Benzoxazole Scaffolds as Novel Toll-Like Receptor-2 Inhibitors: A New Avenue for Pneumocystis Pneumonia Therapy

Pneumocystis pneumonia (PCP) was primarily caused by Pneumocystis jirovecii, is a life-threatening fungal infection affecting immunocompromised individuals. Current treatments face limitations including toxicity, resistance and lack of efficacy. Toll-like receptor 2 (TLR-2), a critical immune modulator plays a pivotal role in the host immune response to Pneumocystis that mediates both protective and pathological inflammation. This study focuses on the rational design and molecular docking of novel benzoxazole derivatives targeting TLR-2. A virtual library of 180 ligands was developed based on pharmacophoric features identified through structure-based drug design. Molecular docking against TLR-2 (PDB ID: 6NIG) identified high-affinity ligands, with five lead compounds (GYP-12, GYP-80, GYP-135, GYP-142, and GYP-158). These compounds demonstrated favorable ADMET profiles indicating their potential as new anti-PCP agents.