Journal
MOLECULES
Volume 23, Issue 8, Pages -Publisher
MDPI
DOI: 10.3390/molecules23081959
Keywords
target-focused pharmacophore modeling; density-based clustering; structure-based drug design; AutoGrid; grid maps; probe energies; method development
Funding
- German Federal Ministry of Education and Research (BMBF) [031A262C]
- German Research Foundation (DFG)
- Charite-Universitatsmedizin Berlin
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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 ((TF)-F-2) 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.
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