Computer-Aided Chemical Biology
The development of publically-available chemical probes for the purpose of target exploration is a new paradigm in drug discovery. This shift has been pioneered by non-profit and open-source ventures such as the SGC and NIH chemical probes.
Having publically available chemical probes for potential drug targets facilitates an open assessment of target viability, paving the way for commercial ventures to develop effective treatments at a lower societal cost. We are applying computational methods such as alchemical free-energy calculation to the development of chemical probes for the purpose of target validation.
The main advantages of these computational methods are that they can analyse multiple structures using a very large number of potential chemical elaborations and identify surprising and sometimes counter-intuitive successes.
Biomolecular simulations: From dynamics and mechanisms to computational assays of biological activity
David J. Huggins, Philip C. Biggin, Marc A. Dämgen, Jonathan W. Essex, Sarah A. Harris, Richard H. Henchman, Syma Khalid, Antonija Kuzmanic, Charles A. Laughton, Julien Michel, Adrian J. Mulholland, Edina Rosta, Mark S. P. Sansom, Marc W. van der Kamp
Wiley Interdisciplinary Reviews: Computational Molecular Science
Computationally-Guided Optimization of Small-Molecule Inhibitors of the Aurora A Kinase – TPX2 Protein-Protein Interaction
Daniel Cole, Matej Janecek, Jamie Stokes, Maxim Rossmann, John Faver, Grahame McKenzie, Ashok Venkitaraman, Marko Hyvönen, David R Spring, David John Huggins and WL Jorgensen
Estimating Atomic Contributions to Hydration and Binding using Free Energy Perturbation
Benedict W. J. Irwin, David John Huggins
Journal of Chemical Theory and Computation
PARP1- dependent recruitment of KDM4D histone demethylase to DNA damage sites promotes double-strand break repair
Hanan Khoury-Haddad, Noga Guttmann-Raviv, Inbal Ipenberg, David Huggins, Anand D. Jeyasekharan, and Nabieh Ayoub
PNAS - 2014
Characterization and tissue-specific expression of two lepidopteran farnesyl diphosphate synthase homologs: implications for the biosynthesis of ethyl-substituted juvenile hormones
Michel Cusson, Catherine Beliveau, Stephanie E. Sen, Sophie Vandermoten, Robert G. Rutledge, Don Stewart, Frederic Francis, Eric Haubruge, Peter Rehse, David J. Huggins, Guy H. Grant
Proteins: Structure, Function and Bioinformatics - 2006, Volume 65: Issue 3
Kanamycin reveals the role played by glutamate receptors in shaping plant resource allocation
Christian Dubos, David J. Huggins, Guy H. Grant, Malcolm M. Campbell
The Plant Journal - 2005, Volume 43: Issue 3
A role for glycine in the gating of plant NMDA-like receptors
Christian Dubos, David Huggins, Guy H. Grant, Marc R. Knight, Malcolm M. Campbell.
The Plant Journal - 2003, Volume 35: Issue 6
Allosteric modulation of AURKA kinase activity by a small-molecule inhibitor of its protein-protein interaction with TPX2
Matej Janecek, Maxim Rossmann, Pooja Sharma, Amy Emery, David J Huggins, Simon R Stockwell, Jamie E Stokes, Yaw S Tan, Estrella Guarino Almeida, Bryn Hardwick, Ana J Narvaez, Marko Hyvönen, David R Spring, Grahame J McKenzie, Ashok R Venkitaraman
Scientific Reports - 2016
A cryptic hydrophobic pocket in the polo-box domain of the polo-like kinase PLK1 regulates substrate recognition and mitotic chromosome segregation
Pooja Sharma, Robert Mahen, Maxim Rossmann, Jamie E. Stokes, Bryn Hardwick, David J. Huggins, Amy Emery, Dominique L. Kunciw, Marko Hyvönen, David R. Spring, Grahame J. McKenzie & Ashok R. Venkitaraman