostatic contour maps. The integrated results from structure-based, ligand-based design approaches and quantum chemical calculations provide useful structural information facilitating the design of new and more potentially effective antitubercular agents as follow: the R substituents of isoniazid derivatives should contain a large plane and both sides of the plane should contain an electropositive group. Moreover, the steric and electrostatic fields of the 4-pyridyl ring are optimal for greater potency.