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Molecules 2018, 23(8), 1959; https://doi.org/10.3390/molecules23081959

Truly Target-Focused Pharmacophore Modeling: A Novel Tool for Mapping Intermolecular Surfaces

In-Silico Toxicology Group, Institute of Physiology, Charité—Universitätsmedizin Berlin, Virchowweg 6, 10117 Berlin, Germany
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Received: 4 June 2018 / Revised: 27 July 2018 / Accepted: 27 July 2018 / Published: 6 August 2018
(This article belongs to the Special Issue Molecular Modeling in Drug Design)
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Abstract

Pharmacophore models are an accurate and minimal tridimensional abstraction of intermolecular interactions between chemical structures, usually derived from a group of molecules or from a ligand-target complex. Only a limited amount of solutions exists to model comprehensive pharmacophores using the information of a particular target structure without knowledge of any binding ligand. In this work, an automated and customable tool for truly target-focused (T²F) pharmacophore modeling is introduced. Key molecular interaction fields of a macromolecular structure are calculated using the AutoGRID energy functions. The most relevant points are selected by a newly developed filtering cascade and clustered to pharmacophore features with a density-based algorithm. Using five different protein classes, the ability of this method to identify essential pharmacophore features was compared to structure-based pharmacophores derived from ligand-target interactions. This method represents an extremely valuable instrument for drug design in a situation of scarce ligand information available, but also in the case of underexplored therapeutic targets, as well as to investigate protein allosteric pockets and protein-protein interactions. View Full-Text
Keywords: target-focused pharmacophore modeling; density-based clustering; structure-based drug design; AutoGrid; grid maps; probe energies; method development target-focused pharmacophore modeling; density-based clustering; structure-based drug design; AutoGrid; grid maps; probe energies; method development
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Mortier, J.; Dhakal, P.; Volkamer, A. Truly Target-Focused Pharmacophore Modeling: A Novel Tool for Mapping Intermolecular Surfaces. Molecules 2018, 23, 1959.

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