Investigating and exploiting best practices in hit identification and hit to lead chemistry

  • Jennifer Anne Borthwick

Student thesis: Doctoral Thesis

Abstract

A fragment-based drug discovery (FBDD) effort was carried out against the enzyme target BCATm. This resulted in elucidation of novel binding interactions against the enzyme. Several series of inhibitors were identified, these are the first known small molecule inhibitors of this enzyme. The compounds identified contained several examples which exhibited potent enzyme binding, excellent activity in a cellular assay and excellent DMPK profiles, making them high quality tools for target validation experiments. A comparative data analysis was carried out to compare the physicochemical properties of molecules discovered by FBDD, high throughput screening (HTS) and encoded library technology (ELT) against BCATm. This showed that the properties of the ELT derived molecules were consistently outside of the established areas of physicochemical properties for drugs and leads, whilst the HTS and FBDD derived compounds largely sat within the desired space. This analysis was extended to clinical candidates against a range of targets described in the literature as being discovered by a range of different techniques. Only slight trends for improved properties for FBDD derived molecules were observed. A phenotypic HTS hit against tuberculosis was identified to be acting through inhibition of the enzyme DprE1. This molecule had physicochemical properties which were far from the established limits for drug molecules. Through careful optimisation, using methodologies first established for FBDD, a lead series with much improved properties was derived. The lead molecules had potent inhibition of DprE1, were efficacious in halting the growth of Mycobacteria tuberculosis in vitro, had excellent DMPK properties and also showed good efficacy in in vivo models of tuberculosis.
Date of Award22 Aug 2016
Original languageEnglish
Awarding Institution
  • University Of Strathclyde
SponsorsUniversity of Strathclyde
SupervisorColin Suckling (Supervisor) & Craig Jamieson (Supervisor)

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