J Chem Inf Model - Freely available conformer generation methods: how good are they?

Tópicos

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Resumo

Conformer generation has important implications in cheminformatics, particularly in computational drug discovery where the quality of conformer generation software may affect the outcome of a virtual screening exercise. We examine the performance of four freely available small molecule conformer generation tools (Balloon, Confab, Frog2, and RDKit) alongside a commercial tool (MOE). The aim of this study is 3-fold: (i) to identify which tools most accurately reproduce experimentally determined structures; (ii) to examine the diversity of the generated conformational set; and (iii) to benchmark the computational time expended. These aspects were tested using a set of 708 drug-like molecules assembled from the OMEGA validation set and the Astex Diverse Set. These molecules have varying physicochemical properties and at least one known X-ray crystal structure. We found that RDKit and Confab are statistically better than other methods at generating low rmsd conformers to the known structure. RDKit is particularly suited for less flexible molecules while Confab, with its systematic approach, is able to generate conformers which are geometrically closer to the experimentally determined structure for molecules with a large number of rotatable bonds (=10). In our tests RDKit also resulted as the second fastest method after Frog2. In order to enhance the performance of RDKit, we developed a postprocessing algorithm to build a diverse and representative set of conformers which also contains a close conformer to the known structure. Our analysis indicates that, with postprocessing, RDKit is a valid free alternative to commercial, proprietary software.

Resumo Limpo

conform generat import implic cheminformat particular comput drug discoveri qualiti conform generat softwar may affect outcom virtual screen exercis examin perform four freeli avail small molecul conform generat tool balloon confab frog rdkit alongsid commerci tool moe aim studi fold identifi tool accur reproduc experiment determin structur ii examin divers generat conform set iii benchmark comput time expend aspect test use set druglik molecul assembl omega valid set astex divers set molecul vari physicochem properti least one known xray crystal structur found rdkit confab statist better method generat low rmsd conform known structur rdkit particular suit less flexibl molecul confab systemat approach abl generat conform geometr closer experiment determin structur molecul larg number rotat bond test rdkit also result second fastest method frog order enhanc perform rdkit develop postprocess algorithm build divers repres set conform also contain close conform known structur analysi indic postprocess rdkit valid free altern commerci proprietari softwar

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