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.
Publications
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
Chemical Communications
Using a Function-First “Scout Fragment”-Based Approach to Develop Allosteric Covalent Inhibitors of Conformationally Dynamic Helicase Mechanoenzymes
Patrick M. M. Shelton, Tyler K. Heiss, Paul Dominic B. Olinares, Lauren E. Vostal, Heather Soileau, Michael Grasso, Sara W. Casebeer, Stephanie Adaniya, Michael Miller, Shan Sun, David J. Huggins, Robert W. Myers, Brian T. Chait, Ekaterina V. Vinogradova, and Tarun M. Kapoor
Journal of the American Chemical Society
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 and Ashok R. Venkitaraman
Scientific Reports
Development of a Novel Cell-Permeable Protein–Protein Interaction Inhibitor for the Polo-box Domain of Polo-like Kinase 1
David J. Huggins, Bryn S. Hardwick, Pooja Sharma, Amy Emery, Luca Laraia, Fengzhi Zhang, Ana J. Narvaez, Meredith Roberts-Thomson, Alex T. Crooks. Robert G. Boyle, Richard Boyce, David W. Walker, Natalia Mateu, Grahame J. McKenzie, David R. Spring, and Ashok R. Venkitaraman
ACS Omega
Small-molecule inhibition of Lats kinases may promote Yap-dependent proliferation in postmitotic mammalian tissues
Nathaniel Kastan, Ksenia Gnedeva, Theresa Alisch, Aleksandra A Petelski, David J Huggins, Jeanne Chiaravalli, Alla Aharanov, Avraham Shakked, Eldad Tzahor, Aaron Nagiel, Neil Segil, AJ Hudspeth
Nature communications
Deglycase-activity oriented screening to identify DJ-1 inhibitors
Igor Maksimovic, Efrat Finkin-Groner, Yoshiyuki Fukase, Qingfei Zheng, Shan Sun, Mayako Michino, David J Huggins, Robert W Myers, Yael David
RSC Medicinal Chemistry
Prediction of GABARAP interaction with the GABA type A receptor
BWJ Irwin, Siniša Vukovič, MC Payne, Mohammad El Gamacy, P‐L Chau
Proteins: Structure, Function, and Bioinformatics
Small-molecule inhibition of the acyl-lysine reader ENL as a strategy against acute myeloid leukemia
Yiman Liu, Qinglan Li, Fatemeh Alikarami, Declan R Barrett, Leila Mahdavi, Hangpeng Li, Sylvia Tang, Tanweer A Khan, Mayako Michino, Connor Hill, Lele Song, Lu Yang, Yuanyuan Li, Sheela Pangeni Pokharel, Andrew W Stamford, Nigel Liverton, Louis M Renzetti, Simon Taylor, Gillian F Watt, Tammy Ladduwahetty, Stacia Kargman, Peter T Meinke, Michael A Foley, Junwei Shi, Haitao Li, Martin Carroll, Chun-Wei Chen, Alessandro Gardini, Ivan Maillard, David J Huggins, Kathrin M Bernt, Liling Wan
Cancer discovery
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
Development of an improved inhibitor of Lats kinases to promote regeneration of mammalian organs
Nathaniel R. Kastan, Sanyukta Oak, Rui Liang, Leigh Baxt, Robert W. Myers, John Ginn, Nigel Liverton, David J. Huggins, John Pichardo, Matthew Paul, Thomas S. Carroll, Aaron Nagiel, Ksenia Gnedeva, A. J. Hudspeth
PNAS