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BCL::Conf: small molecule conformational sampling using a knowledge based rotamer library.

Kothiwale S, Mendenhall JL, Meiler J - J Cheminform (2015)

Bottom Line: BCL::Conf recovers at least one conformation with a root mean square deviation of 2 Å or better to the experimental structure for 99 % of the small molecules in the Vernalis benchmark dataset.The 'rotamer' approach will allow integration of BCL::Conf into respective computational biology programs such as Rosetta.Graphical abstract:Conformation sampling is carried out using explicit fragment conformations derived from crystallographic structure databases.Molecules from the database are decomposed into fragments and most likely conformations/rotamers are used to sample correspondng sub-structure of a molecule of interest.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Center for Structural Biology, Vanderbilt University, Nashville, TN 37232 USA.

ABSTRACT
The interaction of a small molecule with a protein target depends on its ability to adopt a three-dimensional structure that is complementary. Therefore, complete and rapid prediction of the conformational space a small molecule can sample is critical for both structure- and ligand-based drug discovery algorithms such as small molecule docking or three-dimensional quantitative structure-activity relationships. Here we have derived a database of small molecule fragments frequently sampled in experimental structures within the Cambridge Structure Database and the Protein Data Bank. Likely conformations of these fragments are stored as 'rotamers' in analogy to amino acid side chain rotamer libraries used for rapid sampling of protein conformational space. Explicit fragments take into account correlations between multiple torsion bonds and effect of substituents on torsional profiles. A conformational ensemble for small molecules can then be generated by recombining fragment rotamers with a Monte Carlo search strategy. BCL::Conf was benchmarked against other conformer generator methods including Confgen, Moe, Omega and RDKit in its ability to recover experimentally determined protein bound conformations of small molecules, diversity of conformational ensembles, and sampling rate. BCL::Conf recovers at least one conformation with a root mean square deviation of 2 Å or better to the experimental structure for 99 % of the small molecules in the Vernalis benchmark dataset. The 'rotamer' approach will allow integration of BCL::Conf into respective computational biology programs such as Rosetta.Graphical abstract:Conformation sampling is carried out using explicit fragment conformations derived from crystallographic structure databases. Molecules from the database are decomposed into fragments and most likely conformations/rotamers are used to sample correspondng sub-structure of a molecule of interest.

No MeSH data available.


Related in: MedlinePlus

General scheme for BCL::Conf conformation generator. a Scheme for generating the rotamer library. b Flowchart depicting conformation sampling process. See text for a detailed description
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Fig1: General scheme for BCL::Conf conformation generator. a Scheme for generating the rotamer library. b Flowchart depicting conformation sampling process. See text for a detailed description

Mentions: BCL::Conf uses fragments generated from decomposing molecules found in CSD and PDB. For this purpose, non-ring bonds of each molecule are broken iteratively to generate all possible fragments. In a second step all occurrences of one fragment within the structure databases are collected and clustered according to discrete dihedral angle bins. A conformer is then defined as a unique conformation represented as a set of integer numbers, one for each dihedral bond, identifying the bin. This procedure is similar to the definition of ‘rotamers’ that are used to set likely amino acid side chain conformations [20]. A conformer needs to be seen at least four times in the database to be considered a likely conformation of a fragment. It is then added to the rotamer library for sampling. The flowchart for algorithm implemented in BCL::Conf is shown in Fig. 1.Fig. 1


BCL::Conf: small molecule conformational sampling using a knowledge based rotamer library.

Kothiwale S, Mendenhall JL, Meiler J - J Cheminform (2015)

General scheme for BCL::Conf conformation generator. a Scheme for generating the rotamer library. b Flowchart depicting conformation sampling process. See text for a detailed description
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4607025&req=5

Fig1: General scheme for BCL::Conf conformation generator. a Scheme for generating the rotamer library. b Flowchart depicting conformation sampling process. See text for a detailed description
Mentions: BCL::Conf uses fragments generated from decomposing molecules found in CSD and PDB. For this purpose, non-ring bonds of each molecule are broken iteratively to generate all possible fragments. In a second step all occurrences of one fragment within the structure databases are collected and clustered according to discrete dihedral angle bins. A conformer is then defined as a unique conformation represented as a set of integer numbers, one for each dihedral bond, identifying the bin. This procedure is similar to the definition of ‘rotamers’ that are used to set likely amino acid side chain conformations [20]. A conformer needs to be seen at least four times in the database to be considered a likely conformation of a fragment. It is then added to the rotamer library for sampling. The flowchart for algorithm implemented in BCL::Conf is shown in Fig. 1.Fig. 1

Bottom Line: BCL::Conf recovers at least one conformation with a root mean square deviation of 2 Å or better to the experimental structure for 99 % of the small molecules in the Vernalis benchmark dataset.The 'rotamer' approach will allow integration of BCL::Conf into respective computational biology programs such as Rosetta.Graphical abstract:Conformation sampling is carried out using explicit fragment conformations derived from crystallographic structure databases.Molecules from the database are decomposed into fragments and most likely conformations/rotamers are used to sample correspondng sub-structure of a molecule of interest.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Center for Structural Biology, Vanderbilt University, Nashville, TN 37232 USA.

ABSTRACT
The interaction of a small molecule with a protein target depends on its ability to adopt a three-dimensional structure that is complementary. Therefore, complete and rapid prediction of the conformational space a small molecule can sample is critical for both structure- and ligand-based drug discovery algorithms such as small molecule docking or three-dimensional quantitative structure-activity relationships. Here we have derived a database of small molecule fragments frequently sampled in experimental structures within the Cambridge Structure Database and the Protein Data Bank. Likely conformations of these fragments are stored as 'rotamers' in analogy to amino acid side chain rotamer libraries used for rapid sampling of protein conformational space. Explicit fragments take into account correlations between multiple torsion bonds and effect of substituents on torsional profiles. A conformational ensemble for small molecules can then be generated by recombining fragment rotamers with a Monte Carlo search strategy. BCL::Conf was benchmarked against other conformer generator methods including Confgen, Moe, Omega and RDKit in its ability to recover experimentally determined protein bound conformations of small molecules, diversity of conformational ensembles, and sampling rate. BCL::Conf recovers at least one conformation with a root mean square deviation of 2 Å or better to the experimental structure for 99 % of the small molecules in the Vernalis benchmark dataset. The 'rotamer' approach will allow integration of BCL::Conf into respective computational biology programs such as Rosetta.Graphical abstract:Conformation sampling is carried out using explicit fragment conformations derived from crystallographic structure databases. Molecules from the database are decomposed into fragments and most likely conformations/rotamers are used to sample correspondng sub-structure of a molecule of interest.

No MeSH data available.


Related in: MedlinePlus