Discovery of novel BRD4 ligand scaffolds by automated navigation of the fragment chemical space

DOI: 10.1021/acs.jmedchem.1c01108

Authors: Serena G. Piticchio (Universitat de Barcelona) , Miriam Martinez-Cartro (Universitat de Barcelona) , Salvatore Scaffidi (Universitat de Barcelona) , Moira Rachman (Universitat de Barcelona) , Sergio Rodriguez-Arevalo (Universitat de Barcelona) , Ainoa Sanchez-Arfelis (Universitat de Barcelona) , Carmen Escolano (Universitat de Barcelona) , Sarah Picaud (Structural Genomics Consortium, University of Oxford) , Tobias Krojer (Structural Genomics Consortium, University of Oxford) , Panagis Filippakopoulos (Structural Genomics Consortium, University of Oxford) , Frank Von Delft (Structural Genomics Consortium, University of Oxford; Diamond Light Source; Research Complex at Harwell; University of Johannesburg) , Carles Galdeano (Universitat de Barcelona) , Xavier Barril (Universitat de Barcelona)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry

State: Published (Approved)
Published: December 2021
Diamond Proposal Number(s): 15433 , 19301

Abstract: Fragment-based drug discovery (FBDD) is a very effective hit identification method. However, the evolution of fragment hits into suitable leads remains challenging and largely artisanal. Fragment evolution is often scaffold-centric, meaning that its outcome depends crucially on the chemical structure of the starting fragment. Considering that fragment screening libraries cover only a small proportion of the corresponding chemical space, hits should be seen as probes highlighting privileged areas of the chemical space rather than actual starting points. We have developed an automated computational pipeline to mine the chemical space around any specific fragment hit, rapidly finding analogues that share a common interaction motif but are structurally novel and diverse. On a prospective application on the bromodomain-containing protein 4 (BRD4), starting from a known fragment, the platform yields active molecules with nonobvious scaffold changes. The procedure is fast and inexpensive and has the potential to uncover many hidden opportunities in FBDD.

Journal Keywords: Binding modes; Ligands; Scaffolds; Drug discovery; Molecules

Subject Areas: Medicine, Biology and Bio-materials, Information and Communication Technology


Instruments: I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength)

Added On: 15/12/2021 08:58

Discipline Tags:

Health & Wellbeing Biochemistry Technique Development - Life Sciences & Biotech Information & Communication Technologies Chemistry Structural biology Organic Chemistry Data processing Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)