Format

Send to

Choose Destination
Molecules. 2018 Aug 6;23(8). pii: E1959. doi: 10.3390/molecules23081959.

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

Author information

1
In-Silico Toxicology Group, Institute of Physiology, Charité-Universitätsmedizin Berlin, Virchowweg 6, 10117 Berlin, Germany. jeremie.mortier@gmail.com.
2
In-Silico Toxicology Group, Institute of Physiology, Charité-Universitätsmedizin Berlin, Virchowweg 6, 10117 Berlin, Germany. dhakal.pratik@gmail.com.
3
In-Silico Toxicology Group, Institute of Physiology, Charité-Universitätsmedizin Berlin, Virchowweg 6, 10117 Berlin, Germany. andrea.volkamer@charite.de.

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.

KEYWORDS:

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

PMID:
30082611
PMCID:
PMC6222449
DOI:
10.3390/molecules23081959
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Multidisciplinary Digital Publishing Institute (MDPI) Icon for PubMed Central
Loading ...
Support Center