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

The emergence of multi-drug resistance bacteria poses 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 analysis the structural feature of small AMPs against S. aureus or E. coli respectively. Subsequently, Three-Dimensional Quantitative Structure-Activity Relationships (3D-QSAR) models (for S. aureus , CoMFA: Q 2 = 0.512, R 2 = 0.943, F = 59.916; CoMSIA: Q 2 = 0.645, R 2 = 0.993, F = 339.242; for E. Coli, CoMFA: Q 2 = 0.507, R 2 = 0.913, F = 66.862; CoMSIA: Q 2 = 0.573, R 2 = 0.966, F = 96.84) with good predictability and stability were 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 without causing host toxicity. Our findings provide 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.