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

Molecules

Pratik Dhakal¹  Andrea Volkamer¹  Jérémie Mortier¹ 

[1] In-Silico Toxicology Group, Institute of Physiology, Charité—Universitätsmedizin Berlin, Virchowweg 6, 10117 Berlin, Germany;

关键词: target-focused pharmacophore modeling;    density-based clustering;    structure-based drug design;    AutoGrid;    grid maps;    probe energies;    method development;   

DOI  :  10.3390/molecules23081959

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown