NIH, CIT, CMM
Bldg 12A, Room 2049
12 South Drive MSC 5624
Bethesda, MD 20892-5624
I carry out computer simulations at the level of ab-initio quantum chemistry and molecular mechanics to better undersand the structure and function of bio-active compounds at the atomic level. My research interests include protein-ligand interaction, enzyme mechanism, and drug design as well as proton transfer process in both proteins and nanotubes. A brief description of my work is as follows:
Based on the structures of inhibitors/agonists/anatgonists and their experimental data (e.g., IC50 and Ki), I develop pharmacophore requirements for
bio-active compounds to provide a structural basis for their observed experimental data. Examples are geldanamycin, an anti-cancer compound, for Heat Shock Protein 90 (HSP90), opioid analgegics, benzodiazepines, and positron emission tomography (PET) ligands for imaging.
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 of Bioactive Molecules
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.
Enzyme Mechanism and Proton Transfer Process
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.
Brechbiel MW, Guerard F and Lee YS :Tetrahydoxamate Chelators of Zirconium89 and Niobium90 for Use in Diagnostic Applications (2016) U.S. Patent Application Publication No. US 2016/0022844 A1.
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.
Quantum Chemistry and Spectroscopy
Hassan SA, Hummer G and Lee YS:
Effects of Electric Fields on Proton Transport through Water Chains. (2006) J. Chem. Phys. 124, 204510.
Lee YS and Krauss M:
Dynamics of Proton Transfer in Bacteriorhodopsin. (2004) J. Am. Chem. Soc. 126, 2225-2230.
Lee YS and Krauss M:
Structure and Reaction in the Active Site of Mammalian Adenylyl Cyclase . (2004) J. Phys. Chem. B. 108, 4508-4515.
Woodcock HL, Hodoscek M, Sherwood P, Lee YS, Schafer III HF and Brooks BR:
Exploring the QM/MM Replica Method: A pathway optimization of the chorismate to prephenate Claisen Rearrangement Catalyzed by Chorismate Mutase. (2003) Theor. Chem. Acc. 109, 140-148.
Lee YS, Worthington SE, Krauss M and Brooks BR:
Reaction Mechansim of Chorismate Mutase Studied by the Comibined Potentials of Quantum Mechanics and Molecular Mechanics. (2002) J. Phys. Chem. B 106, 12059-12065.
Lee YS, Hodoscek M, Brooks B and Kador PF:
Catalytic Mechanism of Aldose Reductase Studied by the Combined Potentials of Quantum Mechanics and Molecular Mechanics. (1998) Biophys. Chem. 274, 27642-27650.
Lee YS, Pearlstein R and Kador PF: Molecular Modeling Studies of Aldose
Reductase Inhibitors. (1994) J. Med. Chem. 37, 787-792.
Hong SY, Kertesz M, Lee YS and Kim OK:
Geometrical and Electronic Structures of Benzimidazobenzophenanthroline-Type Ladder Polymer (BBL) (1992) Macromolecules 25, 5424-5429.
Lee YS, Kertesz M and Elsenbaumer RL: The Importance of Energetics
in the Design and Synthesis of Small Band Gap Conducting Polymer (1990) Chem. Mater. 2, 526-530.
Kindle JR, Bartoli FJ, Hoffman CA, Kim OK, Lee YS, Shirk JS and Kafafi ZH: Nonlinear Optical Properties of
Heteroaromatic Ladder Polymers, BBL and BBB at 1.064 um . (1990) Appl. Phys. Lett. 56, 712-717.
Lee YS, Sharon DG, McNichol J and Silvers SJ: The Observation of CS2 Continuum-Like Emission Under Collision Free
Conditions. (1989) Chem. Phys. Lett. 161, 116-121.
Kertesz M, Lee YS and Stewart JP: Structure and Electronic Structure of Polyacene . (1989) Int. J. Quantum Chem.
Lee YS and Kertesz M: The Effect of Heteroatomic Substitutions on the Band Gap of Polyacetylene and
Polyparaphenylene Derivatives (1988) J. Chem. Phys. 88, 2609-2617.
Lee YS and Kertesz M: The Electronic Structure of Boron Carbide (BC3) (1988) J. Chem. Soc. Chem. Commun. 1, 75.
Lee YS and Kertesz M: The Effect of Additional Fused Rings on the Stabilities and the Band Gaps of
Heteroconjugated Polymers (1987) Int. J. Quantum Chem. 21, 163-170.
Kertesz M and Lee YS: Energy Gap and Bond Length Alteration in Heterosubstituted Narrow Gap Semiconducting
Polymers. (1987) J. Phys. Chem. 91, 2690-2692.