Biophysical Society Thematic Meeting

Biophysics in the Understanding, Diagnosis, and Treatment of Infectious Diseases Speaker Abstracts

Biophysical Methods and Fragment-based Drug Discovery for Infectious Disease:

Targeting Mycobacterium Tuberculosis and Mycobacterium Abscessus

Tom Blundell

University of Cambridge, Cambridge, United Kingdom.

Structure-guided fragment-based screening techniques have proved effective in lead discovery

not only for classical enzyme targets but also for less “druggable” targets such as protein-protein

interfaces. They also have the advantage of allowing optimisation of a range of physical

chemical properties that allow optimisation for a range of absorption, distribution, metabolism,

excretion and toxicology (admet) properties; these are proving particular challenges in

tuberculosis drug discovery.

As the initial screening involves small fragments with very low, often millimolar affinities,

biophysical methods such as isothermal calorimetry (ITC), analytical ultracentrifugation (AUC),

thermal shift, surface plasmon resonance (SPR), nuclear magnetic resonance (NMR) and X-ray

crystallography are used to explore chemical space of potential ligands. The approach involves a

fast initial screening of a library of around 1000 compounds, followed by a validation step

involving more rigorous use of related methods to define three-dimensional structure, kinetics

and thermodynamics of fragment binding. The use of high throughput approaches does not end

there, as it becomes a rapid technique to guide the elaboration of the fragments into larger

molecular weight lead compounds.

I will discuss progress in using these approaches for targets in Mycobacterium Tuberculosis and

Mycobacterium Abscessus. I will review our work in using fragment-based methods for protein-

protein interfaces and discuss the challenges of the interface surfaces in terms of potential

binding sites where fragment-based methods can efficiently explore protein landscapes; these

tend to have clusters of small but deep pockets rather than the well-defined clefts of traditionally

druggable targets.