I carry out computer simulations at the level of quantum mechanics and molecular mechanics to investigate the reaction mechanism of small molecules, protein-ligand interaction, and enzyme mechanism with the aim of drug discovery. My research interest also includes proton transfer process in both proteins and nanotubes. A brief description of my work is as follows:

Design and Synthesis of Bioactive Compounds

Based on the structures of inhibitors/agonists/antagonists and their experimental data (e.g., IC50 and Ki), I develop pharmacophore requirements for bio-active compounds to facilitate the discovery of novel compounds for the treatments of diseases. Examples are anti-tuberculosis drugs, opioid analgegics, cannabinoid antagonists, transporter protein (TSPO) ligands (e.g., PK11195 and benzodiazepine) for brain imaging, and radiopharmaceticals for tumor imaging (tetrahydroxamate chelators of Zirconium89) as well as for alpha-immunotherapy (At211 labeled antibody, see below).

Enzyme Mechanism

Utilizing hybrid potentials of quantum mechanics (GAMESS) and molecular mechanics (CHARMM), I investigate enzyme mechanism (e.g., aldose reductase, chorismate mutase and adenynyl cyclase). This study not only allows one to map the reaction pathway catalyzed by enzymes but also to ascertain the transition state geometry of a substrate, which in turn can be used for designing transition state analogs that tightly bind to a protein of interest.

Proton Transfer Process

Proton transfer is one of the most fundamental processes in biology and chemistry. In order to gain insight into the mechanism of proton transfer process, we carry out ab-intio quantum chemical molecular dynamics simulations on proteins (e.g., bacteriorhodopsin) and carbon nanotubes. This work does address the question such as energy barrier for proton hopping via a hydrogen-bonded water chain.

Design and Synthesis of Bioactive Compounds

Lee YS, O’Connor RD, and Vasalatiy O: Investigation of Two Zr-p-NO2Bn-DOTA Isomers via NMR and Quantum Chemical Studies (2023) Eur. J. Inorg. Chem. 26, e202300439

Kumar P, Tomita T, Gerken T, Lee YS, Weiss L, and Samara LN: A Toxoplasma gondii O-glycosyltransferase that Modulates Bradyzoite Cyst Wall Rigidity is Structurally and Functionally Distinct from its Host Homologues (2023) (submitted, 2023)

Dvoracsko S, Herrerias A, Oliverio A, Bhattacharjee P, Pommerolle L, Liu Z, D. Feng, Lee YS, Hassan SA, Godlewski G, Cinar R, and Iyer MR Cannabinoformins: (2023) Designing Biguanide-Embedded, Orally Available, Peripherally Selective Cannabinoid-1 Receptor Antagonists for Metabolic Syndrome Disorders J. Med. Chem. 66, 11985

Lee YS, Mou Z, Opina A.C.L., and Vasalatiy O: Origin of the Stability of Polymethylated DOTA Chelates Complexed with Ln3+ Ions (2021) Eur. J. Inorg. Chem. 15, 1428
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Liu Z, Iyer M, Godlewski G, Jourdan T, Liu J, Coffey N, Zawatsky C, Puhl H, Wess J, Meister J, Liow J, Innis R, Hassan SA, Lee YS, Kunos G and Cinar R: Functional Selectivity of a Biased Cannabinoid-1 Receptor Antagonist (2021) ACS Pharmacol. Transl. Sci. 4, 1175
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A Novel Method for Producing Astatine-based Cancer Therapeutics: https://irp.nih.gov/accomplishments/a-novel-method-for-producing-astatine-based-cancer-therapeutics (2020)

Guerard F, Gestin JF, Brechbiel MW and Lee YS: Method for Synthesizing Iodo- or Astatoarenes Using Diaryliodonium Salts: U.S. Patent 10858306 for product (Granted on December 8, 2020)

Guerard F, Gestion JF, Brechbiel MW, and Lee YS:Method for Synthesizing Iodo- or Astatoarenes using Diaryliodonium Salts U.S. Patent No. 10703708 (granted on July 7, 2020)

Guerard F, Lee YS, Tripier R, Szajek LP, Deschamps JR and Brechbiel MW:Reply to 'the Comment on "Investigation of Zr(IV) and 89Zr(IV) complexation with hydroxamates: progress towards designing a better chelator than desferrioxamine B immuno-PET imaging"' by A. Bianchi and M. Savastano (2020) Chem. Commun. 56, D0CC01189D.

E. Gutman, E. Bow, F. Li, A. Sulima, S. Kaska, R. Crowley, T. Prisinzano, Y. S. Lee, S. A. Hassan, G. Imler, J. Deschamps, A. Jacobson, and K. C. Rice: G-Protein Biased Opioid Agonists:3-Hydroxy-N-Phenethyl-5-Phenylmorphans with Three-Carbon Chain Substituents at C9 (2020) RSC Med. Chem. 11, 896.

M. Wang, T. C. Irvin, C. A. Herdman, R. D. Hanna, S. A. Hassan, Y. S. Lee, S. Kaska, R. S. Crowly, T. Prisinzano, S. L. Whithey, C. A. Paronis, J. Bergman, S. Inan, E. B. Geller, M. W. Adler, T. A. Kopajtic, J. L. Katz, A. M. Chadderdon, J. R. Traynor, A. E. Jacobson, and K. C. Rice: The Intriguing Effects of Substituents in the N-Phenethyl Moiety of Norhydromorphone: A Bifunctional Opioid from a Set of "Tail Wags Dog" Experiments (2020) Molecules 25, 2640

Lindberg A, Lu S, Nag S, Schou M, Liow JS, Zoghbi SS, Frankland MP, Gladding RL, Morse CL, Takano A, Amini N, Elmore CS, Lee YS, Innis RB, Halldin C, and Pike VW:Synthesis and Evaluation of Two New Candidate High-affinity Full Agonist PET Radioligands for Imaging 5-HT1B Receptors (2019) Nucelar Med. Bio 70, 1-13.

Guerard F, Lee YS, and Brechbiel MW:Tetrahydroxamate Chelators of Zirconium89 and Niobium90 for use in Diagnostic Applications U.S. Patent No. 10137212 (granted on Nov. 27, 2018)

Guerard F, Navarro L, Lee YS, Alliot C, Cherel M, Brechbiel MW, and Gestina JF:Bifunctional Aryliodonium Salts for Highly Efficient Radioiodination and Astatination of Antibodies (2017) Bioorg. Med. Chem. 25, 5975-5980.

Lee YS, Chun JH, M. Hodoscek M and Pike VW:Crystal Structure of Diaryliodonium Fluorides and their Implications for Fluorination Mechanisms (2017) Chem. Eur. J. 23, 4353-4363.

Truong PM, Hassan SA, Lee YS, Kopajtic TA, Katz JL, Chadderdon AM, Traynor JR, Deschamps JR, Jacobson AR, and Rice KC:Modulation of Opioid Receptor Affinity and Efficacy via N-Substitution of 9b-hydroxy-5-(3-hydroxyphenyl)morphan: Synthesis and Computer Simulation Study (2017) Bioorg. Med. Chem. 25, 2406-2422.

Guerard F, Beyler M, Lee YS, Tripier R, Gestin JF, and Brechbiel MW; Investigation of the Complexation of natZr(IV) and 89Zr(IV) by Hydroxypyridinones for the Development of Chelators for PET Imaging Applications. (2017) Dalton Trans. 46, 4749-4758

Guerard F, Lee YS, Baidoo K, Gestin JF and Brechbiel MW:Unexpected Behavior of the Heaviest Halogen Astatine in the Nucleophilic Substitution of Aryliodonium Salts. (2016) Chem. Eur. J. 22, 12332-12339 -- Featured on Journal Cover.

Opina AC, Strickland M, Lee YS, Tjandra N, Byrd RA, Swenson RE and Vasalatiy O:Analysis of the isomer ratios of polymethylated-DOTA complexes and the implications on protein structural studies. (2016) Dalton. Trans. 45, 4673-4687.

Haskali MB, Telu S, Lee YS, Morse CL, Lu S and Pike VW:An Investigation of (Diacetoxyiodo)arenes as Precursors for Preparing No-Carrier-Added [18F]Fluoroarenes from Cyclotron-Produced [18F]Fluoride Ion. (2016) J. Org. Chem. 81, 297-302.

Iyer MR, Cinar R, Liu J, Godlewski G, Szanda G, Puhl H, Ikeda SR, Deschamps J, Lee YS, Steinbach P.J. and Kunos G:Structural Basis of Species-dependent Differential Affinity of 6-Alkoxy-5-aryl-3-pyridinecarboxamide Cannabinoid Receptor 1 Antagonists. (2015) Mol. Pharmacol. 88, 238-244.

Guerard F, Lee YS and Brechbiel MW:Rational design, synthesis, and evaluation of tetrahydroxamic acid chelators for stable complexation of Zirconium(IV). (2014) Chem. Eur. J. 20, 5584-5591

Guerard F, Lee YS, Tripier R, Szajek LP, Deschamps JR and Brechbiel MW:Investigation of Zr(IV) and 89Zr(IV) complexation with hydroxamates: progress towards designing a better chelator than desferrioxamine B immuno-PET imaging. (2013) Chem. Commun. 49, 1002-1004.

Sulima A, Cheng K, Jacobson AE, Rice K, Gawrisch K and Lee YS:Z and E rotamers of N-formyl-1-bromo-4-hydroxy-3-methoxy-morphinan-6-one and their intercoversion studied by 1H/13C NMR spectroscopy and quantum chemical calculations. (2013) Magn. Reson. Chem. 51, 82-88.

Lee YS, Simeon FG, Briard E and Pike VW:Solution structures of the prototypical 18 kDa translocator protein ligand, PK 11195, elucidated with 1H/13C-NMR and quantum chemistry. (2012) ACS Chem. Neurosci. 3, 325-335.

Iyer MR, Lee YS, Deschamps JR, Dersch CM, Rothman RB, Jacobson AE and Rice KC:Probes for Narcotic Receptor Mediated Phenomena. 44. Synthesis of an N-substituted 4-hydroxy-5-(3-hydroxyphenyl)morphan with high affinity and selective µ-antagonist activity. (2012) Eur. J. Med. Chem. 50, 44-54.

Cellitti SE, Shaffer J, Jones DH, Mukherjee T, Gurumurthy M, Bursulaya B, Boshoff H, Choi IH, Lee YS, Cherian J, Niyomrattanakit P, Dick T, Manjunatha UH, Barry III CE, Spraggon G and Geierstanger BH:Structure of Ddn, the Deazaflavin-dependent nitroreductase from Mycobacterium tuberculosis involved in bioreductive activation of PA-824 (2012) Structure 20, 101-112.

Gurumurthy M, Mukherjee T, Manjunatha U, Barry III Clifton, Dowd, C, Singh R, Niyomrattanakit P, Tay JA, Nayyar A, Lee YS, Cherian J, Boshoff H and Dick T:Substrate specificity of the Deazaflavin-Dependent Nitroreductase (Ddn) from Mycobacterium tuberculosis Responsible for the Bioreductive Activation of Bicyclic Nitroimidazoles (2012) FEBS Journal 279, 113-125.

Cherian J, Choi IH, Nayyar A, Manjunatha H, Mukherjee T, Lee YS, Boshoff H, Singh R, Ha YH, Goodwin M, Lakshminarayana S, Niyomrattanakit P, Jiricek J, Ravindran S, Dick T, Keller T, Dartois V, and Barry III CE:Structure–Activity Relationships of Antitubercular Nitroimidazoles. 3. Exploration of the Linker and Lipophilic Tail of ((S)-2-Nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yl)-(4-trifluoromethoxybenzyl)amine (6-Amino PA-824) (2011) J. Med. Chem.54, 5639–5659.

Cheng K, Lee YS, Rothman RB, Dersch CM, Bittamn RW, Jacobson AE and Rice KC:Probes for Narcotic Receptor Mediated Phenomena. 41. Unusual Inverse mu-agonists and Potent mu-opioid Antagoinists by Modification of the N-substituent in Enatiomeric 5-(3-hydroxyphenyl)morphans (2011) J. Med. Chem.54, 957.

Lee YS, Hodoscek M, Chun JH and Pike VW: Conformational Structure and Energetics of 2-methylphenyl(2'-methoxyphenyl)Iodonium Chloride: Evidence for Solution Clusters (2010) Chem. Eur. J. 16, 10418-10423.

Chun JH, Liu S, Lee YS and Pike VW: Fast and High-Yield Microreactor Syntheses of ortho-Substituted [18F]Fluoroarenes from Reactions of [18F]Fluoride Ion with Diaryliodonium Salts (2010) J. Org. Chem. 75, 3332-3338.

Iyer MR, Lee YS, Deschamps JR, Rothman RB, Dersch CM, Jacobson AE and Rice KC:Probes for Narcotic Receptor Mediated Phenomena. 40. N-substituted cis-4a-ethyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-8-ols (2010) Bioorg. Med. Chem. 18, 91-99.

Zhang Y, Lee YS, Deschamps JR, Rothman RB, Dersch CM, Jacobson AE and Rice KC:Probes for Narcotic Receptor Mediated Phenomena. 39.1 Enantiomeric N-substituted Benzofurol[2,3-c]pyridin-6-ols: Synthesis and Topological Relationship to Oxide-bridged Phenylmorphans (2009) J. Med. Chem. 52, 7570-7579.

Lee YS, Pike VW and Hodoscek M:Identification of the Transition States in the Inversion of 1,4-Benzodiazepines with the Ab-Initio Replica Path Method (2008) J. Phys. Chem. A 112, 1604-1611.

Lee YS, Marcu MG and Neckers L: Quantum Chemical Calculations and Mutational Analysis Suggest Heat Shock Protein 90 Catalyzes Trans-Cis Isomerization of Geldanamycin (2004) Chem. Biol. 11, 991-998.

Neckers L and Lee YS: The Rules of Attraction. (2003) Nature 106, 357-358.

Lee YS, Hodoscek M., Kador PF and Sugiyama K: Hydrogen Bonding Interactions between Aldose Reductase Complexed with NADP(H) and Inhibitor Tolrestat Studied by Molecular Dynamics Simulations and Binding assay (2003) Chem-Biol Interact. 143, 307-316.

Sugiyama K, Chen Z, Lee YS and Kador PF: Isolation of a Non-covalent Aldose Reductase-Nucleotide-Inhibitor Complex. (2000) Biochem. Pharmacol. 59, 329-336.

Lee YS, Sugiyama K and Kador PF: Rotamers of Tolrestat and Their Binding Mode to Aldose Reductase. (1999) Adv. Exp. Med. Biol. 463, 465-472.

Lee YS, Chen Z and Kador PF: Molecular Modeling Studies of the Binding Modes of Aldose Reductase Inhibitors at the Active Site of Human Aldose Reductase. (1998) Bioorg. Med. Chem. 6, 1811-1820.