Nonnucleoside RT inhibitors (NNRTIs) bind to a hydrophobic pocket near, but not at, the polymerase active site.  The binding of an NNRTI does not interfere with the ability of RT to bind to either a nucleic acid substrate or an incoming dNTP; however, the chemical step of DNA synthesis is blocked.  The exact mechanism of inhibition is not clear; however, NNRTI binding distorts the enzyme in several important regions near the polymerase active site and distorts portions of enzyme that contact the nucleic acid.  It is possible that NNRTI binding distorts the active site, alters the position of the DNA at the active site, alters the position of the incoming dNTP, or causes some combination of these changes.

Treatment of patients with NNRTIs selects for mutations in amino acids that surround the NNRTI binding pocket.  Although there is considerable overlap in the mutations selected by different NNRTIs — and, as a consequence, considerable cross resistance — different NNRTIs elicit different spectra of resistance mutations, presumably because there are differences in the size and shape of the various NNRTIs and differences in the specific amino acids they contact.