William Jorgensen
Sterling Professor of Chemistry; Director, Division of Physical Sciences & Engineering
Research & Publications
Biography
News
Research Summary
The research focuses on the application of computational methods to solve problems concerning structure and reactivity for biomolecular systems. This includes development and application of procedures for accurate calculation of protein-ligand binding affinities. Three approaches are taken that include explicit representation of the protein-ligand complexes using molecular mechanics (MM): a scoring function approach with the BOMB program, and extended linear response and free energy perturbation calculations using Monte Carlo sampling with explicit solvent. Recent examples addressed the binding of drug candidates to HIV-1 RT, factor Xa, COX-2, FAAH, and kinases. BOMB is also used for de novo drug design through the creation and screening of large combinatorial libraries. Modeling of reactions in gas phase, in solution and in enzymes is also studied. The aim is elucidation of reaction mechanisms and the origin of medium effects on rates. A QM/MM approach is taken, and the reacting systems are described with the improved semiempirical MO method PDDG/PM3 that we have developed. The enzymes and solvent are represented using MM, and the sampling is performed with Monte Carlo statistical mechanics. Our research group also has a leadership position in the development of force fields for water, organic and biomolecular systems and software for molecular modeling and drug design.
Coauthors
Research Interests
Chemistry
Selected Publications
- From in silico hit to long-acting late-stage preclinical candidate to combat HIV-1 infectionKudalkar SN, Beloor J, Quijano E, Spasov KA, Lee WG, Cisneros JA, Saltzman WM, Kumar P, Jorgensen WL, Anderson KS. From in silico hit to long-acting late-stage preclinical candidate to combat HIV-1 infection. Proceedings Of The National Academy Of Sciences Of The United States Of America 2017, 115: e802-e811. PMID: 29279368, PMCID: PMC5789948, DOI: 10.1073/pnas.1717932115.
- Covalent inhibitors for eradication of drug-resistant HIV-1 reverse transcriptase: From design to protein crystallographyChan AH, Lee WG, Spasov KA, Cisneros JA, Kudalkar SN, Petrova ZO, Buckingham AB, Anderson KS, Jorgensen WL. Covalent inhibitors for eradication of drug-resistant HIV-1 reverse transcriptase: From design to protein crystallography. Proceedings Of The National Academy Of Sciences Of The United States Of America 2017, 114: 9725-9730. PMID: 28827354, PMCID: PMC5594698, DOI: 10.1073/pnas.1711463114.
- Identification and Characterization of JAK2 Pseudokinase Domain Small Molecule BindersPuleo DE, Kucera K, Hammarén H, Ungureanu D, Newton AS, Silvennoinen O, Jorgensen WL, Schlessinger J. Identification and Characterization of JAK2 Pseudokinase Domain Small Molecule Binders. ACS Medicinal Chemistry Letters 2017, 8: 618-621. PMID: 28626521, PMCID: PMC5467198, DOI: 10.1021/acsmedchemlett.7b00153.
- JAK2 JH2 Fluorescence Polarization Assay and Crystal Structures for Complexes with Three Small MoleculesNewton AS, Deiana L, Puleo DE, Cisneros J, Cutrona KJ, Schlessinger J, Jorgensen WL. JAK2 JH2 Fluorescence Polarization Assay and Crystal Structures for Complexes with Three Small Molecules. ACS Medicinal Chemistry Letters 2017, 8: 614-617. PMID: 28626520, PMCID: PMC5467202, DOI: 10.1021/acsmedchemlett.7b00154.
- Structural and Preclinical Studies of Computationally-Designed Non-nucleoside Reverse Transcriptase Inhibitors for Treating HIV infectionKudalkar SN, Beloor J, Chan AH, Lee WG, Jorgensen WL, Kumar P, Anderson KS. Structural and Preclinical Studies of Computationally-Designed Non-nucleoside Reverse Transcriptase Inhibitors for Treating HIV infection. Molecular Pharmacology 2017, 91: mol.116.107755. PMID: 28167742, PMCID: PMC5363707, DOI: 10.1124/mol.116.107755.
- Design, Conformation, and Crystallography of 2‑Naphthyl Phenyl Ethers as Potent Anti-HIV AgentsLee WG, Chan AH, Spasov KA, Anderson KS, Jorgensen WL. Design, Conformation, and Crystallography of 2‑Naphthyl Phenyl Ethers as Potent Anti-HIV Agents. ACS Medicinal Chemistry Letters 2016, 7: 1156-1160. PMID: 27994756, PMCID: PMC5151141, DOI: 10.1021/acsmedchemlett.6b00390.
- Computer-aided discovery of anti-HIV agentsJorgensen WL. Computer-aided discovery of anti-HIV agents. Bioorganic & Medicinal Chemistry 2016, 24: 4768-4778. PMID: 27485603, PMCID: PMC5114837, DOI: 10.1016/j.bmc.2016.07.039.
- Discovery and crystallography of bicyclic arylaminoazines as potent inhibitors of HIV-1 reverse transcriptaseLee WG, Frey KM, Gallardo-Macias R, Spasov KA, Chan AH, Anderson KS, Jorgensen WL. Discovery and crystallography of bicyclic arylaminoazines as potent inhibitors of HIV-1 reverse transcriptase. Bioorganic & Medicinal Chemistry Letters 2015, 25: 4824-4827. PMID: 26166629, PMCID: PMC4607639, DOI: 10.1016/j.bmcl.2015.06.074.
- Structure-Based Evaluation of Non-nucleoside Inhibitors with Improved Potency and Solubility That Target HIV Reverse Transcriptase VariantsFrey KM, Puleo DE, Spasov KA, Bollini M, Jorgensen WL, Anderson KS. Structure-Based Evaluation of Non-nucleoside Inhibitors with Improved Potency and Solubility That Target HIV Reverse Transcriptase Variants. Journal Of Medicinal Chemistry 2015, 58: 2737-2745. PMID: 25700160, PMCID: PMC4378236, DOI: 10.1021/jm501908a.
- Picomolar Inhibitors of HIV‑1 Reverse Transcriptase: Design and Crystallography of Naphthyl Phenyl EthersLee WG, Frey KM, Gallardo-Macias R, Spasov KA, Bollini M, Anderson KS, Jorgensen WL. Picomolar Inhibitors of HIV‑1 Reverse Transcriptase: Design and Crystallography of Naphthyl Phenyl Ethers. ACS Medicinal Chemistry Letters 2014, 5: 1259-1262. PMID: 25408842, PMCID: PMC4233359, DOI: 10.1021/ml5003713.
- Crystallographic and Receptor Binding Characterization of Plasmodium falciparum Macrophage Migration Inhibitory Factor Complexed to Two Potent InhibitorsPantouris G, Rajasekaran D, Garcia AB, Ruiz VG, Leng L, Jorgensen WL, Bucala R, Lolis EJ. Crystallographic and Receptor Binding Characterization of Plasmodium falciparum Macrophage Migration Inhibitory Factor Complexed to Two Potent Inhibitors. Journal Of Medicinal Chemistry 2014, 57: 8652-8656. PMID: 25268646, PMCID: PMC4207548, DOI: 10.1021/jm501168q.
- Structural studies provide clues for analog design of specific inhibitors of Cryptosporidium hominis thymidylate synthase–dihydrofolate reductaseKumar VP, Cisneros JA, Frey KM, Castellanos-Gonzalez A, Wang Y, Gangjee A, White AC, Jorgensen WL, Anderson KS. Structural studies provide clues for analog design of specific inhibitors of Cryptosporidium hominis thymidylate synthase–dihydrofolate reductase. Bioorganic & Medicinal Chemistry Letters 2014, 24: 4158-4161. PMID: 25127103, PMCID: PMC4427026, DOI: 10.1016/j.bmcl.2014.07.049.
- A mechanistic and structural investigation of modified derivatives of the diaryltriazine class of NNRTIs targeting HIV-1 reverse transcriptaseMislak AC, Frey KM, Bollini M, Jorgensen WL, Anderson KS. A mechanistic and structural investigation of modified derivatives of the diaryltriazine class of NNRTIs targeting HIV-1 reverse transcriptase. Biochimica Et Biophysica Acta 2014, 1840: 2203-2211. PMID: 24726448, PMCID: PMC4061246, DOI: 10.1016/j.bbagen.2014.04.001.
- Structure‐Based Evaluation of C5 Derivatives in the Catechol Diether Series Targeting HIV‐1 Reverse TranscriptaseFrey KM, Gray WT, Spasov KA, Bollini M, Gallardo‐Macias R, Jorgensen WL, Anderson KS. Structure‐Based Evaluation of C5 Derivatives in the Catechol Diether Series Targeting HIV‐1 Reverse Transcriptase. Chemical Biology & Drug Design 2014, 83: 541-549. PMID: 24289305, PMCID: PMC3999282, DOI: 10.1111/cbdd.12266.
- Virtual screening reveals allosteric inhibitors of the Toxoplasma gondii thymidylate synthase–dihydrofolate reductaseSharma H, Landau MJ, Sullivan TJ, Kumar VP, Dahlgren MK, Jorgensen WL, Anderson KS. Virtual screening reveals allosteric inhibitors of the Toxoplasma gondii thymidylate synthase–dihydrofolate reductase. Bioorganic & Medicinal Chemistry Letters 2013, 24: 1232-1235. PMID: 24440298, PMCID: PMC3946055, DOI: 10.1016/j.bmcl.2013.12.039.
- Foundations of Biomolecular ModelingJorgensen WL. Foundations of Biomolecular Modeling. Cell 2013, 155: 1199-1202. PMID: 24315087, PMCID: PMC3892588, DOI: 10.1016/j.cell.2013.11.023.
- Picomolar Inhibitors of HIV Reverse Transcriptase Featuring Bicyclic Replacement of a Cyanovinylphenyl GroupLee WG, Gallardo-Macias R, Frey KM, Spasov KA, Bollini M, Anderson KS, Jorgensen WL. Picomolar Inhibitors of HIV Reverse Transcriptase Featuring Bicyclic Replacement of a Cyanovinylphenyl Group. Journal Of The American Chemical Society 2013, 135: 16705-16713. PMID: 24151856, PMCID: PMC3877923, DOI: 10.1021/ja408917n.
- Optimization of diarylazines as anti-HIV agents with dramatically enhanced solubilityBollini M, Cisneros JA, Spasov KA, Anderson KS, Jorgensen WL. Optimization of diarylazines as anti-HIV agents with dramatically enhanced solubility. Bioorganic & Medicinal Chemistry Letters 2013, 23: 5213-5216. PMID: 23937980, PMCID: PMC3759246, DOI: 10.1016/j.bmcl.2013.06.091.
- Extension into the entrance channel of HIV-1 reverse transcriptase—Crystallography and enhanced solubilityBollini M, Frey KM, Cisneros JA, Spasov KA, Das K, Bauman JD, Arnold E, Anderson KS, Jorgensen WL. Extension into the entrance channel of HIV-1 reverse transcriptase—Crystallography and enhanced solubility. Bioorganic & Medicinal Chemistry Letters 2013, 23: 5209-5212. PMID: 23899617, PMCID: PMC3761378, DOI: 10.1016/j.bmcl.2013.06.093.
- Optimization of benzyloxazoles as non-nucleoside inhibitors of HIV-1 reverse transcriptase to enhance Y181C potencyBollini M, Gallardo-Macias R, Spasov KA, Tirado-Rives J, Anderson KS, Jorgensen WL. Optimization of benzyloxazoles as non-nucleoside inhibitors of HIV-1 reverse transcriptase to enhance Y181C potency. Bioorganic & Medicinal Chemistry Letters 2012, 23: 1110-1113. PMID: 23298809, PMCID: PMC3561933, DOI: 10.1016/j.bmcl.2012.11.115.
- Crystal Structures of HIV‑1 Reverse Transcriptase with Picomolar Inhibitors Reveal Key Interactions for Drug DesignFrey KM, Bollini M, Mislak AC, Cisneros J, Gallardo-Macias R, Jorgensen WL, Anderson KS. Crystal Structures of HIV‑1 Reverse Transcriptase with Picomolar Inhibitors Reveal Key Interactions for Drug Design. Journal Of The American Chemical Society 2012, 134: 19501-19503. PMID: 23163887, PMCID: PMC3518392, DOI: 10.1021/ja3092642.
- Virtual Screening and Optimization Yield Low-Nanomolar Inhibitors of the Tautomerase Activity of Plasmodium falciparum Macrophage Migration Inhibitory FactorDahlgren MK, Garcia AB, Hare AA, Tirado-Rives J, Leng L, Bucala R, Jorgensen WL. Virtual Screening and Optimization Yield Low-Nanomolar Inhibitors of the Tautomerase Activity of Plasmodium falciparum Macrophage Migration Inhibitory Factor. Journal Of Medicinal Chemistry 2012, 55: 10148-10159. PMID: 23067344, PMCID: PMC3509768, DOI: 10.1021/jm301269s.
- Small‐Molecule Inhibitors of the Interaction between the E3 Ligase VHL and HIF1αBuckley DL, Gustafson JL, Van Molle I, Roth AG, Tae HS, Gareiss PC, Jorgensen WL, Ciulli A, Crews CM. Small‐Molecule Inhibitors of the Interaction between the E3 Ligase VHL and HIF1α. Angewandte Chemie International Edition 2012, 51: 11463-11467. PMID: 23065727, PMCID: PMC3519281, DOI: 10.1002/anie.201206231.
- Computationally-Guided Optimization of a Docking Hit to Yield Catechol Diethers as Potent Anti-HIV AgentsBollini M, Domaoal RA, Thakur VV, Gallardo-Macias R, Spasov KA, Anderson KS, Jorgensen WL. Computationally-Guided Optimization of a Docking Hit to Yield Catechol Diethers as Potent Anti-HIV Agents. Journal Of Medicinal Chemistry 2011, 54: 8582-8591. PMID: 22081993, PMCID: PMC3258498, DOI: 10.1021/jm201134m.
- Efficient Discovery of Potent Anti-HIV Agents Targeting the Tyr181Cys Variant of HIV Reverse TranscriptaseJorgensen WL, Bollini M, Thakur VV, Domaoal RA, Spasov KA, Anderson KS. Efficient Discovery of Potent Anti-HIV Agents Targeting the Tyr181Cys Variant of HIV Reverse Transcriptase. Journal Of The American Chemical Society 2011, 133: 15686-15696. PMID: 21853995, PMCID: PMC3183387, DOI: 10.1021/ja2058583.
- Aryl extensions of thienopyrimidinones as fibroblast growth factor receptor 1 kinase inhibitorsEkkati AR, Mandiyan V, Ravindranathan KP, Bae J, Schlessinger J, Jorgensen WL. Aryl extensions of thienopyrimidinones as fibroblast growth factor receptor 1 kinase inhibitors. Tetrahedron Letters 2011, 52: 2228-2231. PMID: 21516197, PMCID: PMC3079261, DOI: 10.1016/j.tetlet.2010.12.081.
- Receptor agonists of macrophage migration inhibitory factorJorgensen WL, Gandavadi S, Du X, Hare AA, Trofimov A, Leng L, Bucala R. Receptor agonists of macrophage migration inhibitory factor. Bioorganic & Medicinal Chemistry Letters 2010, 20: 7033-7036. PMID: 20971005, PMCID: PMC2989669, DOI: 10.1016/j.bmcl.2010.09.118.
- Optimization of N-benzyl-benzoxazol-2-ones as receptor antagonists of macrophage migration inhibitory factor (MIF)Hare AA, Leng L, Gandavadi S, Du X, Cournia Z, Bucala R, Jorgensen WL. Optimization of N-benzyl-benzoxazol-2-ones as receptor antagonists of macrophage migration inhibitory factor (MIF). Bioorganic & Medicinal Chemistry Letters 2010, 20: 5811-5814. PMID: 20728358, PMCID: PMC2939296, DOI: 10.1016/j.bmcl.2010.07.129.
- Eastern extension of azoles as non-nucleoside inhibitors of HIV-1 reverse transcriptase; cyano group alternativesLeung CS, Zeevaart JG, Domaoal RA, Bollini M, Thakur VV, Spasov KA, Anderson KS, Jorgensen WL. Eastern extension of azoles as non-nucleoside inhibitors of HIV-1 reverse transcriptase; cyano group alternatives. Bioorganic & Medicinal Chemistry Letters 2010, 20: 2485-2488. PMID: 20304641, PMCID: PMC2880392, DOI: 10.1016/j.bmcl.2010.03.006.
- Discovery of Novel Fibroblast Growth Factor Receptor 1 Kinase Inhibitors by Structure-Based Virtual ScreeningRavindranathan KP, Mandiyan V, Ekkati AR, Bae JH, Schlessinger J, Jorgensen WL. Discovery of Novel Fibroblast Growth Factor Receptor 1 Kinase Inhibitors by Structure-Based Virtual Screening. Journal Of Medicinal Chemistry 2010, 53: 1662-1672. PMID: 20121196, PMCID: PMC2842983, DOI: 10.1021/jm901386e.
- Chemical Control over Immune Recognition: A Class of Antibody-Recruiting Small Molecules That Target Prostate CancerMurelli RP, Zhang AX, Michel J, Jorgensen WL, Spiegel DA. Chemical Control over Immune Recognition: A Class of Antibody-Recruiting Small Molecules That Target Prostate Cancer. Journal Of The American Chemical Society 2009, 131: 17090-17092. PMID: 19888723, PMCID: PMC2794306, DOI: 10.1021/ja906844e.
- In Silico Improvement of β3-Peptide Inhibitors of p53•hDM2 and p53•hDMXMichel J, Harker EA, Tirado-Rives J, Jorgensen WL, Schepartz A. In Silico Improvement of β3-Peptide Inhibitors of p53•hDM2 and p53•hDMX. Journal Of The American Chemical Society 2009, 131: 6356-6357. PMID: 19415930, PMCID: PMC2754742, DOI: 10.1021/ja901478e.
- Discovery of Wild-Type and Y181C Mutant Non-nucleoside HIV-1 Reverse Transcriptase Inhibitors Using Virtual Screening with Multiple Protein StructuresNichols SE, Domaoal RA, Thakur VV, Tirado-Rives J, Anderson KS, Jorgensen WL. Discovery of Wild-Type and Y181C Mutant Non-nucleoside HIV-1 Reverse Transcriptase Inhibitors Using Virtual Screening with Multiple Protein Structures. Journal Of Chemical Information And Modeling 2009, 49: 1272-1279. PMID: 19374380, PMCID: PMC2817966, DOI: 10.1021/ci900068k.
- Novel non-active site inhibitor of Cryptosporidium hominis TS-DHFR identified by a virtual screenMartucci WE, Udier-Blagovic M, Atreya C, Babatunde O, Vargo MA, Jorgensen WL, Anderson KS. Novel non-active site inhibitor of Cryptosporidium hominis TS-DHFR identified by a virtual screen. Bioorganic & Medicinal Chemistry Letters 2008, 19: 418-423. PMID: 19059777, PMCID: PMC2651159, DOI: 10.1016/j.bmcl.2008.11.054.
- From Docking False-Positive to Active Anti-HIV AgentBarreiro G, Kim JT, Guimarães CR, Bailey CM, Domaoal RA, Wang L, Anderson KS, Jorgensen WL. From Docking False-Positive to Active Anti-HIV Agent. Journal Of Medicinal Chemistry 2007, 50: 5324-5329. PMID: 17918923, PMCID: PMC2575345, DOI: 10.1021/jm070683u.
- Why Urea Eliminates Ammonia Rather than Hydrolyzes in Aqueous SolutionAlexandrova AN, Jorgensen WL. Why Urea Eliminates Ammonia Rather than Hydrolyzes in Aqueous Solution. The Journal Of Physical Chemistry B 2007, 111: 720-730. PMID: 17249815, PMCID: PMC2995377, DOI: 10.1021/jp066478s.
- Elucidation of Rate Variations for a Diels−Alder Reaction in Ionic Liquids from QM/MM SimulationsAcevedo O, Jorgensen WL, Evanseck JD. Elucidation of Rate Variations for a Diels−Alder Reaction in Ionic Liquids from QM/MM Simulations. Journal Of Chemical Theory And Computation 2006, 3: 132-138. PMID: 26627159, DOI: 10.1021/ct6002753.
- FEP-Guided Selection of Bicyclic Heterocycles in Lead Optimization for Non-Nucleoside Inhibitors of HIV-1 Reverse TranscriptaseKim JT, Hamilton AD, Bailey CM, Domoal R, Wang L, Anderson KS, Jorgensen WL. FEP-Guided Selection of Bicyclic Heterocycles in Lead Optimization for Non-Nucleoside Inhibitors of HIV-1 Reverse Transcriptase. Journal Of The American Chemical Society 2006, 128: 15372-15373. PMID: 17131993, DOI: 10.1021/ja066472g.
- Optimization of pyrimidinyl- and triazinyl-amines as non-nucleoside inhibitors of HIV-1 reverse transcriptaseThakur VV, Kim JT, Hamilton AD, Bailey CM, Domaoal RA, Wang L, Anderson KS, Jorgensen WL. Optimization of pyrimidinyl- and triazinyl-amines as non-nucleoside inhibitors of HIV-1 reverse transcriptase. Bioorganic & Medicinal Chemistry Letters 2006, 16: 5664-5667. PMID: 16931015, DOI: 10.1016/j.bmcl.2006.08.037.
- Optimization of diarylamines as non-nucleoside inhibitors of HIV-1 reverse transcriptaseRuiz-Caro J, Basavapathruni A, Kim JT, Bailey CM, Wang L, Anderson KS, Hamilton AD, Jorgensen WL. Optimization of diarylamines as non-nucleoside inhibitors of HIV-1 reverse transcriptase. Bioorganic & Medicinal Chemistry Letters 2005, 16: 668-671. PMID: 16298131, DOI: 10.1016/j.bmcl.2005.10.037.
- Computer-aided design of non-nucleoside inhibitors of HIV-1 reverse transcriptaseJorgensen WL, Ruiz-Caro J, Tirado-Rives J, Basavapathruni A, Anderson KS, Hamilton AD. Computer-aided design of non-nucleoside inhibitors of HIV-1 reverse transcriptase. Bioorganic & Medicinal Chemistry Letters 2005, 16: 663-667. PMID: 16263277, DOI: 10.1016/j.bmcl.2005.10.038.
- Relationship between Side Chain Structure and 14-Helix Stability of β3-Peptides in WaterKritzer JA, Tirado-Rives J, Hart SA, Lear JD, Jorgensen WL, Schepartz A. Relationship between Side Chain Structure and 14-Helix Stability of β3-Peptides in Water. Journal Of The American Chemical Society 2004, 127: 167-178. PMID: 15631466, PMCID: PMC2873033, DOI: 10.1021/ja0459375.