Searching for bioactive conformations of drug-like ligands with current force fields: how good are we?

Gürsoy, Oya; Smieško, Martin

doi:10.1186/s13321-017-0216-0

Cited by 35 publications

(30 citation statements)

References 48 publications

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“…Such conformer generation is recommended subsequent to creating an initial threedimensional geometry if desired. [36,38,39,40,41,42,43,44,45]…”

Section: Resultsmentioning

confidence: 99%

Fast, Efficient Fragment-Based Coordinate Generation for Open Babel

Yoshikawa¹,

Hutchison²

2019

Preprint

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<div>Rapidly predicting an accurate three dimensional geometry of a molecule is a crucial task in cheminformatics and a range of molecular modeling. Fast, accurate, and open implementation of structure prediction is necessary for reproducible cheminformatics research. We introduce fragment-based coordinate generation for Open Babel, a widely accepted open source toolkit for cheminformatics. The new implementation significant improves speed and stereochemical accuracy, while retaining or improving accuracy of bond lengths, bond angles, and dihedral torsions. We first separate an input molecule into fragments by cutting at rotatable bonds. Coordinates of fragments are set according to the fragment library, which is prepared from open crystallographic databases. Since coordinates of multiple atoms are decided at once, coordinate prediction is accelerated over the previous rules-based implementation or 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.</div>

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“…Such conformer generation is recommended subsequent to creating an initial threedimensional geometry if desired. [36,38,39,40,41,42,43,44,45]…”

Section: Resultsmentioning

confidence: 99%

Fast, Efficient Fragment-Based Coordinate Generation for Open Babel

Yoshikawa¹,

Hutchison²

2019

Preprint

View full text Add to dashboard Cite

show abstract

“…Such conformer generation is recommended subsequent to creating an initial threedimensional geometry if desired. [36,38,39,40,41,42,43,44,45]…”

Section: Resultsmentioning

confidence: 99%

Fast, Efficient Fragment-Based Coordinate Generation for Open Babel

Yoshikawa¹,

Hutchison

2019

Preprint

View full text Add to dashboard Cite

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.

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“…Clearly, the ideal docking protocol would include all (or a set of most representative) peptides with high affinities for the targeted HLA-variant to ensure experimental success, but in the absence of fully solved HLA-peptide binding modes, this will be a difficult challenge to solve. A recent study by Gürsoy and Smieško [ 96 ] tested the reliability of force fields to accurately predict biologically active conformations of drugs, and revealed that conformational accuracy of a force field decreases as the number of rotatable bonds in a compound increases. Obviously, accurately predicting the binding conformation of peptides will be a major obstacle due to the high number of rotatable bonds, despite some significant progress [ 88 ].…”

Section: Resultsmentioning

confidence: 99%

Adverse drug reactions triggered by the common HLA-B*57:01 variant: virtual screening of DrugBank using 3D molecular docking

Driessche

Fourches

2018

J Cheminform

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BackgroundIdiosyncratic adverse drug reactions have been linked to a drug’s ability to bind with a human leukocyte antigen (HLA) protein. However, due to the thousands of HLA variants and limited structural data for drug-HLA complexes, predicting a specific drug-HLA combination represents a significant challenge. Recently, we investigated the binding mode of abacavir with the HLA-B*57:01 variant using molecular docking. Herein, we developed a new ensemble screening workflow involving three X-ray crystal derived docking procedures to screen the DrugBank database and identify potentially HLA-B*57:01 liable drugs. Then, we compared our workflow’s performance with another model recently developed by Metushi et al., which proposed seven in silico HLA-B*57:01 actives, but were later found to be experimentally inactive.MethodsAfter curation, there were over 6000 approved and experimental drugs remaining in DrugBank for docking using Schrodinger’s GLIDE SP and XP scoring functions. Docking was performed with our new consensus-like ensemble workflow, relying on three different X-ray crystals (3VRI, 3VRJ, and 3UPR) in presence and absence of co-binding peptides. The binding modes of HLA-B*57:01 hit compounds for all three peptides were further explored using 3D interaction fingerprints and hierarchical clustering.ResultsThe screening resulted in 22 hit compounds forecasted to bind HLA-B*57:01 in all docking conditions (SP and XP with and without peptides P1, P2, and P3). These 22 compounds afforded 2D-Tanimoto similarities being less than 0.6 when compared to the structure of native abacavir, whereas their 3D binding mode similarities varied in a broader range (0.2–0.8). Hierarchical clustering using a Ward Linkage revealed different clustering patterns for each co-binding peptide. When we docked Metushi et al.’s seven proposed hits using our workflow, our screening platform identified six out of seven as being inactive. Molecular dynamic simulations were used to explore the stability of abacavir and acyclovir in complex with peptide P3.ConclusionsThis study reports on the extensive docking of the DrugBank database and the 22 HLA-B*57:01 liable candidates we identified. Importantly, comparisons between this study and the one by Metushi et al. highlighted new critical and complementary knowledge for the development of future HLA-specific in silico models.Electronic supplementary materialThe online version of this article (10.1186/s13321-018-0257-z) contains supplementary material, which is available to authorized users.

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Searching for bioactive conformations of drug-like ligands with current force fields: how good are we?

Cited by 35 publications

References 48 publications

Fast, Efficient Fragment-Based Coordinate Generation for Open Babel

Fast, Efficient Fragment-Based Coordinate Generation for Open Babel

Fast, Efficient Fragment-Based Coordinate Generation for Open Babel

Adverse drug reactions triggered by the common HLA-B*57:01 variant: virtual screening of DrugBank using 3D molecular docking

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