NNRTIbinding

NNRTI binding refers to the interaction of non-nucleoside reverse transcriptase inhibitors with the HIV-1 reverse transcriptase enzyme. NNRTIs bind at the non-nucleoside inhibitor binding pocket (NNIBP) in the p66 subunit, an allosteric site separate from the active site used for nucleotide incorporation. Binding is reversible and typically non-competitive with respect to natural nucleoside triphosphates.

The binding pocket is largely hydrophobic and formed by residues in the palm region of the polymerase domain. Inhibitor binding often involves hydrophobic contacts and specific hydrogen bonds with residues such as Y181, Y188, and surrounding amino acids. This interaction induces conformational changes that distort the geometry of the active site and impede the catalytic steps required for reverse transcription, effectively reducing viral DNA synthesis.

A range of drugs exploit this binding mode, including early agents like nevirapine and efavirenz, and later agents such as etravirine and rilpivirine. Second-generation NNRTIs typically retain activity against several common NNRTI-resistant variants, whereas first-generation drugs are more susceptible to resistance. Resistance most commonly arises from mutations within the NNIBP, such as K103N, Y181C, Y188L, and G190A, which decrease inhibitor affinity and broaden cross-resistance among NNRTIs.

Clinically, NNRTIs are used as part of combination antiretroviral therapy. Their effectiveness can be influenced by resistance patterns, pharmacokinetic properties, and tolerability. Adverse effects vary by compound but can include rash, hepatotoxicity, and neuropsychiatric symptoms, and careful selection is required in the context of resistance and drug interactions.