David J. Huggins, Ph.D.

Assistant Professor of Computational Biomedicine Research in Physiology and Biophysics

  • Executive Director, Computational Biomedicine, Sanders Tri-Institutional Therapeutics Discovery Institute

Bronk Laboratory, 510G
1230 York Avenue Box 122
New York, New York 10065

Lab website: http://huggins-lab.tcm.phy.cam.ac.uk/

Techniques

Research Areas

Member of:

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. Sun, S, Huggins, DJ. Comparing Molecules Generated by MMPDB and REINVENT4 with Ideas from Drug Discovery Design Teams. J Chem Inf Model. 2025;65 (8):4219-4231. doi: 10.1021/acs.jcim.5c00250. PubMed PMID:40207451 .
  2. Zimmerman, J, Malone, BF, Finkin-Groner, E, Sun, S, Liang, R, Foronda, M et al.. A potent and selective TNKS2 inhibitor for tumor-selective WNT suppression. bioRxiv. 2025; :. doi: 10.1101/2025.03.04.641305. PubMed PMID:40093088 PubMed Central PMC11908206.
  3. Meyer, C, Garzia, A, Miller, MW, Huggins, DJ, Myers, RW, Hoffmann, HH et al.. Small-molecule inhibition of SARS-CoV-2 NSP14 RNA cap methyltransferase. Nature. 2025;637 (8048):1178-1185. doi: 10.1038/s41586-024-08320-0. PubMed PMID:39663451 .
  4. Huggins, DJ, Baell, J, Brennan, PE, Burgin, A, Scott, DE. The benefits of translating biomedical research at drug discovery institutes. Nat Rev Drug Discov. 2024; :. doi: 10.1038/d41573-024-00142-z. PubMed PMID:39327502 .
  5. Heinzelmann, G, Huggins, DJ, Gilson, MK. Correction to "BAT2: an Open-Source Tool for Flexible, Automated, and Low Cost Absolute Binding Free Energy Calculations". J Chem Theory Comput. 2024;20 (19):8740. doi: 10.1021/acs.jctc.4c01153. PubMed PMID:39286862 PubMed Central PMC11465461.
  6. Heinzelmann, G, Huggins, DJ, Gilson, MK. BAT2: an Open-Source Tool for Flexible, Automated, and Low Cost Absolute Binding Free Energy Calculations. J Chem Theory Comput. 2024;20 (15):6518-6530. doi: 10.1021/acs.jctc.4c00205. PubMed PMID:39088306 PubMed Central PMC11325538.
  7. Sun, S, Ginn, J, Kochanczyk, T, Arango, N, Jiang, X, Huggins, DJ et al.. Indazole to 2-Cyanoindole Scaffold Progression for Mycobacterial Lipoamide Dehydrogenase Inhibitors Achieves Extended Target Residence Time and Improved Antibacterial Activity. Angew Chem Int Ed Engl. 2024;63 (44):e202407276. doi: 10.1002/anie.202407276. PubMed PMID:38997232 PubMed Central PMC11887847.
  8. 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. Parasit Vectors. 2024;17 (1):276. doi: 10.1186/s13071-024-06347-w. PubMed PMID:38937807 PubMed Central PMC11212260.
  9. 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.
  10. 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.
  11. 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 .
  12. 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.
  13. 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.
  14. 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.
  15. 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 .
  16. 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 .
  17. 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.
  18. 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.
  19. 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.
  20. 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.
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