Poster Presentation The 43rd Lorne Conference on Protein Structure and Function 2018

Fragment-based drug design using a fragment library designed for efficient hit-to-lead development (#177)

Menachem J Gunzburg 1 , Bradley C Doak 1 , Beatrice Chiew 2 , Stephen J Headey 1 , Craig Morton 3 , Jamie Simpson 2 , Martin J Scanlon 1 2
  1. Monash Fragment Based Drug Design Platform, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Vic, Australia
  2. Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Vic, Australia
  3. St Vincent's Institute, Fitzroy, Vic, Australia

Fragment Based Drug Design (FBDD) is a method of finding lead compounds by searching for small chemical fragments which may bind weakly but efficiently, and elaborating them to generate leads with high affinity. One of the major hurdles in FBDD is developing the initial low affinity fragment hits found through various screening methods into higher affinity lead like structures and beyond.1

Our new workflow for fragment hit development utilizes the recently reported off-rate screening (ORS) strategy.2 We have used chemoinformatics to design reactive reagent libraries suitable for high throughput and parallel small scale synthesis that enable the strategy of “Rapid Elaboration of Fragments into Leads” (REFiL). At its heart, REFiL uses ORS by Surface Plasmon Resonance (SPR) on minimally purified compounds to elaborate fragments and improve their affinity and can be applied without knowledge of the target protein structure.

We have constructed a library of ~1200 fragments for primary screening with the aim of balancing physicochemical properties, dissimilarity, chemical space coverage of the elaborated compounds and practical considerations. Each fragment has at least 20 commercially available analogues to facilitate rapid analogue screening and REFiL. Our library is an evolution of a previous library used for NMR screening against numerous targets, allowing us to keep a number of compounds from the old library while eliminating frequent hitters. We have performed QC on all compounds by 1D 1H and WaterLOGSY NMR and LCMS to confirm compound identity, concentration and solubility. Additionally, we QC compounds for SPR screens by clean-screening against different surfaces used for protein immobilization, to exclude problematic compounds from SPR based primary screens.

We perform primary screens of our fragment library using either NMR ligand detect or SPR using novel One-Step injections on our SensiQ Pioneer FE instruments or our highly sensitive Biacore S200 and T200 instruments.

  1. Hann & Keserü Nat. Rev. Drug Discov. 2012, 11(5), 355-365
  2. Murray, et. al. J. Med. Chem. 2014, 57(7), 2845–2850