Crystallography and the design of anti-AIDS drugs: conformational flexibility and positional adaptability are important in the design of non-nucleoside HIV-1 reverse transcriptase inhibitors

摘要: Drug resistance is a key cause of failure for treatment HIV infection. The efficacy non-nucleoside reverse transcriptase inhibiting (NNRTI) drugs impaired by rapid emergence drug-resistance mutations. A multidisciplinary effort led to the discovery potent NNRTIs dapivirine and etravirine, both which are diarylpyrimidine (DAPY) derivatives. Systematic structural molecular modeling studies HIV-1 (RT)/NNRTI complexes revealed different modes inhibitor binding, some DAPY inhibitors can bind RT in conformations. torsional flexibility ("wiggling") generate numerous conformational variants compactness permits significant repositioning reorientation (translation rotation) within pocket ("jiggling"). Such adaptations appear be critical ability retain their potency against wide range drug-resistant RTs. Exploitation (such as about strategically located chemical bonds) powerful element drug design, especially design that will effective rapidly mutating targets (which collection related targets).