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. Balbach, M, Rossetti, T, Ferreira, J, Ghanem, L, Ritagliati, C, Myers, RW et al.. On-demand male contraception via acute inhibition of soluble adenylyl cyclase. Nat Commun. 2023;14 (1):637. doi: 10.1038/s41467-023-36119-6. PubMed PMID:36788210 PubMed Central PMC9929232.
  2. Miller, M, Rossetti, T, Ferreira, J, Ghanem, L, Balbach, M, Kaur, N et al.. Design, Synthesis, and Pharmacological Evaluation of Second-Generation Soluble Adenylyl Cyclase (sAC, ADCY10) Inhibitors with Slow Dissociation Rates. J Med Chem. 2022;65 (22):15208-15226. doi: 10.1021/acs.jmedchem.2c01133. PubMed PMID:36346696 PubMed Central PMC9866367.
  3. Sun, S, Huggins, DJ. Assessing the effect of forcefield parameter sets on the accuracy of relative binding free energy calculations. Front Mol Biosci. 2022;9 :972162. doi: 10.3389/fmolb.2022.972162. PubMed PMID:36225254 PubMed Central PMC9549959.
  4. Liu, Y, Li, Q, Alikarami, F, Barrett, DR, Mahdavi, L, Li, H et al.. Small-Molecule Inhibition of the Acyl-Lysine Reader ENL as a Strategy against Acute Myeloid Leukemia. Cancer Discov. 2022;12 (11):2684-2709. doi: 10.1158/2159-8290.CD-21-1307. PubMed PMID:36053276 PubMed Central PMC9627135.
  5. Kastan, NR, Oak, S, Liang, R, Baxt, L, Myers, RW, Ginn, J et al.. Development of an improved inhibitor of Lats kinases to promote regeneration of mammalian organs. Proc Natl Acad Sci U S A. 2022;119 (28):e2206113119. doi: 10.1073/pnas.2206113119. PubMed PMID:35867764 PubMed Central PMC9282237.
  6. Liang, R, Tomita, D, Sasaki, Y, Ginn, J, Michino, M, Huggins, DJ et al.. A Chemical Strategy toward Novel Brain-Penetrant EZH2 Inhibitors. ACS Med Chem Lett. 2022;13 (3):377-387. doi: 10.1021/acsmedchemlett.1c00448. PubMed PMID:35300079 PubMed Central PMC8919293.
  7. Huggins, DJ. Comparing the Performance of Different AMBER Protein Forcefields, Partial Charge Assignments, and Water Models for Absolute Binding Free Energy Calculations. J Chem Theory Comput. 2022;18 (4):2616-2630. doi: 10.1021/acs.jctc.1c01208. PubMed PMID:35266690 .
  8. Fushimi, M, Buck, H, Balbach, M, Gorovyy, A, Ferreira, J, Rossetti, T et al.. Discovery of TDI-10229: A Potent and Orally Bioavailable Inhibitor of Soluble Adenylyl Cyclase (sAC, ADCY10). ACS Med Chem Lett. 2021;12 (8):1283-1287. doi: 10.1021/acsmedchemlett.1c00273. PubMed PMID:34413957 PubMed Central PMC8366019.
  9. Maksimovic, I, Finkin-Groner, E, Fukase, Y, Zheng, Q, Sun, S, Michino, M et al.. Deglycase-activity oriented screening to identify DJ-1 inhibitors. RSC Med Chem. 2021;12 (7):1232-1238. doi: 10.1039/d1md00062d. PubMed PMID:34355187 PubMed Central PMC8292988.
  10. Kastan, N, Gnedeva, K, Alisch, T, Petelski, AA, Huggins, DJ, Chiaravalli, J et al.. Small-molecule inhibition of Lats kinases may promote Yap-dependent proliferation in postmitotic mammalian tissues. Nat Commun. 2021;12 (1):3100. doi: 10.1038/s41467-021-23395-3. PubMed PMID:34035288 PubMed Central PMC8149661.
  11. Scott, DE, Francis-Newton, NJ, Marsh, ME, Coyne, AG, Fischer, G, Moschetti, T et al.. A small-molecule inhibitor of the BRCA2-RAD51 interaction modulates RAD51 assembly and potentiates DNA damage-induced cell death. Cell Chem Biol. 2021;28 (6):835-847.e5. doi: 10.1016/j.chembiol.2021.02.006. PubMed PMID:33662256 PubMed Central PMC8219027.
  12. Ginn, J, Jiang, X, Sun, S, Michino, M, Huggins, DJ, Mbambo, Z et al.. Whole Cell Active Inhibitors of Mycobacterial Lipoamide Dehydrogenase Afford Selectivity over the Human Enzyme through Tight Binding Interactions. ACS Infect Dis. 2021;7 (2):435-444. doi: 10.1021/acsinfecdis.0c00788. PubMed PMID:33527832 PubMed Central PMC7888283.
  13. Huggins, DJ. Structural analysis of experimental drugs binding to the SARS-CoV-2 target TMPRSS2. J Mol Graph Model. 2020;100 :107710. doi: 10.1016/j.jmgm.2020.107710. PubMed PMID:32829149 PubMed Central PMC7417922.
  14. Wade, AD, Huggins, DJ. Identification of Optimal Ligand Growth Vectors Using an Alchemical Free-Energy Method. J Chem Inf Model. 2020;60 (11):5580-5594. doi: 10.1021/acs.jcim.0c00610. PubMed PMID:32810401 .
  15. Balbach, M, Fushimi, M, Huggins, DJ, Steegborn, C, Meinke, PT, Levin, LR et al.. Optimization of lead compounds into on-demand, nonhormonal contraceptives: leveraging a public-private drug discovery institute collaboration†. Biol Reprod. 2020;103 (2):176-182. doi: 10.1093/biolre/ioaa052. PubMed PMID:32307523 PubMed Central PMC7401349.
  16. Huggins, DJ, Hardwick, BS, Sharma, P, Emery, A, Laraia, L, Zhang, F et al.. Development of a Novel Cell-Permeable Protein-Protein Interaction Inhibitor for the Polo-box Domain of Polo-like Kinase 1. ACS Omega. 2020;5 (1):822-831. doi: 10.1021/acsomega.9b03626. PubMed PMID:31956833 PubMed Central PMC6964520.
  17. Sharma, P, Mahen, R, Rossmann, M, Stokes, JE, Hardwick, B, Huggins, DJ et al.. A cryptic hydrophobic pocket in the polo-box domain of the polo-like kinase PLK1 regulates substrate recognition and mitotic chromosome segregation. Sci Rep. 2019;9 (1):15930. doi: 10.1038/s41598-019-50702-2. PubMed PMID:31685831 PubMed Central PMC6828814.
  18. Wade, AD, Huggins, DJ. Optimization of Protein-Ligand Electrostatic Interactions Using an Alchemical Free-Energy Method. J Chem Theory Comput. 2019;15 (11):6504-6512. doi: 10.1021/acs.jctc.9b00976. PubMed PMID:31584802 PubMed Central PMC7007198.
  19. Read, C, Nyimanu, D, Williams, TL, Huggins, DJ, Sulentic, P, Macrae, RGC et al.. International Union of Basic and Clinical Pharmacology. CVII. Structure and Pharmacology of the Apelin Receptor with a Recommendation that Elabela/Toddler Is a Second Endogenous Peptide Ligand. Pharmacol Rev. 2019;71 (4):467-502. doi: 10.1124/pr.119.017533. PubMed PMID:31492821 PubMed Central PMC6731456.
  20. Mullarky, E, Xu, J, Robin, AD, Huggins, DJ, Jennings, A, Noguchi, N et al.. Inhibition of 3-phosphoglycerate dehydrogenase (PHGDH) by indole amides abrogates de novo serine synthesis in cancer cells. Bioorg Med Chem Lett. 2019;29 (17):2503-2510. doi: 10.1016/j.bmcl.2019.07.011. PubMed PMID:31327531 PubMed Central PMC6702104.
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