text: Despite the chemical diversity of NNRTIs they all bind at the same site in the RT. The binding occurs allosterically in a hydrophobic pocket located approximately 10 Å from the catalytic site in the palm domain of the p66 subunit site of the enzyme. The NNRTI binding pocket (NNIBP) contains five aromatic (Tyr-181, Tyr-188, Phe-227 and Trp-229), six hydrophobic (Pro-59, Leu-100, Val-106, Val-179, Leu-234 and Pro-236) and five hydrophilic (Lys-101, Lys-103, Ser-105, Asp-132 and Glu-224) amino acids that belong to the p66 subunit and additional two amino acids (Ile-135 and Glu-138) belonging to the p51 subunit. Each NNRTI interacts with different amino acid residues in the NNIBP.
  An important factor in the binding of the first generation NNRTIs, such as nevirapine, is the butterfly-like shape. Despite their chemical diversity they assume very similar butterfly-like shape. Two aromatic rings of NNRTIs conform within the enzyme to resemble the wings of a butterfly (figure 2). The butterfly structure has a hydrophilic centre as a ‘body’ and two hydrophobic moieties representing the wings. Wing I is usually a heteroaromatic ring and wing II is a phenyl or allyl substituent. Wing I has a functional group at one side of the ring which is capable of accepting and/or donating hydrogen bonds with the main chain of the amino acids Lys-101 and Lys-103. Wing II interacts through π-π interactions with a hydrophobic pocket, formed in most part by the side chains of aromatic amino acids. On the butterfly body a hydrophobic part fills a small pocket which is mainly formed by the side chains of Lys-103, Val-106 and Val-179. However many other NNRTIs have been found to bind to RT in different modes. Second generation NNRTIs such as diarylpyrimidins (DAPYs), have a horseshoe-like shape with two lateral hydrophobic wings and a pyrimidine ring which is the central polar part.
  The NNIBP is elastic and the conformation depends on the size, specific chemical composition and binding mode of the NNRTI. The total structure of RT has segmental flexibility that depends on the nature of the bound NNRTI. It's important for the inhibitor to have flexibility to be able to bind in the modified pockets of a mutant target. Inhibitor flexibility may not affect the inhibitor-target interactions.