MRC DTP 4 Year PhD Programme: InSilico Fragment Screening in Drug Discovery
The process to develop new medicines stars with the identification of small molecules that can modulate a biological target or pathway associated to the disease. In the last twenty years Fragment Based Drug Discovery (FBDD) emerged as a successful alternative to conventional high throughput screening for the generation of chemical hits for drug targets. FBDD offers the adventage of covering larger amounts of chemical space with a relatively small number of different compounds. In addition fragments can also bind very efficiently, usually with 1 or 2 key interactions. If these interactions can be retained during optimization, it is possible to derive very potent and ligand efficient enzyme inhibitors. In FBDD, biophysical detection methods (like Nuclear Magnetic Resonance (NMR) and Surface Plasma Resonance (SPR)) are used to identify small chemical compounds (fragments) that bind to the drug target, and structural biology is usually employed to establish their binding mode and to facilitate their optimisation. The biophysical methods used for screening are very effective in the identification of hit compounds, but their deployment require significant investments both in terms of equipment, logistic and resources reducing their applicability. In Silico approaches can help in addressing those issues and reduced the costs associated to the identification of hits. Several structure-based in silico screening methodologies have been developed in the past to evaluate drug-like molecules but they do not perform well when used to screen molecular fragments. Due to their smaller size, the molecular fragments are characterized by a limited number of interaction and surface complementarity resulting in a lower affinity to the biological target. The project would focus on the development of a structure-based process for the in silico screening and initial optimisation of fragments. Working within the Drug Discovery Unit, the student will use advanced Computational Chemistry methodologies like Molecular Docking, Molecular Dynamics and Quantum Mechanics to develop a structure-based computational platform for the screening in silico of fragments. Experimental biophysical methods for fragment screening (NMR and SPR) will also be used to experimentally validate the computational platform.
Twenty years on: the impact of fragments on drug discovery
Daniel A. Erlanson, Stephen W. Fesik, Roderick E. Hubbard, Wolfgang Jahnke & Harren Jhoti
Nature Reviews Drug Discovery volume 15, pages 605–619 (2016)