S4MPLE 鈥?Sampler For Multiple Protein鈥揕igand Entities: Simultaneous Docking of Several Entities

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• 作者：Laurent Hoffer ; Dragos Horvath
• 刊名：Journal of Chemical Information and Modeling
• 出版年：2013
• 出版时间：January 28, 2013
• 年：2013
• 卷：53
• 期：1
• 页码：88-102
• 全文大小：561K
• 年卷期：v.53,no.1(January 28, 2013)
• ISSN：1549-960X

文摘

S4MPLE is a conformational sampling tool, based on a hybrid genetic algorithm, simulating one (conformer enumeration) or more molecules (docking). Energy calculations are based on the AMBER force field [Cornell et al. J. Am. Chem. Soc. 1995, 117, 5179.] for biological macromolecules and its generalized version GAFF [Wang et al. J. Comput. Chem. 2004, 25, 1157.] for ligands. This paper describes more advanced, specific applications of S4MPLE to problems more complex than classical redocking of drug-like compounds [Hoffer et al. J. Mol. Graphics Modell. 2012, submitted for publication.]. Here, simultaneous docking of multiple entities is addressed in two different important contexts. First, simultaneous docking of two fragment-like ligands was attempted, as such ternary complexes are the basis of fragment-based drug design by linkage of the independent binders. As a preliminary, the capacity of S4MPLE to dock fragment-like compounds has been assessed, since this class of small probes used in fragment-based drug design covers a different chemical space than drug-like molecules. Herein reported success rates from fragments redocking are as good as classical benchmarking results on drug-like compounds (Astex Diverse Set [Hartshorn et al. J. Med. Chem. 2007, 50, 726.]). Then, S4MPLE is successfully challenged to predict locations of fragments involved in ternary complexes by means of multientity docking. Second, the key problem of predicting water-mediated interaction is addressed by considering explicit water molecules as additional entities to be docked in the presence of the 鈥渕ain鈥?ligand. Blind prediction of solvent molecule positions, reproducing relevant ligand-water-site mediated interactions, is achieved in 76% cases over saved poses. S4MPLE was also successful to predict crystallographic water displacement by a therefore tailored functional group in the optimized ligand. However, water localization is an extremely delicate issue in terms of weighing of electrostatic and desolvation terms and also introduces a significant increase of required sampling efforts. Yet, the herein reported results 鈥?not making use of massively parallel deployment of the software 鈥?are very encouraging.