Structural optimization and binding energy prediction for globomycin analogs based on 3D-QSAR and molecular simulations

Lipoprotein signal peptidase II (LspA), a promising therapeutic target for bacterial infections, is essential for the growth of Escherichia coli (E. coli). In this study, 52 globomycin analogs were subjected to three-dimensional quantitative conformational relationships (3D-QSAR) research using comparative molecular field analysis (CoMFA) and the comparative molecular similarity index analysis (CoMSIA) methods. Meanwhile, molecular mechanisms and biological activities were investigated combined with molecular docking and molecular dynamics (MD) simulation. Guided by the contour maps from 3D-QSAR models, we designed 10 novel analogs with potential antimicrobial activity against E. coli. This research could provide theoretical clues for drug design with high activity against E. coli, which was bound to the molecular target LspA.