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Title: New phosphorus analogs of bevirimat: synthesis, evaluation of anti-HIV-1 activity and molecular docking study
Authors: Chrobak, Elwira
Marciniec, Krzysztof
Dąbrowska, Aleksandra
Pęcak, Paweł
Bębenek, Ewa
Kadela-Tomanek, Monika
Bąk, Andrzej
Jastrzębska, Maria
Boryczka, Stanisław
Keywords: anti-HIV-1; molecular docking simulations; bevirimat; natural products; phosphate; phosphonate; molecular docking
Issue Date: 2019
Citation: "International Journal of Molecular Sciences" Vol. 20 (2019), art. no 5209
Abstract: Since the beginning of the human immunodeficiency virus (HIV) epidemic, many groups of drugs characterized by diverse mechanisms of action have been developed, which can suppress HIV viremia. 3-O-(3′,3′-Dimethylsuccinyl) betulinic acid, known as bevirimat (BVM), was the first compound in the class of HIV maturation inhibitors. In the present work, phosphate and phosphonate derivatives of 3-carboxyacylbetulinic acid were synthesized and evaluated for anti-HIV-1 activity. In vitro studies showed that 30-diethylphosphonate analog of BVM (compound 14a) has comparable effects to BVM (half maximal inhibitory concentrations (IC50) equal to 0.02 μM and 0.03 μM, respectively) and is also more selective (selectivity indices: 3450 and 967, respectively). To investigate the possible mechanism of antiviral effect of 14a, molecular docking was carried out on the C-terminal domain (CTD) of HIV-1 capsid (CA)–spacer peptide 1 (SP1) fragment of Gag protein, designated as CTD-SP1, which was described as a molecular target for maturation inhibitors. Compared with interactions between BVM and the protein, an increased number of strong interactions between ligand 14a and protein, generated by the phosphonate group, was observed.
DOI: 10.3390/ijms20205209
ISSN: 1422-0067
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