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SAMPL7 protein-ligand challenge: A community-wide evaluation of computational methods against fragment screening and pose-prediction

DOI: 10.1007/s10822-022-00452-7 DOI Help

Authors: Harold Grosjean (University of Oxford; Diamond Light Source) , Mehtap Işık (Memorial Sloan Kettering Cancer Center) , Anthony Aimon (Diamond Light Source; Research Complex at Harwell) , David Mobley (University of California, Irvine) , John Chodera (Memorial Sloan Kettering Cancer Center) , Frank Von Delft (Diamond Light Source; Research Complex at Harwell; Structural Genomics Consortium, University of Oxford) , Philip C. Biggin (University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Computer-Aided Molecular Design , VOL 14

State: Published (Approved)
Published: April 2022
Diamond Proposal Number(s): 18145

Open Access Open Access

Abstract: A novel crystallographic fragment screening data set was generated and used in the SAMPL7 challenge for protein-ligands. The SAMPL challenges prospectively assess the predictive power of methods involved in computer-aided drug design. Application of various methods to fragment molecules are now widely used in the search for new drugs. However, there is little in the way of systematic validation specifically for fragment-based approaches. We have performed a large crystallographic high-throughput fragment screen against the therapeutically relevant second bromodomain of the Pleckstrin-homology domain interacting protein (PHIP2) that revealed 52 different fragments bound across 4 distinct sites, 47 of which were bound to the pharmacologically relevant acetylated lysine (Kac) binding site. These data were used to assess computational screening, binding pose prediction and follow-up enumeration. All submissions performed randomly for screening. Pose prediction success rates (defined as less than 2 Å root mean squared deviation against heavy atom crystal positions) ranged between 0 and 25% and only a very few follow-up compounds were deemed viable candidates from a medicinal-chemistry perspective based on a common molecular descriptors analysis. The tight deadlines imposed during the challenge led to a small number of submissions suggesting that the accuracy of rapidly responsive workflows remains limited. In addition, the application of these methods to reproduce crystallographic fragment data still appears to be very challenging. The results show that there is room for improvement in the development of computational tools particularly when applied to fragment-based drug design.

Journal Keywords: Pleckstrin-homology domain interacting protein; Bromodomain; Fragment-based drug design; Crystallography; High-throughput screening; SAMPL challenge

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

Diamond Offline Facilities: XChem
Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)

Added On: 20/04/2022 10:55


Discipline Tags:

Health & Wellbeing Data management / presentation Computing & software technologies Information & Communication Technologies Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX) Fragment Screening