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. The NNRTIs act by binding non-competitively to the RT enzyme (figure 3). The binding causes conformational change in the three-dimensional structure of the enzyme and creates the NNIBP. Binding of NNRTI to HIV-1 RT makes the p66 thumb domain hyper extended because it induces rotamer conformation changes in amino acid residues Tyr-181 and Tyr-188. This affects the catalytic activity of the enzyme and blocks the HIV-1 replication by inhibiting the polymerase active site of the RT's p66 subunit. The global conformational change additionally destabilizes the enzyme on its nucleic acid template and reduces its ability to bind nucleotides. The transcription of the viral RNA is inhibited and therefore the replication rate of the virus reduces. Although the exact molecular mechanism is still hypothetical this has been demonstrated by multiple studies to be the primary mechanism of action. In addition to this proposed primary mechanism of action it has been shown that the NNRTIs have other mechanisms of action and interfere with various steps in the reverse transcriptase reaction. It has been suggested that the inhibition of reverse transcription by the NNRTIs may be due to effects on the RT Rnase H activity and/or template/primer binding. Some NNRTIs interfere with HIV-1 Gag-Pol polyprotein processing by inhibiting the late stage of HIV-1 replication. It is important to gain profound understanding of the various mechanism of action of the NNRTIs in order to develop next-generation NNRTIs and for understanding the mechanism of drug resistance. The development of effective anti-HIV drugs is difficult due to wide variations in nucleotide and amino acid sequences. The perfect anti-HIV drug chemical should be effective against drug resistance mutation. Understanding the target RT enzyme and its structure, mechanism of drug action and the consequence of drug resistance mutations provide useful information which can be helpful to design more effective NNRTIs. The RT enzyme can undergo change due to mutations that can disturb NNRTI binding. The first two classes of compounds that were identified as NNRTIs were the 1-(2-2-hydroxyethoxymethyl)-6-(phenylthio)thymine (HEPT) and tetrahydroimidazo[4,5,1-jkj][1,4]benzodiazepin-2(1H)-one and -thione (TIBO) compounds.