Expanding FTMap for fragment-based identification of pharmacophore regions in ligand binding sites

DOI: 10.1021/acs.jcim.3c01969

Authors: Omeir Khan (Boston University) , George Jones (Stony Brook University) , Maria Lazou (Boston University) , Diane Joseph-Mccarthy (Boston University) , Dima Kozakov (Stony Brook University) , Dmitri Beglov (Boston University) , Sandor Vajda (Boston University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Chemical Information And Modeling , VOL 37

State: Published (Approved)
Published: March 2024

Abstract: The knowledge of ligand binding hot spots and of the important interactions within such hot spots is crucial for the design of lead compounds in the early stages of structure-based drug discovery. The computational solvent mapping server FTMap can reliably identify binding hot spots as consensus clusters, free energy minima that bind a variety of organic probe molecules. However, in its current implementation, FTMap provides limited information on regions within the hot spots that tend to interact with specific pharmacophoric features of potential ligands. E-FTMap is a new server that expands on the original FTMap protocol. E-FTMap uses 119 organic probes, rather than the 16 in the original FTMap, to exhaustively map binding sites, and identifies pharmacophore features as atomic consensus sites where similar chemical groups bind. We validate E-FTMap against a set of 109 experimentally derived structures of fragment–lead pairs, finding that highly ranked pharmacophore features overlap with the corresponding atoms in both fragments and lead compounds. Additionally, comparisons of mapping results to ensembles of bound ligands reveal that pharmacophores generated with E-FTMap tend to sample highly conserved protein–ligand interactions. E-FTMap is available as a web server at https://eftmap.bu.edu.

Subject Areas: Medicine, Biology and Bio-materials, Chemistry

Diamond Offline Facilities: XChem
Instruments: NONE-No attached Diamond beamline

Added On: 11/03/2024 08:50

Discipline Tags:

Health & Wellbeing Biochemistry Chemistry Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX) Fragment Screening