In Silicon Design of Antimicrobial Oligopeptides Based on 3D-QSAR Modelling and Bioassay Evaluation

The emergence of multidrug resistance bacteria poses a great health theat. Therefore, it is a crucial demand to obtain new antibacterial drugs. Antimicrobial peptides (AMPs) have the characteristics of wide antimicrobial spectrum and lower drug resistance, hence, it is hopeful to substitute for classical antibiotics. In this study, two classic methods, comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA), were used to analyze the structural feature of AMPs against Staphylococcus aureus or Escherichia coli, respectively. Subsequently, the models established by three-dimensional quantitative structure–activity relationships (3D-QSAR) (for S. aureus, CoMFA: Q2 = 0.512, R2 = 0.943, F = 59.916; CoMSIA: Q2 = 0.645, R2 = 0.993, F = 339.242; for E. Coli, CoMFA: Q2 = 0.507, R2 = 0.913, F = 66.862; CoMSIA: Q2 = 0.573, R2 = 0.966, F = 96.84) have good predictability and stability was constructed. Seven novel small AMPs were designed and synthesized based on the theoretical model. The novel AMPs showed potent antibacterial activity against S. aureus and E. coli while causing low host toxicity. This study provides a potential therapeutic option using 3D-QSAR models guiding the design and modification of novel AMPs, to address the prevalent infections caused by MDR bacterial.