The latest developments in the design and discovery of non-nucleoside reverse transcriptase inhibitors (NNRTIs) for the treatment of HIV.

Introduction: This review encapsulates the recent strides in the development of non-nucleoside reverse transcriptase inhibitors (NNRTIs) for HIV treatment, focusing on the novel structural designs that promise to overcome limitations of existing therapies, such as drug resistance and toxicity.

Areas covered: We underscore the application of computational chemistry and structure-based drug design in refining NNRTIs with enhanced potency and safety.

Expert opinion: Highlighting the emergence of diverse chemical scaffolds like diarylpyrimidines, indoles, DABOs and HEPTs, the review reveals compounds with nanomolar efficacy and improved pharmacokinetics. The integration of artificial intelligence in drug discovery is poised to accelerate the evolution of NNRTIs, laying the foundation for addressing drug resistance in the era of anti-HIV therapy through innovative designs and multi-target strategies.