Department of Medicinal & Biological Chemistry : Peter I. Nagy

Institutions/Degrees

Computational chemistry, molecular modeling. Ab initio/DFT and Monte Carlo simulations of the conformational and tautomeric equilibria of small molecules in the gas phase and in solution. Intra- and intermolecular molecular hydrogen bond(s). Molecular mechanics and dynamics calculations for studying the ligand-receptor interaction in condensed phase.

Research Interests

The focus of my interest is the structure analysis and computer modeling of systems consisting of molecules with biological relevance. The ultimate goal is to calculate both the enthalpy and entropy, regulating the ligand-receptor interactions in solution. Theoretical analysis of the structures of monomers and dimers, and calculations of the interaction energy and/or free energy can help develop ligands with more favorable interactions with a particular receptor.

In van der Waals complexes, such as enzyme-inhibitor and ligand-receptor complexes, the hydrogen-bond formation is one of the major stabilizing interactions. An intermolecular bond can be formed only if the monomer conformations are favorable in the dimer. Ligands with more than one polar functional group can form intramolecular hydrogen bonds that may or may not be maintained through the interaction with a receptor. Solvent effects have turned out to be crucial for disrupting the intramolecular hydrogen bond for 1,2-ethylene glycol, 2-hydroxybenzoic acid, and the neurotransmitters histamine, dopamine, norepinephrine, and GABA. Calculations of the conformational/tautomeric equilibria involve high-level ab initio/DFT procedures for obtaining the relative internal free energy, and Monte Carlo simulations using the free energy perturbation method for estimating the relative solvation free terms.

Drugs in the delivery process must pass through both hydrophilic and lipophilic phases. The chemical environment influences the conformation of the drug and its protonation state, favoring in cases the formation of protonated/deprotonated ions in the condensed phase. All these structural changes affect the partitioning process. Interaction with the solvent is a decisive factor in partitioning among various phases. Our research has been extended recently to this field, including considerations of the counterion effect and of the possible zwitterion formation.

The software package Sybyl has been used in modeling ligand-receptor interactions. This package can handle systems as large as the human estrogen receptor and the muscarinic receptor. In the former case, a research has been conducted to explore the structural conditions when some non-natural estrogens or chlorinated phenols can compete with estradiol in binding to the receptor. In an endeavor to develop selective agonists to the muscarinic 1 receptor, a central problem in treating the Alzheimer's disease, a rhodopsin-based receptor model was considered. By comparison of theoretical results with those from experimental binding assays, a model binding pocket formed by residues Asp105, Thr192, and Asn382 has been proposed.

Representative Publications

1. Nagy, P.I., Dunn III, W.J., and Nicholas, J.B. Investigations on the convergence rate of the thermodynamic and structural parameters from Monte Carlo simulations of aqueous solutions of methanol and methylamine. J. Chem. Phys. 91, 3707 (1989).
   
   
2. Dunn III, W.J. and Nagy, P.I. Monte Carlo studies on aqueous solutions of methylamine and acetonitrile. Hydration of sp3 and sp nitrogen. J. Phys. Chem. 94, 2099 (1990).
   
   
3. Nagy, P.I., W.J. Dunn III, G. Alagona, and C. Ghio. Theoretical calculations on the gauche-trans equilibrium of 1,2-ethanediol in gas phase and aqueous solution. J. Am. Chem. Soc. 113, 6719., (1991).
   
   
4. Nagy, P.I., Patel, H.C., Dreyer, W., and Hopfinger, A.J. Conformational analysis and aqueous hydration studies of model peptides for the adhesive protein of mussel, Mytilus edulis L. Int. J. Pept. Protein Res. 38, 84 (1991).
   
   
5. Dunn III, W.J., Nagy P.I., and Collantes, E.R. A computer-assisted method for estimation of the partition coefficient. Monte Carlo simulations of the chloroform/water log P for methanol, methylamine and acetonitrile. J. Am. Chem. Soc. 113, 7898 (1991).
   
   
6. Nagy, P.I., Dunn III, W.J., Alagona, G., and Ghio, C. Theoretical calculations on 1,2-ethanediol. Part. 2. Equilibrium of the gauche conformers with and without intramolecular hydrogen bond in aqueous solution. J. Am. Chem. Soc. 114, 4752 (1992).
   
   
7. Dunn III, W.J. and Nagy, P.I. Relative log P and solution structure for small organic solutes in the chloroform/water system using Monte Carlo methods. J. Comput. Chem. 13, 468 (1992).
   
   
8. Nagy, P.I., Dunn III, W.J., Alagona, G., and Ghio, C. Theoretical studies of the 2-hydroxy- and 4-hydroxybenzoic acids with competing hydrogen bonds in gas phase and aqueous solution. J. Phys. Chem. 97, 4628 (1993).
   
   
9. Nagy, P.I., Durant, G.J., and Smith, D.A. Theoretical studies on hydration of pyrrole, imidazole and protonated imidazole in the gas phase and aqueous solution. J. Am. Chem. Soc. 115, 2912 (1993).
   
   
10. Nagy, P.I., G.J. Durant, W.P. Hoss and D.A.Smith. Theoretical analyses of the tautomeric and conformational equilibria of histamine and (R,S)-dimethylhistamine in the gas phase and in aqueous solution. J. Am. Chem. Soc. 116, 4898 (1994).
    
    
11. Alagona, G., Ghio, C., Nagy, P.I., and Durant, G.J.. Theoretical studies on the relative stability of neutral and protonated N, N'-diarylguanidines in solution. J. Phys. Chem. 98, 5422 (1994).
    
    
12. Nagy, P.I., Smith, D.A., Alagona, G., and Ghio, C. Ab initio studies of free and monohydrated carboxylic acids in the gas phase. J. Phys. Chem. 98, 486 (1994).
    
    
13. Nagy, P.I., Bitar, J.E., and Smith, D.A. Comparison of the molecular mechanics and generalized Born/surface area and the ab initio + Monte Carlo simulation methods in estimating conformational equilibria in aqueous solution. J. Comput. Chem. 15, 1228 (1994).
    
    
14. Nagy, P.I., Tokarski, J., and Hopfinger, A.J. Molecular shape and QSAR analyses of a family of substituted dichlorodiphenyl aromatase inhibitors. J. Chem. Inf. Comp. Sci. 34, 1190 (1994).
    
    
15. Nagy, P.I., Ulmer II, C.W., and Smith, D.A. Ab initio studies of the complexes of benzene with carbon monoxide and formaldehyde. J. Chem. Phys. 102, 6812 (1995).
    
    
16. Nagy, P.I. and Durant, G.J. Monte Carlo simulations of the counter ion effect on the conformational equilibrium of the N, N'-diphenylguanidinium ion in aqueous solution. J. Chem. Phys. 104, 1452 (1996).
    
    
17. Ojo, B., Dunbar, P.G., Durant, G.J., Nagy, P.I., Huzl III, J.J., Periyasamy, S., Ngur, D.O., El-Assadi, A.A., Hoss, W.P., and Messer Jr., W.S. Synthesis and biochemical activity of novel amidine derivatives as m1 muscarinic receptor agonists. Bioorg. Med. Chem. 14, 1605 (1996).
    
    
18. Nagy, P.I., Flock, M., and Ramek, M. Theoretical studies on the conformational equilibria of the gamma-hydroxybutyric acid in the gas phase and in solution. J. Phys. Chem. A 101, 5942 (1997).
    
    
19. Nagy, P.I. and K. Takács-Novák. Theoretical and experimental studies of the zwitterion/neutral form equilibrium of ampholytes in pure solvents and mixtures. J. Am. Chem. Soc. 119, 4999 (1997).
    
    
20. Messer Jr., W.S., Abuh, Y.F., Liu, Y., Periyasamy, S., Ngur, D.O., Edgar, M.A.N., El-Assadi, A.A., Sbeih, S., Dunbar, P.G., Roknich, S., Rho, T., Fang, Z., Ojo, B., Zhang, H., Huzl III, J.J., and Nagy, P.I. Synthesis and biological characterization of 1,4,5,6-tetrahydropyrimidine and 2-amino-3,4,5,6-tetrahydropyridine derivatives as selective m1 agonists. J. Med. Chem. 40, 1230 (1997).
    
    
21. Maillard, M.C., Pearlman, M.E., Amitay, O., Baxter, D., Berlove, D., Connaughton, S., Fischer, J.B., Guo, F.Q., Hu, L.Y., McBurney, R.N., Nagy, P.I., Subbaro, K., Yost, E.A., Zhang, L., and Durant, G.J. Design, synthesis and pharmacological evaluation of conformationally constrained analogues of N, N'--diaryl-and N-aryl-N-aralryl guanidines as potent inhibitors of neuronal Na+ channels. J. Med. Chem. 41, 3048 (1998).
    
    
22. Huang, X.-P., Nagy, P.I., Williams, F.E., Peseckis, S.M., and Messer Jr., W.S. Jr. Role of threonine 192 and asparagine 382 in agonist and antagonist interactions with M1 muscarinic receptors. Br. J. Pharmacol. 126, 735 (1999).
    
    
23. Alagona, G., Ghio, C., Nagy, P.I., and Durant, G.J. Theoretical studies on the continuum solution of some N,N’-dimethyl-and N-methyl, N’-acetyl guanidine and guanidinium conformers. J. Phys. Chem. A 103, 1857 (1999).
    
    
24. Nagy, P.I. Theoretical calculations for the conformational/tautomeric equilibria of biologically important molecules in solution. Recent Research Development in Physical Chemistry, Transworld Research Network 3, 1-21, (1999).
    
    
25. Nagy, P.I., Alagona G., and Chio, C. Theoretical studies on the conformation of protonated dopamine in the gas phase and in aqueous solution. J. Am. Chem. Soc. 121, 4984 (1999).
    
    
26. Messer, W.S., Jr., Rajeswaran, W.G., Cao, Y., Zhang, H.-J., El-Assadi, A.A., Dockery, C., Liske, J. O'Brien, J., Williams, F.E., Huang, X.-P., Wroblewski, M.E., Nagy, P.I., and Peseckis, S.M. Design anddevelopment of selective muscarinic agonists for the treatment of Alzheimer's disease: characterization of tetrahydropyrimidine derivatives and development of new approaches for improved affinity and selectivity for M1 receptors. Pharm. Acta Helv. 74, 135 (2000).
    
    
27. Erhardt, P.W., Klis, W.A., Nagy, P.I., Kirschbaum, K., Wu, N., Martin, A., and Pinkerton, A. A.. 2-Phenylglycerol: crystal structure and conformational considerations pertaining to formation of its related oxetane. J. Chem. Crystallogr. 30, 83 (2000).
    
    
28. Nagy, P.I. and Takács-Novák, K. Theoretical and experimental study on ion-pair formation and partitioning of organic salts in octanol/water and dichoromethane/water systems. J. Am. Chem. Soc. 122, 6583 (2000).
    
    
29. Nagy, P.I. and Noszál, B. Theoretical study of the tautomeric/conformational equilibrium of aspartic acid zwitterions in aqueous solution. J. Phys. Chem. A. 104, 6834 (2000).
    
    
30. Ramek, M. and Nagy, P.I. Theoretical investigation of the neutral/zwitterionic equilibrium of gamma-aminobutyric acid (GABA) conformers in aqueous solution. J. Phys. Chem. A 104, 6844 (2000).
    
    
31. Szárics, E., Nyikos, L., Barabás, P., Kovács, I., Skuban, N., Temesvárine-Major, E., Egyed, O., Nagy, P.I., Kökösi, J., Takács-Novák, K., and Kardos, J. Quinazoline-alkyl-carboxylic acid derivatives inhibit transmembrane Ca2+ ion flux to (+)-(S)-a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid. Mol. Pharmacol. 59, 920 (2001).
    
    
32. Nagy, P.I., Takács-Novák, K., and Ramek, M. Theoretical and experimental studies on partitions of gamma-substituted butyric acids in chloroform/water and dichloromethane/water systems. J. Phys. Chem. B 105, 5772 (2001).
    
    
33. Rajeswaran, W.G., Cao, Y., Huang, X.-P., Wroblewski, M.E., Colclough, T., Lee, S., Liu, F., Nagy, P.I., Ellis, J., Levine, B.A., Nocka, K.H., and Messer Jr., W.S. Design, synthesis, and biological characterization of bivalent 1-methyl-1,2,5,6-tetrahydropirydyl-1,2,5-thiadiazole derivates as selective muscarinic agonist. J. Med. Chem. 44, 4563 (2001).
    
    
34. Nagy, P.I. Theoretical calculations on the torsion potential of peroxynitrite anion in aqueous solution. J. Phys. Chem. A 106, 2659 (2002).
    
    
35. Nagy, P.I., Alagona, G., Ghio, C., and Takács-Novák, K. Theoretical studies of conformations of neurotransmitters in the gas phase and aqueous solution. Norepinephrine J. Am. Chem. Soc. 125, 2770 (2003).
    
    
36. Cao, Y., Zhang, M., Wu, C., Lee, S., Wroblewski, M. E., Whipple, T., Nagy, P. I., Takács-Novák, K., Balázs, A., Tõrös S., and Messer, W. S., Jr. Synthesis and biological characterization of 1-methyl-1,2,5,6-tetrahydropyridyl-1,2,5-thiadiazole derivatives as muscarinic agonists for the treatment of neurological disorders J. Med. Chem. Soc. 46, 4273 (2003).
    
    
37. Nagy, P. I., Kökösi, J., Gergely, A., and Rácz A. Theoretical conformational analysis for codeinone-6-oximes in gas phase and in solution J. Phys. Chem. A 107, 7861 (2003).
    
    
38. Alagona, G., Ghio, C., and Nagy, P. I. Theoretical studies on the effects of methods and parameterization on the calculated free energy of hydration for small molecules. Int. J. Quant. Chem. in press (2004).
    
    
39. Nagy, P. I. and Takács-Novák, K. Theoretical and experimental studies of tautomeric equilibria of small, biologically important molecules in solution. Phys. Chem. Chem. Phys. invited paper, in press (2004).
    
    
40. Nagy, P. I. Effects of the solute model and concentration on the calculated free energy of hydration in explicit solvent solution. Submitted for publication (2004).
    
    
41. Nagy, P. I., Tejada, F. R., Sarver, J. G., and Messer, W. S., Jr. Conformational analysis and derivation of molecular mechanics parameters for esters and thioesters. Submitted for publication (2004).