Research

The overall research goal of the Brenk group is to improve methods used for structure-based drug design and to apply these methods to design inhibitors for enzymes with biological relevance. A key point in our research is the interplay of theoretical and experimental methods.

Currently, we are working on the following topics:

1. Drugs for neglected diseases. We are involved in the tropical disease initiative at the University of Dundee. We deal with all aspects of computational chemistry, in particular compound selection and structure-based ligand design. Recent publications: Frearson JA, Brand S, McElroy SP, Cleghorn LA, Smid O, Stojanovski L, Price HP, Guther ML, Torrie LS, Robinson DA, Hallyburton I, Mpamhanga CP, Brannigan JA, Wilkinson AJ, Hodgkinson M, Hui R, Qiu W, Raimi OG, van Aalten DM, Brenk R, Gilbert IH, Read KD, Fairlamb AH, Ferguson MA, Smith DF, Wyatt PG. N-myristoyltransferase inhibitors as new leads to treat sleeping sickness. Nature 464 (7289), 728-32 (2010). [Pubmed | DOI] Mpamhanga CP, Spinks D, Tulloch LB, Shanks EJ, Robinson DA, Collie IT, Fairlamb AH, Wyatt PG, Frearson JA, Hunter WN, Gilbert IH, Brenk R. One Scaffold, Three Binding Modes: Novel and Selective Pteridine Reductase 1 Inhibitors Derived from Fragment Hits Discovered by Virtual Screening. J Med Chem 52 (14), 4454-65 (2009). [Pubmed | DOI | Faculty of 1000 Biology | Practical Fragments] Brenk R, Schipani A, James D, Krasowski A, Gilbert IH, Frearson J, Wyatt PG. Lessons Learnt from Assembling Screening Libraries for Drug Discovery for Neglected Diseases. ChemMedChem 3 (3), 435-444 (2008). [Pubmed | DOI]
2. Navigating chemical space. Several million unique compounds are available for screening from commercial suppliers. Screening all of these compounds, virtually or experimentally, is not feasible. Therefore, methods are needed to efficiently navigate chemical space in order to derive focused libraries or representative subsets. Recent publications: Mok NY, Brenk R. Mining the ChEMBL Database: An Efficient Chemoinformatics Workflow for Assembling an Ion Channel-Focused Screening Library. J Chem Inf Model 51 (10), 2449-54 (2011). [Pubmed | DOI] Brenk R, Schipani A, James D, Krasowski A, Gilbert IH, Frearson J, Wyatt PG. Lessons Learnt from Assembling Screening Libraries for Drug Discovery for Neglected Diseases. ChemMedChem 3 (3), 435-444 (2008). [Pubmed | DOI]
3. Analysis of protein binding sites. Hit discovery programs are expensive. Accordingly, it would be valuable to know how high the chance of finding a selective, drug-like inhibitor for a given target is before starting the campaign. We are developing methods that can assist in this assesment. Recent publications: Krasowski A, Muthas D, Sarkar A, Schmitt S, Brenk R. DrugPred: A Structure-Based Approach To Predict Protein Druggability Developed Using an Extensive Nonredundant Data Set. J Chem Inf Model , (2011). [Pubmed | DOI]
4. Structure-based inhibitor design. In collaboration with other labs we are working on the structure-based design of inhibitors for a variety of targets. Recent publications: Bhat VT, Caniard AM, Luksch T, Brenk R, Campopiano DJ, Greaney MF. Nucleophilic catalysis of acylhydrazone equilibration for protein-directed dynamic covalent chemistry. Nat Chem 2 (6), 490-7 (2010). [Pubmed | DOI] Ramsden NL, Buetow L, Dawson A, Kemp LA, Ulaganathan V, Brenk R, Klebe G, Hunter WN. A structure-based approach to ligand discovery for 2C-methyl-D-erythritol-2,4-cyclodiphosphate synthase: a target for antimicrobial therapy. J Med Chem 52 (8), 2531-42 (2009). [Pubmed | DOI]
5. RNA-ligand docking. We are developing methods to predict the binding modes and affinities of RNA-ligand complexes. Further, we are exploiting these methods to discover ligands for riboswitches which are novel targets for antibiotics. Recent publications: Daldrop P, Reyes FE, Robinson DA, Hammond CM, Lilley DM, Batey RT, Brenk R. Novel Ligands for a Purine Riboswitch Discovered by RNA-Ligand Docking. Chem Biol 18 (3), 324-35 (2011). [Pubmed | DOI]