Rational Design of Broad-Spectrum Non-Nucleoside Reverse Transcriptase Inhibitors via Pharmacophore-Oriented Generative Artificial Intelligence

Guided by the pharmacophore-oriented molecular generation platform PhoreGen, we employed rilpivirine (RPV) as a lead compound to generate 300 structurally diverse analogs that preserve key pharmacophoric features. Subsequent drug-likeness evaluation, molecular docking score, and synthetic feasibility led to the identification of compound No.102 (A19), which displayed potent inhibition activity against WT HIV-1 (EC₅₀ = 3.15 nM) and low cytotoxicity (CC₅₀ > 335