Dynamic pharmacophore model optimization: identification of novel HIV-1 integrase inhibitors

Journal of Medicinal Chemistry
Jinxia DengJames M Briggs

Abstract

We extended the previously described dynamic pharmacophore model studies of HIV-1 integrase (IN) by considering more key residues in the active site, including Mg2+. First, we applied a Monte Carlo sampling method to map the complementary features of the IN binding surface. Two types of dynamic pharmacophore models were generated. One considers Mg2+ as part of the IN and therefore as an excluded volume, and the other treats Mg2+ as a positively charged feature, representing a new type of pharmacophore model aimed to identify compounds potentially preventing Mg2+ binding. Second, we validated the models with 385 known active (IC50 < 20 microM) and 235 (IC50 > 100 microM) inactive IN inhibitors. Third, we used the derived models to screen our small molecule database. Twenty-two structurally novel compounds were tested in an in vitro assay specific for IN, and two of them showed IC50 < or = 10 microM for strand transfer reaction.

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Citations

Dec 3, 2008·Journal of Molecular Modeling·Devendra K DhakedEvans C Coutinho
Nov 5, 2013·ACS Combinatorial Science·Tao JiAihua Zhou
Mar 9, 2011·Journal of Medicinal Chemistry·Jing TangZhengqiang Wang
Mar 24, 2011·Future Medicinal Chemistry·Chenzhong Liao, Marc C Nicklaus
Jun 29, 2007·Bioinformation·Janani Jaganatharaja, Ragul Gowthaman
Dec 9, 2014·Drug Discovery Today·Yang LiAixia Yan
Jun 11, 2016·Journal of Medicinal Chemistry·Bulan WuZhengqiang Wang
Jun 16, 2007·Chemistry : a European Journal·Cláudio N AlvesEstanislao Silla
Nov 6, 2007·Medicinal Research Reviews·Raveendra DayamNouri Neamati
Feb 8, 2020·Topics in Current Chemistry·Bhaskar DekaPranjal K Baruah
Oct 22, 2020·Chemistry : a European Journal·Yan ZhangLutz Ackermann
Jan 16, 2007·Organic Letters·Mauro F A Adamo, Vivekananda R Konda

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