Molecular Design For Drug Discovery

Computational molecular design is a useful tool in modern drug discovery. Virtual screening is an approach that evaluates individual members of compound libraries. In contrast, design approaches construct compounds by combining scaffolds and sidegroups to optimise the calculated binding affinity. We develop software tools and apply molecular design to drug discovery projects.

Publications

Estimating Atomic Contributions to Hydration and Binding using Free Energy Perturbation

Benedict W. J. Irwin, David John Huggins

Journal of Chemical Theory and Computation
Optimization of lead compounds into on-demand, non-hormonal contraceptives: leveraging a public-private drug discovery institute collaboration

Melanie Balbach, Makoto Fushimi, David J Huggins, Clemens Steegborn, Peter T Meinke, Lonny R Levin, Jochen Buck

Biology of Reproduction
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
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
Modulating Protein-Protein Interactions of the Mitotic Polo-like Kinases to Target Mutant KRAS

Ana J. Narvaez, Suzan Ber, Alex Crooks, Amy Emery, Bryn Hardwick, Estrella Guarino Almeida, David J. Huggins, David Perera, Meredith Roberts-Thomson, Roberta Azzarelli, Fiona E. Hood, Ian A. Prior, David W. Walker, Richard Boyce, Robert G. Boyle, Samuel P. Barker, Christopher J. Torrance, Grahame J. McKenzie, Ashok R. Venkitaraman

Cell Chemical Biology
Computational Fluorine Scanning Using Free-Energy Perturbation

Alexander D Wade, Andrea Rizzi, Yuanqing Wang, and David J Huggins

Journal of Chemical Information and Modeling
Combining Solvent Thermodynamic Profiles with Functionality Maps of the Hsp90 Binding Site to Predict the Displacement of Water Molecules

Kamran Haider and David J Huggins

Journal of Chemical Information and Modeling - 2013 53 (10), 2571-2586
Overcoming Chemical, Biological, and Computational Challenges in the Development of Inhibitors Targeting Protein-Protein Interactions

Luca Laraia, Grahame McKenzie, David R Spring, Ashok R Venkitaraman, David J Huggins

Chemistry & Biology - 2015
Design, Synthesis, and Biological and Structural Evaluations of Novel HIV-1 Protease Inhibitors To Combat Drug Resistance

Maloy Kumar Parai, David J Huggins, Hong Cao, Madhavi NL Nalam, Akbar Ali, Celia A Schiffer, Bruce Tidor, Tariq M Rana

Journal of Medicinal Chemistry - 2012, Volume 55: Issue 14
Rational Approaches to Improving Selectivity in Drug Design

David J. Huggins, Woody Sherman, and Bruce Tidor

Journal of Medicinal Chemistry - 2012 , Volume 55: Issue 4
Systematic placement of structural water molecules for improved scoring of protein-ligand interactions

David J. Huggins and Bruce Tidor

Protein Engineering, Design and Selection - 2011, Volume 24: Issue 10
Evaluation of an Inverse Molecular Design Algorithm in a Model Binding Site

David J. Huggins, Michael Altman, Bruce Tidor

Proteins: Structure, Function and Bioinformatics - 2009, Volume 75: Issue 1
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
Inhibition of 3-Phosphoglycerate Dehydrogenase (PHGDH) by Indole Amides Abrogates de novo Serine Synthesis in Cancer Cells

Edouard Mullarky, Jiayi Xu, Anita Robin, David Huggins, Andy Jennings, Naoyoshi Noguchi, Michael Miller, Nigel Liverton, Daisuke Tomita, Mayako Michino, Taojunfeng Su, Guoan Zhang, Andy Stamford, Peter Meinke, Stacia Kargman and Lewis C. Cantley

Bioorganic & Medicinal Chemistry Letters

Optimization of Protein-Ligand Electrostatic Interactions Using An Alchemical Free-Energy Method

Alexander D Wade and David J Huggins

Journal of Chemical Theory and Computation
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

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