New Scoring Functions for Virtual Screening from Molecular Dynamics Simulations with a Quantum-Refined Force-Field (QRFF-MD). Application to Cyclin-Dependent Kinase 2

Ferrara, Philippe; Curioni, A.; Vangrevelinghe, Eric; Meyer, T.; Mordasini, Tiziana; Andreoni, Wanda; Acklin, Pierre; Jacoby, Edgar

doi:10.1021/ci050289+

Cited by 26 publications

(14 citation statements)

References 40 publications

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“…The algorithm is based on the molecular docking of chemical compounds to the known 3D model of a target protein, which predicts the possible position of a compound in the protein–ligand binding site, the calculation of the molecular dynamics being used to refine the binding energies for the best suiting compounds. As shown in our study, as well as in previous studies [14–19], this multi-level approach is not only efficient, but it also considerably reduces the amount of experiments to be carried out. In this case, it enabled the discovery of several ligands of the transcription factor DLX5 that have potential for cancer therapy.…”

Section: Introductionsupporting

confidence: 61%

Transcription Factor DLX5 As a New Target for Promising Antitumor Agents

et al. 2011

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The crystal structure of the human transcription factor DLX5 has been used for the screening of a library consisting of 106 compounds by the molecular docking technique.In vitro testsof the 14 top-rated ligands showed that compound Q12 displays the best ability to inhibit the proliferation ofDlx5 positive mouse lymphoma cells, which correlates with the down-regulation ofc-mycexpression. Compound Q12 has low toxicity on normal human ovarian epithelial cells and mouse lymphoma cells with absent expression ofDlx5, and can be used for further chemical optimization and for the development of novel, highly efficient cancer treatments.

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Section: Introductionsupporting

confidence: 61%

Transcription Factor DLX5 As a New Target for Promising Antitumor Agents

et al. 2011

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“…Several scoring methods have been developed over the years; these include empirical, 3−11 knowledge-based, 12−21 and force field-based. 22−29 We recently developed a new scoring approach that combines machine learning and statistical knowledge-based potentials for rank-ordering Support Vector Regression Knowledge-Based (SVRKB) 30 and database enrichment Support Vector Machine SPecific (SVMSP). 31 The former is regression-based and trained on crystal structures using corresponding experimental binding affinities, while the latter is based on classification and is trained strictly on three-dimensional structures of protein–ligand complexes using both actives and decoys.…”

Section: Introductionmentioning

confidence: 99%

Enrichment of Chemical Libraries Docked to Protein Conformational Ensembles and Application to Aldehyde Dehydrogenase 2

Wang

Buchman

et al. 2014

J. Chem. Inf. Model.

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Molecular recognition is a complex process that involves a large ensemble of structures of the receptor and ligand. Yet, most structure-based virtual screening is carried out on a single structure typically from X-ray crystallography. Explicit-solvent molecular dynamics (MD) simulations offer an opportunity to sample multiple conformational states of a protein. Here we evaluate our recently developed scoring method SVMSP in its ability to enrich chemical libraries docked to MD structures of seven proteins from the Directory of Useful Decoys (DUD). SVMSP is a target-specific rescoring method that combines machine learning with statistical potentials. We find that enrichment power as measured by the area under the ROC curve (ROC-AUC) is not affected by increasing the number of MD structures. Among individual MD snapshots, many exhibited enrichment that was significantly better than the crystal structure, but no correlation between enrichment and structural deviation from crystal structure was found. We followed an innovative approach by training SVMSP scoring models using MD structures (SVMSPMD). The resulting models were applied to two difficult cases (p38 and CDK2) for which enrichment was not better than random. We found remarkable increase in enrichment power, particularly for p38, where the ROC-AUC increased by 0.30 to 0.85. Finally, we explored approaches for a priori identification of MD snapshots with high enrichment power from an MD simulation in the absence of active compounds. We found that the use of randomly selected compounds docked to the target of interest using SVMSP led to notable enrichment for EGFR and Src MD snapshots. SVMSP rescoring of protein–compound MD structures was applied for the search of small-molecule inhibitors of the mitochondrial enzyme aldehyde dehydrogenase 2 (ALDH2). Rank-ordering of a commercial library of 50 000 compounds docked to MD structures of ALDH2 led to five small-molecule inhibitors. Four compounds had IC50s below 5 μM. These compounds serve as leads for the design and synthesis of more potent and selective ALDH2 inhibitors.

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“…When a binding site or a pharmacophoric model is known then it is possible to use de novo design methods [13,14] that are to develop novel molecules with significantly different scaffolds thereby providing potential areas of greater potency and novel intellectual property. Extant molecules may also be virtually docked against the protein binding site to investigate the potential binding energies of the molecules [15][16][17]. However, when the receptor structure information is not known, it is necessary for extant molecules that are known to invoke a desired response to be applied in an attempt to discover or develop new molecules with diverse scaffolds that maintain a likelihood of being of interest in terms of the objective of the study: ligand-based scaffold hopping.…”

Section: Ligand-based Scaffold Hoppingmentioning

confidence: 99%

On Scaffolds and Hopping in Medicinal Chemistry

Brown

Jacoby²

2006

MRMC

140

130

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The molecular scaffold is an oft-cited concept in medicinal chemistry suggesting that the definition of what makes a scaffold is rigorous and objective. However, this is far from the case with the definition of a scaffold being highly dependent on the particular viewpoint of a given scientist. It follows, therefore, that the definition of scaffold hopping and, more importantly, the detection of what constitutes a scaffold hop, is also ill-defined and highly subjective. Essentially, it is agreed that scaffolds should be substantially different from each other, although significantly similar to each other, to constitute a hop. In the latter, the scaffolds must permit a similar geometric arrangement of functional groups to permit the mode of action. However, this leaves the paradox of how to describe both scaffold similarity and dissimilarity simultaneously. In this paper, the current statuses of scaffolds and scaffold hopping are reviewed based on published examples of scaffold hopping from the literature. An investigation of the degree to which it is possible to formulate a more rigorous definition of scaffolds and hopping in the context of molecular topologies is considered. These techniques are adapted from chemoinformatics to be applied in the design of new medicinal compounds.

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New Scoring Functions for Virtual Screening from Molecular Dynamics Simulations with a Quantum-Refined Force-Field (QRFF-MD). Application to Cyclin-Dependent Kinase 2

Cited by 26 publications

References 40 publications

Transcription Factor DLX5 As a New Target for Promising Antitumor Agents

Transcription Factor DLX5 As a New Target for Promising Antitumor Agents

Enrichment of Chemical Libraries Docked to Protein Conformational Ensembles and Application to Aldehyde Dehydrogenase 2

On Scaffolds and Hopping in Medicinal Chemistry

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