Computer-Aided Virtual Design of 3-Dehydroquinic Acid Analogues Inhibitors of Dehydroquinase Type II of Mycobacterium tuberculosis with Favorable Pharmacokinetics Profile

Abstract

New potent 3-dehydroquinic acid (AQs) inhibitors of 3-dehydroquinate dehydratase (dehydroquinase type II) of Mycobacterium tuberculosis (MtDHQ2) were obtained by using structure-based molecular design via the in situ modification of the template inhibitor AQ1 within the MtDHQ2-AQ1 crystal structure (PDB ID: 2XB8), in order to describe the interactions upon the formation of the complex MtDHQ2-inhibitor. A training set of 14 AQs with known inhibition constants (Kiexp) was used to establish a quantitative structure-activity relationship (QSAR) model for correlating the pKiexp (pKiexp = ‑log10 (Kiexp)) to the computed Gibbs free energies of formation (ΔΔGcom) of MtDHQ2-AQs complexes (pKiexp= -0.278 ΔΔGcom + 7.653 , R² = 0.98) is derived. This accounts for the solvent effect and the loss of inhibitor entropy upon enzyme binding. Validation of this QSAR model was performed with 3D- QSAR pharmacophore generation (PH4). The structural information derived from the 3D model and breakdown of computed MtDHQ2-AQs interaction energies up to individual active site residue contribution led to the design of a virtual combinatorial library of 1600 AQs that was screened through the PH4 filter to retain about forty molecules. The absorption, distribution, metabolism and excretion parameters of these designed molecules were computed with the QikProp program while the inhibition constants were predicted by the generated QSAR model. Our computational approach, which combines molecular modeling, pharmacophore generation and analysis of MtDHQ2-AQ interaction energies, resulted in the proposed novel predicted potent antitubercular agents with favorable pharmacokinetic profile, of which the best candidate predicted inhibition constant (Kipre) value within the picomolar range.