ClsDiff-AMP30: Generating Antimicrobial Peptides by a Classifier Guidance Noise Predictor

Antimicrobial peptides (AMPs) represent a promising therapeutic strategy to combat the increasing challenge of multidrug-resistant pathogens, a crisis intensified by the overuse of conventional antibiotics. In addition to their broad-spectrum antimicrobial activity, low toxicity, and reduced propensity for resistance development, AMPs offer significant advantages over traditional antibiotic therapies. However, the discovery of novel AMPs through biological experiments remains constrained by high costs, labor-intensive workflows, and time-consuming procedures, underscoring the urgent need for in silico computational methods to design AMP sequences. Notably, shorter AMPs ( ≤ 30 residues) demonstrate superior antimicrobial efficacy, improved structural stability, and minimal cytotoxicity toward human cells. To address these challenges, we present a classifier-guided diffusion framework specialized for generating AMPs shorter than 30 residues (ClsDiff-AMP30). The architecture integrates two interdependent submodels, including a noisy AMP classifier that evaluates AMP likelihood at intermediate denoising steps and a noise predictor guided by classifier-derived probability scores, dynamically adjusted via a self-optimized coefficient to modulate guidance strength. ClsDiff-AMP30 achieves a validation accuracy of 66% across 10,000 synthesized sequences by a self-developed AMP classifier. Furthermore, wet lab experiments demonstrated that all 11 selected sequences exhibited high antimicrobial activity against at least one of the three tested bacterial strains and low hemolytic activity.