Realisation of CNS-relevant Molecular Scaffolds Using an Integrated Computational and Synthetic Approach

The physicochemical properties of leads are of vital importance to obtain drugs with the desired therapeutic effect. In central nervous system (CNS) drug discovery, the properties of CNS-leads are even more restricted due to the fact that the resulting drugs must cross the blood-brain barrier (BBB). This thesis is focused on the development of computational and synthetic approaches that can assist the identification of molecular scaffolds that, after decoration, can yield high-quality lead-like molecules for CNS drug discovery. Chapter 1 describes the drug discovery process and its productivity decline. It discusses the importance of physicochemical properties in the early stages, particularly for CNS-drugs. It describes the current computational methodologies and synthetic approaches used to obtain high-quality lead-like molecules. Chapter 2 features the development and validation of a novel computational tool to assist the identification of scaffolds likely to yield high-quality lead-like molecules for CNS drug discovery. Successively, it describes the exemplification of this tool using a Lead-Oriented Synthesis (LOS) approach. Chapter 3 details the elaboration of a novel LOS approach for the synthesis of diverse scaffolds able to yield lead-like molecules with the desired properties for CNS. This approach involves the preparation of highly functionalised cyclisation precursors. Subsequently, different cyclisation reactions are investigated and optimised to yield a library of different scaffolds. The previously developed computational tool is used to assess the value of the scaffolds for CNS. Chapter 4 shows the decoration of some of the prior scaffolds to produce diverse derived molecules, which are used for ligand discovery against the CNS-target BACE1 (β-site amyloid precursor protein cleaving enzyme 1). Chapter 5 describes the methods and materials for the preparation of the computational tool, for the synthesis of all the scaffolds and derived compounds and for the assessment of the biological activity

Modular synthesis of thirty lead-like scaffolds suitable for CNS drug discovery

A modular synthetic approach was developed that yielded thirty diverse lead-like scaffolds suitable for CNS drug discover

Assessing molecular scaffolds for CNS drug discovery

There is a need for high-quality screening collections that maximise hit rate and minimise the time taken in lead optimisation to derive a candidate drug. Identifying and accessing molecules that meet these criteria is a challenge. Within central nervous system (CNS)-focused drug discovery, this challenge is heightened by the requirement for lead compounds to cross the blood–brain barrier. Herein, we demonstrate use of a multiparameter optimisation tool to prioritise the synthesis of molecular scaffolds that, when subsequently decorated, yield screening compounds with experimentally determined properties that align with CNS lead generation needs. Prospective use of this CNS Lead Multiparameter Optimisation (MPO) scoring protocol can guide the further development of novel synthetic methodologies to access CNS-relevant and lead-like chemical space

Discovery of Novel Inhibitors of Uridine Diphosphate-N-Acetylenolpyruvylglucosamine Reductase (MurB) from Pseudomonas aeruginosa, an Opportunistic Infectious Agent Causing Death in Cystic Fibrosis Patients.

Pseudomonas aeruginosa is of major concern for cystic fibrosis patients where this infection can be fatal. With the emergence of drug-resistant strains, there is an urgent need to develop novel antibiotics against P. aeruginosa. MurB is a promising target for novel antibiotic development as it is involved in the cell wall biosynthesis. MurB has been shown to be essential in P. aeruginosa, and importantly, no MurB homologue exists in eukaryotic cells. A fragment-based drug discovery approach was used to target Pa MurB. This led to the identification of a number of fragments, which were shown to bind to MurB. One fragment, a phenylpyrazole scaffold, was shown by ITC to bind with an affinity of Kd = 2.88 mM (LE 0.23). Using a structure guided approach, different substitutions were synthesized and the initial fragment was optimized to obtain a small molecule with Kd = 3.57 μM (LE 0.35).M.A.G.D.E. was supported by American leprosy Missions Grant (G88726). J.M.L., S.Y.K. and O.D.P. were funded by the Cystic Fibrosis Trust and Fondation Botnar (Grant No. 6063). C.M. was funded by the Bill and Melinda Gates Foundation, Hit-TB (OPP1024021). J.H. was funded by the Swiss National Science Foundation (SNSF Early PostDoc. Mobility Fellowship P2ZHP2_164947) and the Marie Curie Research Grant Scheme, EU H2020 Framework Programme (H2020-MSCA-IF-2017, ID: 789607). V.M. was funded by the Bill and Melinda Gates Foun- dation, Hit-TB (OPP1024021) and SHORTEN-TB (OPP1158806). KPB and RAF were funded by NIHR Cambridge Biomedical Research Centre. CA, RAF and TLB by the UK Cystic Fibrosis Trust (SRC010). RAF was funded by the Well- come Trust 107032AIA. And RAF and TLB were founded by the UK Cystic Fibrosis Trust (Innovation Hub grant 001)