HIV reverse transcriptase inhibitor

HIV is an RNA retrovirus that binds to surface molecules (CD4 and chemoldne receptors) on white blood cells that are crucial for host defence. The virus then enters the cell and uses its own biochemical machinery to transcribe the viral RNA into DNA, which is then integrated into the DNA of the host cell chromosomes. The host cell then starts generating viral proteins, which are modified by viral proteases and used to construct new viruses that leave the cell to infect other cells. 

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Eriksson M A L, J Pitera and P A Kollman 1999. Prediction of the Binding Free Energies of New TIBO-like HIV-1 Reverse Transcriptase Inhibitors Using a Combination of PROFEC, PB/SA, CMC/MD, and Free Energy Calculations. Journal of Medicinal Chemistry 42 868-881. 

Mertens A, Zilch H, Konig B, Schafer W, Poll T, Kampe W, Seidel H, Leser U, Leinert H. Selective non-nucleoside HIV-1 reverse transcriptase inhibitors. New 2,3-dihydrothiazolo[2,3-a]isoindol-5(97>77)-ones and related compounds with anti-HIV-1 activity. J Med Chem 1993 36 2526-2535. 

Mestres, J., Rohrer, D. C., and Maggiora, G. M. (1999) A molecular-field-based similarity study of non-nucleoside HIV-1 reverse transcriptase inhibitors. J. Comput.-Aided Mol. Design 13, 79-93. 

Delavirdine mesylate is a member of the /7w(heteroaryl)piperazine (BHAP) class of nonnucleoside HIV-1 reverse transcriptase inhibitors (Adams et al., 1998 Romero et al., 1993 Romero, 1994). This class of compounds was discovered by Upjohn scientists from a computer-directed dissimilarity analysis of the Pharmacia Upjohn chemical library to select compounds for screening against HIV-1 RT. The result of the in vitro assay (Deibel et al., 1990) is an IC50 of 0.260 p,M, which is comparable to AZT. In accordance with the previous NNRTIs, delavirdine is a noncompetitive inhibitor of reverse transcriptase, and has a synergistic effect with nucleoside transcriptase and protease inhibitors (Chong et al., 1994). 

Treatment of the 3,l-benzoxazin-2-one derivative 249 with cerium ammonium nitrate (CAN) resulted in removal of the /i-methoxybenzyl substituent, by oxidation of its a-position, which led to the human immunodeficiency vims-1 (HIV-1) reverse transcriptase inhibitor efavirenz 250 and anisaldehyde (Equation 24) <1998JOC8536>. 

Erickson DA, Mather G, Trager WE, Levy RH, Keirns JJ. Characterization of the in vitro biotransformation of the HIV-1 reverse transcriptase inhibitor nevirapine by human hepatic cytochromes P-450. Drug Metab Dispos 1999 27(12) 1488-1495. 

In our recent studies we were fortunate to recruit experimental collaborators who have validated computational hits identified by virtual screening of commercially available compound libraries using rigorously validated QSAR models. Examples include anticonvulsants (25), HIV-1 reverse transcriptase inhibitors (32), D1 antagonists (33), antitumor compounds (34), beta-lactamase inhibitors (35), human histone deacetylase (HDAC) inhibitors... 

Medina-Franco, J. L., Golbraikh, A., Oloff, S., Castillo, R., Tropsha, A. (2005) Quantitative structure-activity relationship analysis of pyridinone HIV-1 reverse transcriptase inhibitors using the nearest neighbor method and QSAR-based database mining. J Comput Aided Mol Des 19, 229-242. 

Locatelli GA, Cancio R, Spadari S, Maga G. HIV-1 reverse transcriptase inhibitors current issues and future perspectives. Curr Drug Metab. 2004 5 283-290. 

Chromenes (Phe a-pyran) include encecalin (a phototoxic antimicrobial from various Asteraceae) and the phloroglucinol derivative mallotochromene (cytotoxic and an HIV-1 reverse transcriptase inhibitor). Precocene 1 (7-methoxy-2,2-dimethylchromene) and pre-cocene 2 (6,7-dimethoxy-2,2-dimethylchromene) produced by Ageratum species (Asteraceae) inhibit the production of insect juvenile hormone (JH) as a result of suicidal conversion of these pro-toxins to cytotoxic derivatives by the JH-producing insect cells. 

Cimniiigliam PH, Smidi DG, Satchell C, Cooper DA, Brew B (2000) Evidence for independent development of resistance to HIV-1 reverse transcriptase inhibitors in die cerebrospinal fluid. AIDS... 

Shockcor, J.P. Unger, S.E. Savina, P. Nicholson, J.K. Lindon, J.C. Application of directly coupled LC-NMR-MS to the structural elucidation of metabolites of the HIV-1 reverse-transcriptase inhibitor BW935U83. J. Chromatogr., B, Biomed. Sci. Appl. 2000, 748, 269-279. 

Hannongbua, S., Lawtrakul, L., Sotriffer, C.A. and Rode, B.M. (1996b). Comparative Molecular Field Analysis of HIV-1 Reverse Transcriptase Inhibitors in the Class of 1((2-Hydroxyethoxy)-Methyl)-6(Phenylthio)Thymine. Quant.Struct.-Act.Relat., 15, 389-394. 

We also reported a design of MIP with high-binding capacity suitable for large scale extraction of abacavir, a HIV-1 reverse transcriptase inhibitor.78 The MIP based on IA possessed very high-binding capacity for the template, up to 15.7% in 50mM Na-acetate buffer (pH 4.0). 

Douali, L., ViDemin, D., Zyad, A. and Cherqaoui, D. (2004) Artificial neural networks non-hnear QSAR studies of HEPT derivatives as HIV-1 reverse transcriptase inhibitors. Mol. Div., 8, 1-8. 

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