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

Abstract

Sortase A (SrtA) is an enzyme that catalyzes the attachment of proteins to the cell wall of Gram-positive bacterial membrane, preventing the spread of pathogenic bacterial strains. Here, one class of oxadiazole compounds was distinguished as an efficient inhibitor of SrtA via the “S. aureus Sortase A” substrate-based virtual screening. The current study on 3D-QSAR was done by utilizing preparation of the structure in the Schrödinger software suite and an assessment of 120 derivatives with the crystal structure of 1,2,4-oxadiazole which was extracted from the PDB data bank. The docking operation of the best compound in terms of pMIC ( $\text{pMIC}=2.77$ ) was done to determine the drug likeliness and binding form of 1,2,4-oxadiazole derivatives as antibiotics in the active site. Using the kNN-MFA way, seven models of 3D-QSAR were created and amongst them, and one model was selected as the best. The chosen model based on $q^2$ (pred_ $r^2$ ) and $R^2$ values related to the sixth factor of PLS illustrates better and more acceptable external and internal predictions. Values of crossvalidation (pred_ $r^2$ ), validation ( $q^2$ ), and $F$ were observed 0.5479, 0.6319, and 179.0, respectively, for a test group including 24 molecules and the training group including 96 molecules. The external reliability outcomes showed that the acceptable and the selective 3D-QSAR model had a high predictive potential ( $R^2=0.9235$ ) which was confirmed by the $Y$ -randomization test. Besides, the model applicability domain was described successfully to validate the estimation of the model.