The main objective of this project is to contribute to the development of novel chemical probes of Cyclophilins function using a range of state-of the art methodologies from chemical, structural and computational biology.
Inhibition of diverse Cyclophilin isoforms could pave the way for novel therapeutic treatments in diverse areas of immunosuppression, neuroprotection, and viral diseases. Yet drug development efforts have been limited historically due to the challenge of selectively inhibiting a given Cyclophilin isoform.
Our laboratories have a long-standing interest in the use of biophysical and computational methods to discover novel Cyclophilin ligands.1 In this PhD project you will build on our previous and current body of work and pursue the challenge of Cyclophilin inhibition by exploiting protein dynamics to reveal ‘transient protein states’ that are not apparent in structures readily solved by X-ray crystallography experiments.2 We have developed a methodology to detect such transient protein states via an integrative structural biology approach that combines X-ray crystallography and protein NMR measurements with molecular dynamics simulations to deliver dynamical models of Cyclophilins. Model analysis informs the rational design of small molecules to selectively bind and stabilize such transient states. Such small molecules are selected from existing libraries, or synthesized and assayed for binding and functional behaviour using NMR and isothermal titration calorimetry experiments. Through targeting a transient protein state that is unique to a given Cyclophilin isoform, you will identify small molecules with high sub-type selectivity.
The ideal applicant will have a strong academic record, a BSc or MChem/MSc degree in Chemistry, Biochemistry or related fields, and previous research experience in structural, chemical or computational biology. The ideal candidate will also demonstrate keen interest in molecular recognition, enthusiasm for multidisciplinary research, and a passion for improving human health with small-molecules.
1) ‘’Pushing The Limits Of Detection Of Weak Binding Using Fragment Based Drug Discovery: Identification Of New Cyclophilin Binders’’ Georgiou, C. ; McNae, I. W. ; Wear, M. A. ; Ioannidis, H. ; Michel, J. ; Walkinshaw, M. D. J Mol. Biol., 429(16), 2556-2570, 2017
2) ‘’Exploiting Transient Protein States for the Design of Small-Molecule Stabilizers of Mutant p53.’’ Joerger, A. C.; Bauer, M. R. ; Wilcken, R. ; Baud, M. G. ; Harbrecht, H. ; Exner, T. E.; Boeckler, F. M.; Spencer, J. ; Fersht, A. R. Structure, 23(12):2246-55, 2015.