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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

Graph database for storing rotamer library for fast searching. The figure illustrates a rooted graph layout of fragments where each node is a unique constitution. The child nodes originating from the root are such that the root (in this case, benzene fragment) is their immediate substructure among all the fragments shown in the graph. Fragments contained in the molecule of interest are colored in blue while those that are not are in red or black. For fragments in black no substructure search is performed because their parent fragments were not found in the molecule of interest. The edges represent all possible search paths for finding fragments contained in the molecule of interest. Paths in blue are the actual searches that were performed for finding fragments for the query molecule. Paths in red and black are never taken during the search. Red colored paths are redundant search paths that have already been covered in a previous search
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Fig4: Graph database for storing rotamer library for fast searching. The figure illustrates a rooted graph layout of fragments where each node is a unique constitution. The child nodes originating from the root are such that the root (in this case, benzene fragment) is their immediate substructure among all the fragments shown in the graph. Fragments contained in the molecule of interest are colored in blue while those that are not are in red or black. For fragments in black no substructure search is performed because their parent fragments were not found in the molecule of interest. The edges represent all possible search paths for finding fragments contained in the molecule of interest. Paths in blue are the actual searches that were performed for finding fragments for the query molecule. Paths in red and black are never taken during the search. Red colored paths are redundant search paths that have already been covered in a previous search

Mentions: Conformational sampling begins with searching fragments contained in a molecule of interest. This involves substructure searches to identify all suitable fragments in the rotamer library. A hierarchical search has been implemented to minimize the number of substructure searches. The rotamer library is represented as multiple rooted graphs where each node is a unique constitution. The root nodes are not contained in any other fragments. Child nodes are such that the parent node is an immediate substructure. Figure 4 illustrates a rooted graph with benzene as root. Benzene is an immediate substructure of its child nodes i.e. toluene-like fragment which is an immediate substructure of cyclohexylbenzene-like fragment.Fig. 4


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

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

Graph database for storing rotamer library for fast searching. The figure illustrates a rooted graph layout of fragments where each node is a unique constitution. The child nodes originating from the root are such that the root (in this case, benzene fragment) is their immediate substructure among all the fragments shown in the graph. Fragments contained in the molecule of interest are colored in blue while those that are not are in red or black. For fragments in black no substructure search is performed because their parent fragments were not found in the molecule of interest. The edges represent all possible search paths for finding fragments contained in the molecule of interest. Paths in blue are the actual searches that were performed for finding fragments for the query molecule. Paths in red and black are never taken during the search. Red colored paths are redundant search paths that have already been covered in a previous search
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig4: Graph database for storing rotamer library for fast searching. The figure illustrates a rooted graph layout of fragments where each node is a unique constitution. The child nodes originating from the root are such that the root (in this case, benzene fragment) is their immediate substructure among all the fragments shown in the graph. Fragments contained in the molecule of interest are colored in blue while those that are not are in red or black. For fragments in black no substructure search is performed because their parent fragments were not found in the molecule of interest. The edges represent all possible search paths for finding fragments contained in the molecule of interest. Paths in blue are the actual searches that were performed for finding fragments for the query molecule. Paths in red and black are never taken during the search. Red colored paths are redundant search paths that have already been covered in a previous search
Mentions: Conformational sampling begins with searching fragments contained in a molecule of interest. This involves substructure searches to identify all suitable fragments in the rotamer library. A hierarchical search has been implemented to minimize the number of substructure searches. The rotamer library is represented as multiple rooted graphs where each node is a unique constitution. The root nodes are not contained in any other fragments. Child nodes are such that the parent node is an immediate substructure. Figure 4 illustrates a rooted graph with benzene as root. Benzene is an immediate substructure of its child nodes i.e. toluene-like fragment which is an immediate substructure of cyclohexylbenzene-like fragment.Fig. 4

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