Pharmacophore modelling, QSAR study, molecular docking and insilico ADME prediction of 1,2,3-triazole and pyrazolopyridones as DprE1 inhibitor antitubercular agents

Abstract

Tuberculosis (TB) is a chronic lung infected airborne disease caused by Mycobacterium tuberculosis (MTB). The development of resistance towards available antitubercular agents leads to the discovery of new drugs for treatment against these resistant bacteria. Decaprenyl phosphoryl-β-D-Ribose 20-epimerase (DprE1) is a vulnerable target for the design of antitubercular agents which are more acting against multidrug resistant bacterial pathogens. DprE1 is an oxidase involved in the synthesis of arabinogalactan. Inhibition of DprE1 leads to blocking off cell wall synthesis, causing the death of the bacteria. A series of 50 DprE1 inhibitors having activity were subjected to 2D, 3D QSAR, Pharmacophore Modeling, Molecular Docking and in silico ADME studies. Prediction of preliminary Pharmacokinetic and the Drug Likeliness profile was performed for these compounds by in silico ADME study. 2D-QSAR and 3D-QSAR models developed by Partial Least Square associated with the Sphere Exclusion method (PLS-SE) and StepWise variable selection method (SW-kNN MFA) based on k-Nearest Neighbor technique are more significant which have cross-validated squared correlation coefficient (q2), coefficient of determination (r2), Fisher ratio (F) values as 0.7499, 0.8917 and 85.04 and the internal (q2 = 0.8198), external (pred_r2 = 0.6109) model validation correctly predicts activity ~ 81% and ~ 61% for the training and test set, respectively. Pharmacophore model was developed with two aromatic regions (Aro), one aliphatic (Ala) and one hydrogen donor (HDr). Docking studies of the selected inhibitors with the active site of DprE1 enzyme showed hydrogen bond interaction with Gly-116, His-131, Arg-118, Thr-117 and Gln-299 residues present at the active site. The results of the present work provide more useful information and important structural insights for designing DprE1 inhibitors with much more enhanced potency.

Computational approaches: Atom-based 3D-QSAR, molecular docking, ADME-Tox, MD simulation and DFT to find novel multi-targeted Anti-tubercular agents

“…Nowadays, the study of ADME-Tox properties has become an essential eld of drug discovery which signi cantly reduces the clinical failure of lead compounds. ADME-Tox prediction for all the ligands selected from virtual screening was made through ADMET lab 2.0 a user-friendly freely available web server (https://admetmesh.scbdd.com) [24,32]. The properties assessed during the study are partition coe cient, aqueous solubility, % of oral absorption, plasma protein binding, skin permeability, blood-brain barrier, plasma protein binding, metabolism, and elimination.…”

“…Mycobacterial cell wall is composed of polysaccharide arabinogalactan, which is synthesised through DprE1 enzyme mediated redox reaction. During the reaction the oxidase enzyme DprE1 carried out conversion of decaprenylphosphoryl-dribose (DPR) to decaprenylphosphoryl-d-arabinose (DPA) by epimerization via an intermediate decaprenylphosphoryl-2-keto-β-derythro-pentofuranose (DPX) [23][24][25]. Inhibition of DprE1 disrupts the synthesis of arabinogalactan, weakening the bacterial cell wall and making the bacteria more susceptible towards the chemotherapeutic agents used for the treatment of MTB, MDR-TB and XDR-TB [26].…”

Antimycobacterial, Molecular Docking and ADME Studies of Spiro Naphthyridine Pyrimidine and N‐(Quinolin‐8‐yl)acetamide Derivatives

“…As described in earlier literature [43][44][45] "This section comprises clean molecular and physicochemical characteristics of the compounds like molecular formula, molecular weight, number of heavy atoms, number of aromatic heavy atoms, fraction csp3, number of rotatable bonds, number of hydrogen bond acceptors, number of hydrogen bond donors, molar refractivity, TPSA respectively. Lipinski's rule of five is a thumb rule for evaluating drug-likeness and deciding if an inhibitor with a certain biological and pharmacological property would be an orally active drug in the human body.…”

3D-QSAR Studies of 1,2,4-Oxadiazole Derivatives as Sortase A Inhibitors

“…The 2D pictures of the docked conformation of compound 89 are exhibited in Figure 6(b). The compound position in the protein active site is illustrated in Figure 6(c) [59][60][61][62][63][64][65]. best model was observed for the sixth PLS factor owing to its high statistical importance and predictability.…”