Computer-aided molecular design of potent antitubercular agents highly specific to Mycobacterium tuberculosis CYP130

Cytochrome P450 (CYPs) enzymes were discovered about 50 years ago and they belong to the super family of proteins containing a heme cofactor. They can be found in many organisms such as bacteria, fungi, plants, and animals. There are 61 CYP genes in humans, and these form 18 families and 43 sub-families. CYP130 is one of the 20 Mycobacterium tuberculosis cytochrome P450 enzymes and is one of three protiens (CYP51, CYP121, and CYP130) that have been studied in detail so that each individual was expressed and the 3D structure was determined. Recently, CYP121 enzyme was shown to catalyze the C-C reaction of tyrosine. For CYP130, the gene is missing in the virulent Mycobacterium bovis BCG strain and avirulent counterpart, Mycobacterium bovis BCG. This suggests that CYP130 is not essential for Mycobacterium bovis BCG growth, but may be relevant for Mycobacterium tuberculosis virulence and infectivity towards the human host. The potential of Mycobacterium tuberculosis CYP130 for pharmacologic development was initially suggested by their susceptibility to inhibition by antifungal azole drugs such as fluconazole, econazole, ketonazole, and clotrimazole. Based on the potential antitubercular agents of the azole drugs, monocyclic nitroimidazoles as econazole derivatives were developed and shown to be active against Mycobacterium tuberculosis. In the present study, molecular modeling approaches were employed to carry out the beneficial information at the molecular level for the development of a new and more potent CYP130 inhibitor. To identify the specific interactions of econazole derivatives in CYP130 binding pocket, molecular docking calculations were performed. The molecular docking results provided significant insight into inhibitor-enzyme interactions of the econazole derivatives. Results revealed that the hydrogen bond interacytions were main interactions. Moreover, to clearly delineate the linear relationship between the structure and activity of econazole derivatives, QSAR studies were performed. The obtained CoMSIA results showed high correlation between the molecular properties and the biological activities of the econazole derivatives. A graphic interpretation derived from different contour maps provided a structural requirement and important information about inhibitor-enzyme interactions, thus offering guidelines for the synthesis of a novel and more potent CYP130 inhibitor. To achieve more details about the structural basis important for the improvement of antimycobacterial activity, the dynamic behaviors of CYP130 inhibitor and econazole derivatives were investigated by molecular dynamics (MD) simulations. Moreoover, Thai natural database was screened by the virtual screening method to indentify new active substances with high potential to inhibit the Mycobacterium tuberculosis CYP130. Consequently, the results integrated from structure-based and ligand-based design approaches can provide crucial structural information at the molecular level which is beneficial guideline in the design of effective antitubercular agents.