Research in the Brenk lab
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. 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.
- Mok NY, Brenk R, Brown N. Increasing the coverage of medicinal chemistry-relevant space in commercial fragments screening. J Chem Inf Model 54 (1), 79-85 (2014). [Pubmed | DOI | F1000 recommended | practicalfragments.blogspot.co.uk]
- 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]
2. 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. This is a partner project of Digital Life Norway.
- Rekand IH, Brenk R. Ligand design for riboswitches, an emerging target class for novel antibiotics. Future Med Chem. 2017 Sep;9(14):1649-1662. [Pubmed | DOI | Post-print version]
- Wehler, T.; Brenk, R. Structure-Based Discovery of Small Molecules Binding to RNA. In RNA Therapeutics; Topics in Medicinal Chemistry; Springer, 2017; pp 47–77. [DOI]
- Daldrop P, Brenk R. Structure-Based Virtual Screening for the Identification of RNA-Binding Ligands. Methods Mol Biol 1103, 127-39 (2014). [Pubmed | DOI]
- Daldrop P, Reyes FE, Robinson DA, Hammond CM, Lilley DM, Batey RT, Brenk R. Novel Ligands for a Purine Riboswitch iscovered by RNA-Ligand Docking. Chem Biol 18 (3), 324-35 (2011). [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.
- Sarkar A, Brenk R. To Hit or Not to Hit, That Is the Question - Genome-wide Structure-Based Druggability Predictions for Pseudomonas aeruginosa Proteins. PLoS One 10 (9), e0137279 (2015). [Pubmed | DOI]
- 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 51 (11), 2829-42 (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.
- Klein R, Linciano P, Celenza G, Bellio P, Papaioannou S, Blazquez J, Cendron L, Brenk R, Tondi D. In silico identification and experimental validation of hits active against KPC-2 β-lactamase. PLoS One. 2018 Nov 29;13(11):e0203241. [Pubmed | DOI | bioRxiv]
- Urich R, Wishart G, Kiczun M, Richters A, Tidten-Luksch N, Rauh D, Sherborne B, Wyatt PG, Brenk R. De novo design of protein kinase inhibitors by in silico identification of hinge region-binding fragments. ACS Chem Biol 8 (5), 1044-52 (2013). [Pubmed | DOI]
- 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 | F1000 recommended]
- 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 | F1000 recommended | Practical Fragments]