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. Michino, M, Khan, TA, Miller, MW, Fukase, Y, Vendome, J, Adura, C et al.. Lead Optimization of Small Molecule ENL YEATS Inhibitors to Enable In Vivo Studies: Discovery of TDI-11055. ACS Med Chem Lett. 2024;15 (4):524-532. doi: 10.1021/acsmedchemlett.4c00016. PubMed PMID:38628784 PubMed Central PMC11017412.
  2. Zeledon, EV, Baxt, LA, Khan, TA, Michino, M, Miller, M, Huggins, DJ et al.. Next Generation Neuropeptide Y Receptor Small Molecule Agonists Inhibit Mosquito Biting Behavior. bioRxiv. 2024; :. doi: 10.1101/2024.02.28.582529. PubMed PMID:38464241 PubMed Central PMC10925335.
  3. Sun, S, Fushimi, M, Rossetti, T, Kaur, N, Ferreira, J, Miller, M et al.. Addition to "Scaffold Hopping and Optimization of Small Molecule Soluble Adenyl Cyclase Inhibitors Led by Free Energy Perturbation". J Chem Inf Model. 2024;64 (3):1106. doi: 10.1021/acs.jcim.4c00068. PubMed PMID:38258980 .
  4. Michino, M, Beautrait, A, Boyles, NA, Nadupalli, A, Dementiev, A, Sun, S et al.. Shape-Based Virtual Screening of a Billion-Compound Library Identifies Mycobacterial Lipoamide Dehydrogenase Inhibitors. ACS Bio Med Chem Au. 2023;3 (6):507-515. doi: 10.1021/acsbiomedchemau.3c00046. PubMed PMID:38144256 PubMed Central PMC10739260.
  5. Ramsey, JR, Shelton, PMM, Heiss, TK, Olinares, PDB, Vostal, LE, Soileau, H et al.. Using a Function-First "Scout Fragment"-Based Approach to Develop Allosteric Covalent Inhibitors of Conformationally Dynamic Helicase Mechanoenzymes. J Am Chem Soc. 2024;146 (1):62-67. doi: 10.1021/jacs.3c10581. PubMed PMID:38134034 PubMed Central PMC10958666.
  6. Ramsey, JR, Shelton, PMM, Heiss, TK, Olinares, PDB, Vostal, LE, Soileau, H et al.. Using a function-first 'scout fragment'-based approach to develop allosteric covalent inhibitors of conformationally dynamic helicase mechanoenzymes. bioRxiv. 2023; :. doi: 10.1101/2023.09.25.559391. PubMed PMID:37808863 PubMed Central PMC10557574.
  7. Chen, W, Cui, D, Jerome, SV, Michino, M, Lenselink, EB, Huggins, DJ et al.. Enhancing Hit Discovery in Virtual Screening through Absolute Protein-Ligand Binding Free-Energy Calculations. J Chem Inf Model. 2023;63 (10):3171-3185. doi: 10.1021/acs.jcim.3c00013. PubMed PMID:37167486 .
  8. Sun, S, Fushimi, M, Rossetti, T, Kaur, N, Ferreira, J, Miller, M et al.. Scaffold Hopping and Optimization of Small Molecule Soluble Adenyl Cyclase Inhibitors Led by Free Energy Perturbation. J Chem Inf Model. 2023;63 (9):2828-2841. doi: 10.1021/acs.jcim.2c01577. PubMed PMID:37060320 .
  9. 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.
  10. 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.
  11. 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.
  12. 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.
  13. 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.
  14. 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.
  15. 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 .
  16. 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.
  17. 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.
  18. 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.
  19. 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.
  20. 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.
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