Crystal structures of HIV-1 reverse transcriptase complexes with thiocarbamate non-nucleoside inhibitors.
O-Phthalimidoethyl-N-arylthiocarbamates (TCs) have been recently identified as a new class of potent HIV-1 reverse transcriptase (RT) non-nucleoside inhibitors (NNRTIs), by means of computer-aided drug design techniques [Ranise A. Spallarossa, S. Cesarini, F. Bondavalli, S. Schenone, O. Bruno, G. Menozzi, P. Fossa, L. Mosti, M. La Colla, et al., Structure-based design, parallel synthesis, structure-activity relationship, and molecular modeling studies of thiocarbamates, new potent non-nucleoside HIV-1 reverse transcriptase inhibitor isosteres of phenethylthiazolylthiourea derivatives, J. Med. Chem. 48 (2005) 3858-3873]. To elucidate the atomic details of RT/TC interaction and validate an earlier TC docking model, the structures of three RT/TC complexes were determined at 2.8-3.0A resolution by X-ray crystallography. The conformations adopted by the enzyme-bound TCs were analyzed and compared with those of bioisosterically related NNRTIs.
Spallarossa
Andrea
A
Dipartimento di Scienze Farmaceutiche, Universita' di Genova, viale Benedetto XV, 3, I-16132 Genova, Italy.
Cesarini
Sara
S
Ranise
Angelo
A
Ponassi
Marco
M
Unge
Torsten
T
Bolognesi
Martino
M
D001665:Binding Sites; D003198:Computer Simulation; D003461:Crystallography / Q000379:methods; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000737:chemistry; D054303:HIV Reverse Transcriptase / Q000737:chemistry* / Q000648:ultrastructure*; D008956:Models, Chemical; D008958:Models, Molecular; D009705:Nucleosides / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D013859:Thiocarbamates / Q000737:chemistry*
D004791:Enzyme Inhibitors; D009705:Nucleosides; D013859:Thiocarbamates; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase