About

William Jorgensen is a Sterling Professor of Chemistry at Yale University and has been a member of the Yale faculty since 1990. His research interests encompass organic chemistry, theoretical chemistry, medicinal chemistry, and biophysical chemistry. His work includes simulations of organic and enzymatic reactions, computer-aided drug design, and the synthesis and development of therapeutic agents targeting infectious, inflammatory, and hyperproliferative diseases. Professor Jorgensen's approach features focused synthetic organic chemistry driven by state-of-the-art molecular design, with a focus on modeling protein-inhibitor complexes, virtual high-throughput screening, and lead-optimization guided by Monte Carlo free-energy simulations. His group has pioneered computational studies of chemistry in solution, contributing to the development and application of force fields, free-energy methods, semiempirical MO methods, and QM/MM simulations for organic and enzymatic reactions. His contributions have enabled the efficient discovery of potent anti-HIV, anti-inflammatory, and anti-cancer agents. Recognized with numerous awards and honors, including election to the American Academy of Arts and Sciences and the National Academy of Sciences, Professor Jorgensen is a leading figure in computational and theoretical chemistry.

Research topics

• Pharmacology
• Chemistry
• Biology
• Biochemistry
• Combinatorial chemistry
• Computational biology
• Stereochemistry
• Internal medicine
• Genetics
• Medicine
• Computational chemistry
• Virology

Selected publications

• The need to implement FAIR principles in biomolecular simulations

  Nature Methods · 2025-04-01 · 53 citations

  articleOpen access
  PublisherOA PDFDOI

• Free Energies of Solvation in Benzene and Hexafluorobenzene: Is Explicit Polarization Needed?

  The Journal of Physical Chemistry B · 2025-06-18 · 1 citations

  article1st authorCorresponding

  Free energies of solvation in liquid benzene and hexafluorobenzene have been computed for 42 uncharged solutes. Monte Carlo statistical mechanics was used with the free-energy perturbation theory and the OPLS-AA force field. The results address the transferability of the potential functions developed for pure liquids to mixed systems and the potential importance of explicit polarization for neutral organic molecules in aromatic solvents. Although the free-energy results cover an 11 kcal/mol range, the average error in comparison with experimental data points is only 0.4 kcal/mol. There is no systematic pattern to the discrepancies, so the need to add explicit treatment of solute-solvent polarization effects is not supported. This contrasts the situation with cationic solutes as reflected in cation-π interactions. Results for free energies of hydration are also provided for the 42 solutes in TIP4P water and give an average error of 0.49 kcal/mol. Implications for modeling biomolecular systems with standard force fields are considered. It is also interesting to note the overall similar values for free energies of solvation in benzene and hexafluorobenzene despite the reversal of polarity for the aromatic rings; the most significant exception is the more favorable solvation of perfluoroalkanes in the perfluoro solvent. Alternative accommodations of solutes in the two solvents are illustrated.

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• Polycyclic Aromatic Hydrocarbons: Solvation, Solubility, and Hydrophobic Effects from Monte Carlo Simulations

  The Journal of Physical Chemistry B · 2025-09-25

  article1st authorCorresponding

  Free energies of solvation in water and liquid cyclohexane have been computed for 20 arenes ranging in size from cyclobutadiene to coronene. Monte Carlo statistical mechanics (MC) was used with free-energy perturbation theory (FEP) and the OPLS-AA force field. The computed results for free energies of hydration are in close agreement with experimental data giving an average error of 0.4 kcal/mol. Some discrepancies are found for larger arenes for which the experimental data have greater uncertainties owing to low solubility. The free energies of solvation and free energy of transfer from cyclohexane to water all display strong correlations with the solvent-accessible surface area (SASA) or volume of the arene. In contrast to the hydration of alkanes, the free energies of hydration of arenes become much more favorable with increasing size covering an 11 kcal/mol range. The free energies of solvation in cyclohexane are still more favorable, resulting in a 5 kcal/mol range for the resistance to transfer of arenes from cyclohexane to aqueous solution. Strong correlations are also found between the aqueous solubility of arenes and the free energies of solvation in cyclohexane and water. The reported results provide fundamental thermodynamic data for solution-phase properties of arenes, with relevance to materials and environmental science.

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• Mechanistic basis for a novel dual-function Gag-Pol dimerizer potentiating CARD8 inflammasome activation and clearance of HIV-infected cells

  npj Drug Discovery. · 2025-09-01

  articleOpen access

  A strategy to functionally cure AIDS by eliminating latent HIV-1 reservoirs involves non-nucleoside reverse transcriptase inhibitors (NNRTIs) that promote pyroptosis of HIV-1 infected cells. These NNRTIs stimulate dimerization of the Gag-Pol polyprotein, resulting in premature HIV-1 protease (PR) dimerization and cleavage of intracellular CARD8. A unique cell-based high-throughput screen was developed to identify potent compounds activating the CARD8 inflammasome through Gag-Pol dimerization. Our in-house library of NNRTIs was evaluated, including a series of catechol diethers, which are potent, nontoxic antivirals. JLJ648 was identified as a promising dual-function antiviral and Gag-Pol dimerizer. Cryo-EM studies of HIV reverse transcriptase p66 bound to JLJ648 revealed populations of homodimers and, surprisingly, a homotetramer. This novel homotetramer structure resembling an 'infinity knot' revealed two JLJ648-bound homodimers forming an extensive interface and nucleated around a dimer of JLJ648 molecules. Structure-guided mutagenesis studies indicate that Gag-Pol homotetramerization may play a critical role in facilitating PR self-cleavage and triggering pyroptosis.

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• Exploring Possible Drug-Resistant Variants of SARS-CoV-2 Main Protease (M^pro) with Noncovalent Preclinical Candidate, Mpro61

  ACS Bio & Med Chem Au · 2025-01-27 · 1 citations

  articleOpen access

  SARS-CoV-2 Mpro inhibitors, such as nirmatrelvir, have proven efficacy in clinical use. Nirmatrelvir was developed in a target-based approach against wild-type Mpro, with the anticipation that prolonged usage may cause enrichment of drug-resistant mutations and persistence of COVID infections. Although globally prevalent drug-resistant mutations have not yet been observed, individual cases have recently been reported among patients following treatment with Paxlovid─a formulation of nirmatrelvir. Mutations E166V and E166A have been detected in these drug-resistant clinical isolates, consistent with predictions from in vitro viral passage experiments and therefore necessitate ongoing drug development. In this study, we selected seven Mpro variants (T21I, L50F, E166V, A173V, T190I, E166V/L50F, and A173V/L50F), which have been repeatedly found in viral passage experiments. We investigated their kinetic and structural properties, as well as resistance level to Mpro inhibitors: nirmatrelvir, GC376─a similar peptidomimetic for feline COVID infections, and our in-house-developed nonpeptidomimetic inhibitor Mpro61. Mpro61 maintains potency against the single variants (except for E166V) and the A173/L50F double variant, with Ki values similar to those of the wild type. In contrast, while nirmatrelvir and GC376 were still effective against the A173V/L50F double variant, their Ki values significantly increased up to 10-fold. None of the inhibitors appeared to be potent against E166V-containing variants. Our structural analysis revealed a significant movement of Ser1 residue in all E166V-containing variants in the presence or absence of an inhibitor. The new orientation of the Ser1 suggested potential strategies for medicinal chemistry modifications of Mpro61 to enhance hydrogen-bonding interactions between these variants and Mpro61 derivatives. These studies provide critical insights into guiding the future design of additional Mpro61 derivatives that would potentially inhibit variants with the pan-drug-resistant E166V mutation.

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• Enthalpies and entropies of hydration from Monte Carlo simulations

  Physical Chemistry Chemical Physics · 2024-01-01 · 4 citations

  articleOpen access1st authorCorresponding

  . In addition, the results permit breakdown of the errors in the free energy changes from the OPLS-AA force field into their enthalpic and entropic components. The excess hydrophobicity of organic solutes is enthalpic in origin.

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• The Beginnings of JCTC

  Journal of Chemical Theory and Computation · 2024-09-24

  editorial1st authorCorresponding
  PublisherDOI

• Monte Carlo simulations for free energies of hydration: Past to present

  The Journal of Chemical Physics · 2024-08-13 · 11 citations

  articleOpen access1st authorCorresponding

  A summary of the development of Monte Carlo statistical mechanics simulations for the computation of free energies of hydration of organic molecules is followed by presentation of results with the latest version of the optimized potentials for liquid simulations-all atom force field and the TIP4P water model. Scaling of the Lennard-Jones interactions between water, oxygen, and carbon atoms by a factor of 1.25 is found to improve the accuracy of free energies of hydration for 50 prototypical organic molecules from a mean unsigned error of 1.0-1.2 to 0.4 kcal/mol.

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• Prodrug nanotherapy demonstrates <i>in vivo</i> anticryptosporidial efficacy in a mouse model of chronic <i>Cryptosporidium</i> infection

  RSC Pharmaceutics · 2024-01-01

  articleOpen access

  for 5 days, when examined 6 and 20 days postinfection, offering a new avenue of drug delivery to be further explored.

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• Proof-of-concept studies with a computationally designed M^proinhibitor as a synergistic combination regimen alternative to Paxlovid

  Proceedings of the National Academy of Sciences · 2024-04-15 · 15 citations

  articleOpen accessCorresponding

  As the SARS-CoV-2 virus continues to spread and mutate, it remains important to focus not only on preventing spread through vaccination but also on treating infection with direct-acting antivirals (DAA). The approval of Paxlovid, a SARS-CoV-2 main protease (M pro ) DAA, has been significant for treatment of patients. A limitation of this DAA, however, is that the antiviral component, nirmatrelvir, is rapidly metabolized and requires inclusion of a CYP450 3A4 metabolic inhibitor, ritonavir, to boost levels of the active drug. Serious drug–drug interactions can occur with Paxlovid for patients who are also taking other medications metabolized by CYP4503A4, particularly transplant or otherwise immunocompromised patients who are most at risk for SARS-CoV-2 infection and the development of severe symptoms. Developing an alternative antiviral with improved pharmacological properties is critical for treatment of these patients. By using a computational and structure-guided approach, we were able to optimize a 100 to 250 μM screening hit to a potent nanomolar inhibitor and lead compound, Mpro61. In this study, we further evaluate Mpro61 as a lead compound, starting with examination of its mode of binding to SARS-CoV-2 M pro . In vitro pharmacological profiling established a lack of off-target effects, particularly CYP450 3A4 inhibition, as well as potential for synergy with the currently approved alternate antiviral, molnupiravir. Development and subsequent testing of a capsule formulation for oral dosing of Mpro61 in B6-K18-hACE2 mice demonstrated favorable pharmacological properties, efficacy, and synergy with molnupiravir, and complete recovery from subsequent challenge by SARS-CoV-2, establishing Mpro61 as a promising potential preclinical candidate.

  PublisherOA PDFDOI

Recent grants

• Molecular Recognition of Proteins and Ligand Design

  NIH · $10.9M · 1990–2025

• Theoretical Bioorganic Chemistry

  NSF · $460k · 2005–2008

• Computer-Aided Design of Anti-HIV Drugs

  NIH · $7.8M · 1999–2024

Frequent coauthors

• Julian Tirado‐Rives

  Yale University

  140 shared

• Alanna Schepartz

  Arc Research Institute

  91 shared

• Scott J. Miller

  NextFlex

  89 shared

• Kenneth M. Merz

  Michigan State University

  87 shared

• Courtney C. Aldrich

  University of Minnesota System

  85 shared

• Harry A. Atwater

  California Institute of Technology

  85 shared

• Jillian M. Buriak

  University of Alberta

  85 shared

• William B. Tolman

  Washington University in St. Louis

  85 shared

Education

• Ph. D.

  Harvard University

  1975

• A. B.

  Princeton University

  1970

Awards & honors

• A. C. Cope Scholar Award (1990)
• Fellow, American Association for the Advancement of Science…
• ACS Award for Computers in Chemical and Pharmaceutical Resea…
• Sato International Award (2004)
• ISQBP Award in Computational Biology (2004)