Summary of CACHE#5 Round 1 experimental Validation Data

Receptor binding profiles, and agonist/antagonist functional data were generously provided by the National Institute of Mental Health's Psychoactive Drug Screening Program, Contract # 75N95023C00021 (NIMH PDSP). The NIMH PDSP is Directed by Bryan L. Roth MD, PhD at the University of North Carolina at Chapel Hill and Project Officer Jamie Driscoll at NIMH, Bethesda MD, USA. 
 

Here are the results from the experimental validation of compounds from the first round (hit identification) of CACHE challenge #5. The full data will be released upon completion of the second round (hit expansion).

 

THE CHALLENGE

  • CACHE participants were asked to use their computational methods to find chemically novel antagonists of MCHR1, a GPCR. See details
  • After a double-blind peer review where each applicant reviewed 5 applications, 24 participants joined the challenge, representing a diverse array of physics-based and AI computational methods.
  • Participants collectively selected 1455 compounds (no more than 100 compounds per participant) that we ordered and received from Enamine.
  • Compounds were first tested for their ability to compete with an MCHR1 antagonist (SNAP94847) using cell membrane preparations.
  • 147 compounds showed at least 50% inhibition at 30 µM and were advanced to dose response experiment [concentration range: 10nM to 100 µM].
  • A full dose response was observed for 26 compounds, leading to inhibitory activity (Ki) ranging from 170 nM to 30 µM while another 18 compounds had a partial allosteric modulator (PAM) profile.
  • These 44 compounds were advanced to Round 2, even though some (mostly PAMs) showed signs of insolubility.
  • The 44 compounds are expected to behave as antagonists and were also tested in functional GloSensor cAMP antagonist and agonist assays using transiently transfected HEK293 T cells. Thirteen compounds displayed weak or very weak antagonist activity. Some of the other compounds clearly interfered in both agonist and antagonist assays.
  • All experimental data except the structure of the compounds are summarized here.
  • The structure of the compounds will be provided at the end of the second round (hit-expansion) of the challenge.