Nivesanond Kanda, Peeters Anik, Lamoen Dirk, Van Alsenoy Christian
Department of Chemistry, University of Antwerp, Drie Eiken Campus, B-2610 Antwerp, Belgium.
J Chem Inf Model. 2008 Jan;48(1):99-108. doi: 10.1021/ci7001318. Epub 2008 Jan 4.
TMC114, a potent novel HIV-1 protease inhibitor, remains active against a broad spectrum of mutant viruses. In order to bind to a variety of mutants, the compound needs to make strong, preferably backbone, interactions and have enough conformational flexibility to adapt to the changing geometry of the active site. The conformational analysis of TMC114 in the gas phase yielded 43 conformers in which five types of intramolecular H-bond interactions could be observed. All 43 conformers were subject to both rigid and flexible ligand docking in the wild-type and a triple mutant (L63P/V82T/I84V) of HIV-1 protease. The largest binding energy was calculated for the conformations that are close to the conformation observed in the X-ray complexes of TMC114 and HIV-1 protease.
TMC114是一种强效的新型HIV-1蛋白酶抑制剂，对多种突变病毒仍具有活性。为了与各种突变体结合，该化合物需要形成强相互作用，最好是主链相互作用，并且具有足够的构象灵活性以适应活性位点不断变化的几何形状。TMC114在气相中的构象分析产生了43种构象异构体，其中可以观察到五种类型的分子内氢键相互作用。所有43种构象异构体都在野生型和HIV-1蛋白酶的三重突变体（L63P/V82T/I84V）中进行了刚性和柔性配体对接。对于与TMC114和HIV-1蛋白酶的X射线复合物中观察到的构象接近的构象，计算出了最大结合能。
