Lewi Paul J, de Jonge Marc, Daeyaert Frits, Koymans Luc, Vinkers Maarten, Heeres Jan, Janssen Paul A J, Arnold Eddy, Das Kalyan, Clark Art D, Hughes Stephen H, Boyer Paul L, de Béthune Marie-Pierre, Pauwels Rudi, Andries Koen, Kukla Mike, Ludovici Donald, De Corte Bart, Kavash Robert, Ho Chih
Center for Molecular Design, J&JPRD, Janssen Pharmaceutica N.V, Vosselaar, Belgium.
J Comput Aided Mol Des. 2003 Feb-Apr;17(2-4):129-34. doi: 10.1023/a:1025313705564.
There are several indications that a given compound or a set of related compounds can bind in different modes to a specific binding site of a protein. This is especially evident from X-ray crystallographic structures of ligand-protein complexes. The availability of multiple binding modes of a ligand in a binding site may present an advantage in drug design when simultaneously optimizing several criteria. In the case of the design of anti-HIV compounds we observed that the more active compounds that are also resilient against mutation of the non-nucleoside binding site of HIV1-reverse transcriptase make use of more binding modes than the less active and resilient compounds.
有若干迹象表明，某一特定化合物或一组相关化合物能够以不同模式结合到蛋白质的特定结合位点上。这从配体 - 蛋白质复合物的X射线晶体学结构中尤为明显。当同时优化多个标准时，配体在结合位点的多种结合模式的存在可能在药物设计中具有优势。在抗HIV化合物的设计中，我们观察到，相比于活性较低且抗突变能力较弱的化合物，那些对HIV1逆转录酶非核苷结合位点的突变具有抗性的活性更高的化合物利用了更多的结合模式。
