David J. Huggins, Ph.D.

Assistant Professor of Computational Biomedicine Research in Physiology and Biophysics

  • Senior Director, Computational Biomedicine in the Tri-Institutional Therapeutics Discovery Institute


Belfer Research Building
413 East 69th Street, Room BB-1624
New York, NY 10021


Research Areas

Research Summary:

Our research is focused on the development of novel computational methods to solve problems in the field of medicine. We use statistical mechanical methods such as free-energy perturbation and inhomogeneous fluid solvation theory to understand and predict the thermodynamics of binding, with specific application to molecular design tools for developing effective new therapeutics.

On the theoretical side, we are interested in computing entropy and mutual information from high-order correlations. We also devise methods to probe the surfaces and binding sites of proteins to find druggable targets, by identifying binding hot spots. This work is applied to a number of drug discovery projects within the Tri-I, applying rational methods to design small-molecule inhibitors for a wide variety of diseases.



Recent Publications:

  1. Wade, AD, Rizzi, A, Wang, Y, Huggins, DJ. Computational Fluorine Scanning Using Free-Energy Perturbation. J Chem Inf Model. 2019; :. doi: 10.1021/acs.jcim.9b00228. PubMed PMID:31046267 .
  2. Irwin, BWJ, Vukovic, S, Payne, MC, Huggins, DJ. Large-Scale Study of Hydration Environments through Hydration Sites. J Phys Chem B. 2019;123 (19):4220-4229. doi: 10.1021/acs.jpcb.9b02490. PubMed PMID:31025866 .
  3. Wade, AD, Wang, LP, Huggins, DJ. Assimilating Radial Distribution Functions To Build Water Models with Improved Structural Properties. J Chem Inf Model. 2018;58 (9):1766-1778. doi: 10.1021/acs.jcim.8b00166. PubMed PMID:30113842 PubMed Central PMC6175054.
  4. Irwin, BWJ, Huggins, DJ. Estimating Atomic Contributions to Hydration and Binding Using Free Energy Perturbation. J Chem Theory Comput. 2018;14 (6):3218-3227. doi: 10.1021/acs.jctc.8b00027. PubMed PMID:29712434 .
  5. Vukovic, S, Huggins, DJ. Quantitative metrics for drug-target ligandability. Drug Discov. Today. 2018;23 (6):1258-1266. doi: 10.1016/j.drudis.2018.02.015. PubMed PMID:29522887 .
  6. Narvaez, AJ, Ber, S, Crooks, A, Emery, A, Hardwick, B, Guarino Almeida, E et al.. Modulating Protein-Protein Interactions of the Mitotic Polo-like Kinases to Target Mutant KRAS. Cell Chem Biol. 2017;24 (8):1017-1028.e7. doi: 10.1016/j.chembiol.2017.07.009. PubMed PMID:28807782 PubMed Central PMC5563081.
  7. Cole, DJ, Janecek, M, Stokes, JE, Rossmann, M, Faver, JC, McKenzie, GJ et al.. Computationally-guided optimization of small-molecule inhibitors of the Aurora A kinase-TPX2 protein-protein interaction. Chem. Commun. (Camb.). 2017;53 (67):9372-9375. doi: 10.1039/c7cc05379g. PubMed PMID:28787041 PubMed Central PMC5591577.
  8. Irwin, BWJ, Huggins, DJ. On the accuracy of one- and two-particle solvation entropies. J Chem Phys. 2017;146 (19):194111. doi: 10.1063/1.4983654. PubMed PMID:28527450 PubMed Central PMC5438298.
  9. Huggins, DJ. Studying the role of cooperative hydration in stabilizing folded protein states. J. Struct. Biol. 2016;196 (3):394-406. doi: 10.1016/j.jsb.2016.09.003. PubMed PMID:27633532 PubMed Central PMC5131609.
  10. Vukovic, S, Brennan, PE, Huggins, DJ. Exploring the role of water in molecular recognition: predicting protein ligandability using a combinatorial search of surface hydration sites. J Phys Condens Matter. 2016;28 (34):344007. doi: 10.1088/0953-8984/28/34/344007. PubMed PMID:27367338 .
  11. Janeček, M, Rossmann, M, Sharma, P, Emery, A, Huggins, DJ, Stockwell, SR et al.. Allosteric modulation of AURKA kinase activity by a small-molecule inhibitor of its protein-protein interaction with TPX2. Sci Rep. 2016;6 :28528. doi: 10.1038/srep28528. PubMed PMID:27339427 PubMed Central PMC4919790.
  12. Laraia, L, McKenzie, G, Spring, DR, Venkitaraman, AR, Huggins, DJ. Overcoming Chemical, Biological, and Computational Challenges in the Development of Inhibitors Targeting Protein-Protein Interactions. Chem. Biol. 2015;22 (6):689-703. doi: 10.1016/j.chembiol.2015.04.019. PubMed PMID:26091166 PubMed Central PMC4518475.
  13. Huggins, DJ. Quantifying the entropy of binding for water molecules in protein cavities by computing correlations. Biophys. J. 2015;108 (4):928-936. doi: 10.1016/j.bpj.2014.12.035. PubMed PMID:25692597 PubMed Central PMC4336375.
  14. Huggins, DJ. Estimating Translational and Orientational Entropies Using the k-Nearest Neighbors Algorithm. J Chem Theory Comput. 2014;10 (9):3617-25. doi: 10.1021/ct500415g. PubMed PMID:26588506 .
  15. Huggins, DJ. Comparing distance metrics for rotation using the k-nearest neighbors algorithm for entropy estimation. J Comput Chem. 2014;35 (5):377-85. doi: 10.1002/jcc.23504. PubMed PMID:24311273 PubMed Central PMC4238811.
  16. Haider, K, Huggins, DJ. Combining solvent thermodynamic profiles with functionality maps of the Hsp90 binding site to predict the displacement of water molecules. J Chem Inf Model. 2013;53 (10):2571-86. doi: 10.1021/ci4003409. PubMed PMID:24070451 PubMed Central PMC3840717.
  17. Huggins, DJ, Payne, MC. Assessing the accuracy of inhomogeneous fluid solvation theory in predicting hydration free energies of simple solutes. J Phys Chem B. 2013;117 (27):8232-44. doi: 10.1021/jp4042233. PubMed PMID:23763625 PubMed Central PMC3756531.
  18. Huggins, DJ. Application of inhomogeneous fluid solvation theory to model the distribution and thermodynamics of water molecules around biomolecules. Phys Chem Chem Phys. 2012;14 (43):15106-17. doi: 10.1039/c2cp42631e. PubMed PMID:23037989 .
  19. Parai, MK, Huggins, DJ, Cao, H, Nalam, MN, Ali, A, Schiffer, CA et al.. Design, synthesis, and biological and structural evaluations of novel HIV-1 protease inhibitors to combat drug resistance. J. Med. Chem. 2012;55 (14):6328-41. doi: 10.1021/jm300238h. PubMed PMID:22708897 PubMed Central PMC3409094.
  20. Huggins, DJ. Benchmarking the thermodynamic analysis of water molecules around a model beta sheet. J Comput Chem. 2012;33 (15):1383-92. doi: 10.1002/jcc.22971. PubMed PMID:22457119 PubMed Central PMC4768347.
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