Rational design of some 1,3,4 trisubstituted pyrazole-thiazole derivatives to serve as MtInhA inhibitors using QSAR, ADMET, molecular docking, MM-GBSA, and molecular dynamics simulations approach

Abstract

Using computational approaches, the potential efficacy and specificity of 1,3,4 trisubstituted pyrazole derivatives as MtInhA inhibitors which will aid in rational drug design for tubercular therapy were forecasted. QSARINS software was used to investigate the ability of compound to inhibit MtInhA. Three noteworthy descriptors with significant correlations and impressive statistical values were identified by the produced QSAR model: Correlation of coefficient(R2)= 0.8789, Cross-validation leave one out correlation coefficient (Q2LOO)= 0.8402, Cross-validation leave-many-out correlation coefficient(Q2LMO)=0.7321, Concordance Correlation Coefficient for cross-validation(CCCtr)=0.9355, CCCext =0.888. The descriptor generated by the QSAR model includes Centered Broto-Moreau autocorrelation weighted by Sanderson electronegativities (ATSC1e), Radial distribution functions at 15.0 and 2.0 Å inter-atomic distances weighted by relative van der Waals volumes (RDF150v), Radial distribution function – 145/weighted by relative I-state (RDF145s). Using these, three descriptor model was developed and the designed compounds were evaluated for their MtInhA inhibitory activity. Further, ADMET prediction and Molecular docking studies were carried out using Schrodinger's Software. ADMET prediction were used to evaluate drug likeliness and molecular docking was used to determine the interactions of designed compounds with the target protein. After the docking studies, the compounds were subjected for MM-GBSA calculations and MD simulation. Among the designed compounds, AP2 had the strongest binding affinity towards the MtInhA enzyme. The result of this work helps to understand the key interactions between 1,3,4 trisubstituted pyrazole derivatives and MtInhA protein that may be necessary to develop new lead compounds against tuberculosis.