ligand-based structural hypotheses for virtual screening
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Ligand-Based Structural Hypotheses for Virtual Screening. Ajay N. Jain Uses the tool described in the pervious paper. Agenda. - PowerPoint PPT PresentationTRANSCRIPT
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Ligand-Based Structural Hypotheses for Virtual Screening
Ajay N. Jain
Uses the tool described in the pervious paper
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Agenda• To investigate adequacy of the utility of a model
comprised by the overlap of known ligands for a given target in identifying novel ligands with high sensitivity and specificity– The target’s structure is not known– Justification: “Given a small number of potentially quite
flexible molecules of diverse chemical structures, one must generate a hypothesis consisting of a single pose for each input molecule such that the joint superposition of all molecules will lead to predictive models of biological activity”
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Molecules Used:Chose 4 therapeutically interesting targets with
unknown three-dimensional structure, and identified ligands known to associate with those:
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Positive Testing Set:
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Control Test Sets
Estrogen Receptor Ligands
HSV-1 Thymidine kinase inhibitors
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Control Test Sets Alignments
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GPCR Models
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GABAA Model
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ROC Curves
TanimotoSurflex-Sim
TanimotoSurflex-Sim
TanimotoSurflex-Sim
TanimotoSurflex-Sim
Serotonin Model Muscarinic Model
Histamine Model GABAA Model
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Examples of High Scoring Ligands
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Selectivity of the Models
GABAA vs. GPCRGABAA vs. Random
Musc. vs. NonMusc. vs. Random
Hist. vs. NonHist. vs. Random
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Serotonin Model Binding Affinity
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Conclusions• “Offers a generally applicatble method for producing
ligand-based binding site hypotheses, which can be used directly for high-throughput virtual screening or to form the basis on which to construct more detailed models of molecular activity”
• “Performance in terms of screening utility is comparable to that of many structure-based molecular docking techniques, but the best docking methods are capable of better sensitivity and specificity”
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Applicability• “where many existing ligands are known but where
they share side-effects or biological properties that limit their biological utility”
• “where a small number of ligands have been discovered for a target that has not been extensively probed and augmentation of the set is a primary goal of a medicinal chemistry effort”
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Filler for Surflex Similarity Function