Abstract:Computer-aided drug design methods such as docking, pharmacophore searching, 3D database searching, and the creation of 3D-QSAR models need conformational ensembles to handle the flexibility of small molecules. Here, we present Conformator, an accurate and effective knowledgebased algorithm for generating conformer ensembles. With 99.9% of all test molecules processed, Conformator stands out by its robustness with respect to input formats, molecular geometries, and the handling of macrocycles. With an extended… Show more
“…The implementation could potentially be improved by using distance geometry to create fragment geometries for species not in the database. Other techniques to augment generation of unusual ring systems and macrocycles should also be explored [46, 47]. Fig.…”
Rapidly predicting an accurate three dimensional geometry of a molecule is a crucial task for cheminformatics and across a wide range of molecular modeling. Consequently, developing a fast, accurate, and open implementation of structure prediction is necessary for reproducible cheminformatics research. We introduce a fragment-based coordinate generation implementation for Open Babel, a widely-used open source toolkit for cheminformatics. The new implementation improves speed and stereochemical accuracy, while retaining or improving accuracy of bond lengths, bond angles, and dihedral torsions. Input molecules are broken into fragments by cutting at rotatable bonds. The coordinates of fragments are set according to a fragment library, prepared from open crystallographic databases. Since the coordinates of multiple atoms are decided at once, coordinate prediction is accelerated over the previous rules-based implementation in Open Babel, as well as the widely-used distance geometry methods in RDKit. This new implementation will be beneficial for a wide range of applications, including computational property prediction in polymers, molecular materials and drug design.
Electronic supplementary material
The online version of this article (10.1186/s13321-019-0372-5) contains supplementary material, which is available to authorized users.
“…The implementation could potentially be improved by using distance geometry to create fragment geometries for species not in the database. Other techniques to augment generation of unusual ring systems and macrocycles should also be explored [46, 47]. Fig.…”
Rapidly predicting an accurate three dimensional geometry of a molecule is a crucial task for cheminformatics and across a wide range of molecular modeling. Consequently, developing a fast, accurate, and open implementation of structure prediction is necessary for reproducible cheminformatics research. We introduce a fragment-based coordinate generation implementation for Open Babel, a widely-used open source toolkit for cheminformatics. The new implementation improves speed and stereochemical accuracy, while retaining or improving accuracy of bond lengths, bond angles, and dihedral torsions. Input molecules are broken into fragments by cutting at rotatable bonds. The coordinates of fragments are set according to a fragment library, prepared from open crystallographic databases. Since the coordinates of multiple atoms are decided at once, coordinate prediction is accelerated over the previous rules-based implementation in Open Babel, as well as the widely-used distance geometry methods in RDKit. This new implementation will be beneficial for a wide range of applications, including computational property prediction in polymers, molecular materials and drug design.
Electronic supplementary material
The online version of this article (10.1186/s13321-019-0372-5) contains supplementary material, which is available to authorized users.
“…Note that the exocyclic bond angles are kept fixed in the sampling. This approach is contrary to typical knowledge-based sampling methods, 33,34 where ring templates and heuristic rules are used to sample ring conformations, and substituents position are then assigned by minimizing a clash function or force field energy. Our new models do not require force field minimization, although as discussed below, minimization can also improve cases where bond lengths or angles slightly differ from our model.…”
Section: Connection Between Ring Puckering Substituent Orientations mentioning
<div>The geometry of a molecule plays a significant role in determining its physical and chemical properties. Despite its importance, there are relatively few studies on ring puckering and conformations, often focused on small cycloalkanes, five- and six-membered carbohydrate rings and specific macrocycle families. We lack a general understanding of the puckering preferences of medium-sized rings and macrocycles. To address this, we provide an extensive conformational analysis of a diverse set of rings. We used Cremer-Pople puckering coordinates to study the trends of the ring conformation across a set of 140,000 diverse small molecules, including small rings, macrocycles and cyclic peptides. By standardizing using key atoms, we show that the ring conformations can be classified into relatively few conformational clusters, based on their canonical forms. The number of such canonical clusters increases slowly with ring size. Ring puckering motions, especially pseudo-rotations, are generally restricted, and differ between clusters. More importantly, we propose models to map puckering preferences to torsion space, which allows us to understand the interrelated changes in torsion angles during pseudo-rotation and other puckering motions. Beyond ring puckers, our models also explain the change in substituent orientation upon puckering. In summary, this work provides an improved understanding of general ring puckering preferences, which will in turn accelerate the identification of low energy ring conformations for applications from polymeric materials to drug binding.</div>
“…Importantly, however, as noted in Cole et al 2018, the CSD conformer generator is initiated with input coordinates from the native protein-bound ligand conformation 5 . In contrast, we obtained the original 3D starting conformations generated by NAOMI for more accurate comparison to recently developed methods 4,15 , which removes bias toward native bond angles and lengths.…”
Section: Table 2 Arithmetic Mean and Median Rmsd In å Obtained For Tmentioning
<div>This paper describes recent
improvements made to the BCL::Conf rotamer generation algorithm and comparison
of its performance against other freely available and commercial conformer
generation software. We demonstrate that BCL::Conf, with the use of
rotamers derived from the COD, more effectively recovers crystallographic
ligand-binding conformations seen in the PDB than other commercial and freely
available software. BCL::Conf is now distributed with the COD-derived rotamer
library, free for academic use. The BCL can be downloaded at <a href="http://meilerlab.org/index.php/bclcommons/show/b_apps_id/1">http://meilerlab.org/
bclcommons</a> for Windows, Linux, or Apple operating systems.<br></div>
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