Fragment-based drug discovery using cryo-EM

Drug Discov Today. 2020 Mar;25(3):485-490. doi: 10.1016/j.drudis.2019.12.006. Epub 2019 Dec 23.

Abstract

Recent advances in electron cryo-microscopy (cryo-EM) structure determination have pushed the resolutions obtainable by the method into the range widely considered to be of utility for drug discovery. Here, we review the use of cryo-EM in fragment-based drug discovery (FBDD) based on in-house method development. We demonstrate not only that cryo-EM can reveal details of the molecular interactions between fragments and a protein, but also that the current reproducibility, quality, and throughput are compatible with FBDD. We exemplify this using the test system β-galactosidase (Bgal) and the oncology target pyruvate kinase 2 (PKM2).

Publication types

  • Review

MeSH terms

  • Carrier Proteins / chemistry
  • Carrier Proteins / metabolism
  • Cryoelectron Microscopy / methods*
  • Drug Discovery / methods*
  • High-Throughput Screening Assays
  • Humans
  • Membrane Proteins / chemistry
  • Membrane Proteins / metabolism
  • Reproducibility of Results
  • Thyroid Hormones / chemistry
  • Thyroid Hormones / metabolism
  • beta-Galactosidase / chemistry
  • beta-Galactosidase / metabolism

Substances

  • Carrier Proteins
  • Membrane Proteins
  • Thyroid Hormones
  • thyroid hormone-binding proteins
  • beta-Galactosidase