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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

Determination of priority dihedral bonds in molecules. Bond priorities are determined using rules analogous to Cahn–Ingold–Prelog (CIP) rules. In the figure priority dihedral bonds are colored in grey. a The priority dihedral angle of 2-butanol is c4–c3–c2–O. b Priority dihedral bonds in cyclohexanol are defined such that all atoms that define priority dihedral angles are in the ring. Thus for bond C1–C2, C3–C2–C1–C6 is the priority dihedral angle instead of C3–C2–C1–O. c For multiple ring systems like 1,2,3,4-tetrahydro-1,8-naphthyridine, priority angles are determined by atom priority using the assumption that all atoms in the multiple ring system are part of one ring. Thus C2–N1–C8a–N8 is the priority dihedral angle instead of C2–N1–C8a–C4a as N8 is counted to be in the same ring system as the N1–C2 bond of interest
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Fig3: Determination of priority dihedral bonds in molecules. Bond priorities are determined using rules analogous to Cahn–Ingold–Prelog (CIP) rules. In the figure priority dihedral bonds are colored in grey. a The priority dihedral angle of 2-butanol is c4–c3–c2–O. b Priority dihedral bonds in cyclohexanol are defined such that all atoms that define priority dihedral angles are in the ring. Thus for bond C1–C2, C3–C2–C1–C6 is the priority dihedral angle instead of C3–C2–C1–O. c For multiple ring systems like 1,2,3,4-tetrahydro-1,8-naphthyridine, priority angles are determined by atom priority using the assumption that all atoms in the multiple ring system are part of one ring. Thus C2–N1–C8a–N8 is the priority dihedral angle instead of C2–N1–C8a–C4a as N8 is counted to be in the same ring system as the N1–C2 bond of interest

Mentions: Since multiple dihedral angles can be measured at each torsion bond, a scheme is required to prioritize which dihedral angle to use and arrive at unambiguous bin-signatures. Therefore a priority dihedral angle is defined. This is accomplished using rules analogous to the Cahn–Ingold–Prelog (CIP) system [28]. For example, as shown in Fig. 3a, 2-butanol has one torsion bond but two dihedral bonds about the single rotatable bond. According to CIP rules, the O–C–C–C dihedral angle will have a higher priority over the C–C–C–C dihedral angle. If out of three possible dihedral angles, two dihedral angles of equally high priority exist, then the third dihedral angle with lowest priority is used. If ambiguity still exists in assigning unique dihedral bonds, for example in the case where all dihedral angles have the same priority, the one with the smallest angle measure is chosen. Priority dihedral bonds in rings are defined in a special way in that all atoms constituting a priority bond are contained in the ring, as shown in Fig. 3b for cyclohexanol. This ensures that for the same ring conformation, a substituted ring system has the same dihedral-signature as an un-substituted ring system. If a fused ring system is present, then priority dihedrals are determined using atom priorities and the assumption that all atoms of the ring system are part of one ring (Fig. 3c). BCL::Conf can identify different ring conformations and use these in conformational sampling. Since dihedral angles are assigned in a unique way for a molecule of interest, a unique rotamer of the molecule has a unique dihedral bin signature. Table 2 shows different rotamers for a fragment from the rotamer library and their bin signatures.Fig. 3


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

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

Determination of priority dihedral bonds in molecules. Bond priorities are determined using rules analogous to Cahn–Ingold–Prelog (CIP) rules. In the figure priority dihedral bonds are colored in grey. a The priority dihedral angle of 2-butanol is c4–c3–c2–O. b Priority dihedral bonds in cyclohexanol are defined such that all atoms that define priority dihedral angles are in the ring. Thus for bond C1–C2, C3–C2–C1–C6 is the priority dihedral angle instead of C3–C2–C1–O. c For multiple ring systems like 1,2,3,4-tetrahydro-1,8-naphthyridine, priority angles are determined by atom priority using the assumption that all atoms in the multiple ring system are part of one ring. Thus C2–N1–C8a–N8 is the priority dihedral angle instead of C2–N1–C8a–C4a as N8 is counted to be in the same ring system as the N1–C2 bond of interest
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig3: Determination of priority dihedral bonds in molecules. Bond priorities are determined using rules analogous to Cahn–Ingold–Prelog (CIP) rules. In the figure priority dihedral bonds are colored in grey. a The priority dihedral angle of 2-butanol is c4–c3–c2–O. b Priority dihedral bonds in cyclohexanol are defined such that all atoms that define priority dihedral angles are in the ring. Thus for bond C1–C2, C3–C2–C1–C6 is the priority dihedral angle instead of C3–C2–C1–O. c For multiple ring systems like 1,2,3,4-tetrahydro-1,8-naphthyridine, priority angles are determined by atom priority using the assumption that all atoms in the multiple ring system are part of one ring. Thus C2–N1–C8a–N8 is the priority dihedral angle instead of C2–N1–C8a–C4a as N8 is counted to be in the same ring system as the N1–C2 bond of interest
Mentions: Since multiple dihedral angles can be measured at each torsion bond, a scheme is required to prioritize which dihedral angle to use and arrive at unambiguous bin-signatures. Therefore a priority dihedral angle is defined. This is accomplished using rules analogous to the Cahn–Ingold–Prelog (CIP) system [28]. For example, as shown in Fig. 3a, 2-butanol has one torsion bond but two dihedral bonds about the single rotatable bond. According to CIP rules, the O–C–C–C dihedral angle will have a higher priority over the C–C–C–C dihedral angle. If out of three possible dihedral angles, two dihedral angles of equally high priority exist, then the third dihedral angle with lowest priority is used. If ambiguity still exists in assigning unique dihedral bonds, for example in the case where all dihedral angles have the same priority, the one with the smallest angle measure is chosen. Priority dihedral bonds in rings are defined in a special way in that all atoms constituting a priority bond are contained in the ring, as shown in Fig. 3b for cyclohexanol. This ensures that for the same ring conformation, a substituted ring system has the same dihedral-signature as an un-substituted ring system. If a fused ring system is present, then priority dihedrals are determined using atom priorities and the assumption that all atoms of the ring system are part of one ring (Fig. 3c). BCL::Conf can identify different ring conformations and use these in conformational sampling. Since dihedral angles are assigned in a unique way for a molecule of interest, a unique rotamer of the molecule has a unique dihedral bin signature. Table 2 shows different rotamers for a fragment from the rotamer library and their bin signatures.Fig. 3

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