Biasing conformational ensembles towards bioactive-like conformers for ligand-based drug design

Musafia, Boaz; Senderowitz, Hanoch

doi:10.1517/17460441.2010.513711

Cited by 19 publications

(13 citation statements)

References 87 publications

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“…(Removal of coulombic terms [6,32-35] eliminated a bias towards conformations with energy-lowering intra-molecular interactions that tend not to be important for inter-molecular interactions, an important consideration given that the 3-D coordinates are generated in vacuo. Removal of attractive van der Waals terms did not have any noticeable effect [6]. )…”

Section: Construction and Contentmentioning

confidence: 99%

“…All conformers were generated by the OpenEye Scientific Software, Inc., OMEGA software [ 27 - 31 ] using the C++ interface, the MMFF94s force field [ 24 - 26 ] minus coulombic terms, and an energy filter of 25 kcal/mol. (Removal of coulombic terms [ 6 , 32 - 35 ] eliminated a bias towards conformations with energy-lowering intra-molecular interactions that tend not to be important for inter-molecular interactions, an important consideration given that the 3-D coordinates are generated in vacuo. Removal of attractive van der Waals terms did not have any noticeable effect [ 6 ].)…”

Section: Construction and Contentmentioning

confidence: 99%

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PubChem3D: a new resource for scientists

et al. 2011

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BackgroundPubChem is an open repository for small molecules and their experimental biological activity. PubChem integrates and provides search, retrieval, visualization, analysis, and programmatic access tools in an effort to maximize the utility of contributed information. There are many diverse chemical structures with similar biological efficacies against targets available in PubChem that are difficult to interrelate using traditional 2-D similarity methods. A new layer called PubChem3D is added to PubChem to assist in this analysis.DescriptionPubChem generates a 3-D conformer model description for 92.3% of all records in the PubChem Compound database (when considering the parent compound of salts). Each of these conformer models is sampled to remove redundancy, guaranteeing a minimum (non-hydrogen atom pair-wise) RMSD between conformers. A diverse conformer ordering gives a maximal description of the conformational diversity of a molecule when only a subset of available conformers is used. A pre-computed search per compound record gives immediate access to a set of 3-D similar compounds (called "Similar Conformers") in PubChem and their respective superpositions. Systematic augmentation of PubChem resources to include a 3-D layer provides users with new capabilities to search, subset, visualize, analyze, and download data.A series of retrospective studies help to demonstrate important connections between chemical structures and their biological function that are not obvious using 2-D similarity but are readily apparent by 3-D similarity.ConclusionsThe addition of PubChem3D to the existing contents of PubChem is a considerable achievement, given the scope, scale, and the fact that the resource is publicly accessible and free. With the ability to uncover latent structure-activity relationships of chemical structures, while complementing 2-D similarity analysis approaches, PubChem3D represents a new resource for scientists to exploit when exploring the biological annotations in PubChem.

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Section: Construction and Contentmentioning

confidence: 99%

Section: Construction and Contentmentioning

confidence: 99%

PubChem3D: a new resource for scientists

et al. 2011

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“…Firstly, ligands larger than tetrasaccharides will require very long conformational searches in order to sample a large enough conformational space, thus may not be represented adequately. Secondly, it is possible that different approaches for conformational searching could give rise to different conformational ensembles 9 (Musafia, B. and Senderowitz, H. 2010). Therefore, the consistency of the predicted binding poses with FRED is likely to be highly dependent on the approach to conformer generation used and the performance of FRED observed must be interpreted with this in mind.…”

Section: Evaluation Of Cognate Molecular Dockingmentioning

confidence: 99%

Development and application of site mapping methods for the design of glycosaminoglycans

Agostino¹,

Gandhi²,

Mancera³

2014

Glycobiology

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Glycosaminoglycans (GAGs) are complex polysaccharides involved in a wide range of biological signaling events, as well as being important as biological structural materials. Despite the ubiquity and importance of GAG-protein interactions in biological systems and potentially as therapeutic targets, detailed structures of such interactions are sparse in availability. Computational methods can provide detailed structural knowledge of these interactions; however, they should be evaluated against suitable test systems prior to their widespread use. In this study, we have investigated the application of automated molecular docking and interaction mapping techniques to characterizing GAG-protein interactions. A series of high-resolution X-ray crystal structures of GAGs in complex with proteins was used to evaluate the approaches. Accurately scoring the pose fitting best with the crystal structure was a challenge for all docking programs evaluated. The site mapping technique offered excellent prediction of the key residues involved in ligand recognition, comparable to the best pose and improved over the top-ranked pose. A design protocol incorporating site- and ligand-based mapping techniques was developed and applied to identify GAGs capable of binding to acidic fibroblast growth factor (aFGF). The protocol was able to identify ligands known to bind to aFGF and accurately able to predict the binding modes of those ligands when using a known ligand-binding conformation of the protein. This study demonstrates the value of mapping-based techniques in identifying specific GAG epitopes recognized by proteins and for GAG-based drug design.

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“…(Yongye, Bender et al 2010) This protocol and other important aspects of conformational coverage in ligand-based virtual screening methods have been recently revised. (Musafia and Senderowitz 2010) On the other hand, docking-based approaches are most valuable when experimental structures of receptors are available. The absence of experimental opioid receptor structures means docking-based methods must rely on homology models.…”

Section: Pharmacophoric Features Of Opioid Ligandsmentioning

confidence: 99%