A Combined QSAR and Molecular Docking Approach for Identifying Pyrimidine Derivatives as Penicillin Binding Protein Inhibitors

Abstract

Background: Antimicrobial resistance has been rising continuously in the past few years due to the overuse and exploitation of existing antimicrobials. This has motivated the search for a novel scaffold that has the capability of rapid antimicrobial action. The hybridized pyrimidines have attracted us due to their widespread biological activities, such as anti-bacterial and antifungal activities. Objective: The present study incorporates a series of pyrimidine-based antimicrobial agents for the 2D quantitative structure-activity relationship analysis (2D QSAR) and docking analysis. Methods: The exploration of the chemical structures in combination with the biological activity in CPMLR led to the detection of six descriptors (Constitutional descriptors, Topological descriptors, Modified Burden Eigenvalues and 2D autocorrelations) for modeling the activity. The resulted QSAR model has been validated using combinatorial protocol in multiple linear regression (CP-MLR) and partial least squares (PLS) analysis. Methods: The exploration of the chemical structures in combination with the biological activity in CPMLR led to the detection of six descriptors (Constitutional descriptors, Topological descriptors, Modified Burden Eigenvalues and 2D autocorrelations) for modeling the activity. The resulted QSAR model has been validated using a combinatorial protocol in multiple linear regression (CP-MLR) and partial least squares (PLS) analysis. Results: The best QSAR model displays the r2 t value of 0.594, Q2 LOO value of 0.779, Q2 L5O value of 0.767. Further docking study was executed using Autodock Vina against Penicillin-binding protein (PBP2a). Conclusion: From the results, Compounds 4, 11and 24 were found to possess a good binding affinity towards PBP2a.