György M. Keserü

Phospholes with reduced pyramidal character from steric crowding III NMR and X-ray diffraction studies on 1-(2,4,6-tri-isopropylphenyl)-3-methylphosphole

Abstract The 2,4,6-tri-isopropylphenyl substituent was placed on the phosphorus of a phosphole to reduce the pyramidal character. That this was accomplished was revealed by single crystal X-ray diffraction analysis; with respect to the plane of C2ue5f8Pue5f8C5 in the phosphole ring, the ipso carbon of the benzene ring was deflected by only 58.0°, whereas the deflection is 66.9° in the uncrowded 1-benzylphosphole. This proves that the concept of reducing the pyramidal character (with the goal of increasing the electron delocalization) through steric crowding can be realized. In the crystal the two rings are in orthogonal planes, but this relation is not retained in solution; NMR studies show that the two edges of the benzene ring, as well as the 2,6-isopropyl groups, are identical.

Activation mechanism of the human histamine H4 receptor--an explicit membrane molecular dynamics simulation study.

Molecular dynamics (MD) simulations in a membrane-embedded environment were carried out on the homology model of the human histamine H4 receptor (hH4R) alone and in complex with its endogenous activator histamine and with the first reported selective hH4R antagonist JNJ7777120. During the simulation of the histamine-hH4R complex, considerable changes occurred in the hH4R structure as well as in the interaction pattern of histamine at the binding site. These changes are in agreement with experimental data published on GPCR activation. In particular, the intracellular side of TM helix VI moved significantly away from TM helices III and VII. Moreover, histamine formed an interaction with Asn147 (4.57) that was previously proved to be important in hH4R activation. Results of the MD simulations of the native hH4R and the JNJ7777120-hH4R complex suggest that these models represent an inactive conformation of hH4R. MD simulation in the presence of JNJ7777120 resulted in the movement of the intracellular side of TM helix VI in the direction of TM helix III. Snapshots of the simulations may serve as functionally relevant models in the development of novel hH4R ligands in the future.

Protonation state of Asp30 exerts crucial influence over surface loop rearrangements responsible for NO release in nitrophorin 4.

pK a values of ionizable residues were calculated for the crystal structures describing the pH and NO binding dependant conformations of nitrophorin 4, a pH sensitive NO carrier heme protein. Comparison of resultant H‐bonding patterns allowed the identification of the amino acids that take part in signaling pH change. We carried out MD simulations to show that the protonation state of Asp30, buried in the closed conformation, is crucial for maintaining the tight packed conformation of the closed form of the complex – presenting a model for the functional decrease of NO binding affinity of nitrophorins at physiological pH.

Calmodulin in Complex with Proteins and Small Molecule Ligands: Operating with the Element of Surprise.Implications for Structure-Based Drug Design

Calmodulin plays a role in several life processes, its flexibility allows binding of a number of different ligands from small molecules to amphiphilic peptide helices and proteins. Through the diversity of its functions, it is quite difficult to find new drugs, which bind to calmodulin as a target. We present available structural information on the protein, obtained by X-ray diffraction, nuclear magnetic resonance spectroscopy and molecular modeling and try to derive some conclusions on structure-activity relationships.

Conformational analysis of (S,S)-dimethyldiketopyridino-18-crown-6

The crystal structure of (S,S)-dimethyldiketopyridino-18-crown-6, (I), C 17 H 23 NO 7 , an effective host for chiral organic ammonium salts is described. A minimum-energy conformation was obtained by a pseudo-Monte-Carlo conformational search in the gas phase and was compared with the crystal structure. Structural changes in chiral recognition processes are also discussed.

Theoretical studies on long-range substituent effects in the reduction of 7-norbornanones

The energetics of the stereoselective reduction of norbornan-7-one derivatives have been studied by semiempirical AM1 molecular orbital calculations. It was found that the reaction is kinetically controlled; correct prediction of the selectivity is possible only on the basis of the relative energies of the transition states of the reaction. Theoretically calculated and experimental anti–syn product ratios are in semiquantitative agreement, in contrast to results obtained from molecular electrostatic potentials. Geometry relaxation of the transition state is essential in obtaining reliable isomer ratios.

Steric vs. electrostatic effects in the nucleophilic addition to a hindered cyclohexanone

The relative importance of steric vs. electrostatic effects in the nucleophilic addition to (4R,6S)-4-(tert-butyldimethylsiloxy)-2,2,6-trimethylcyclohexanone (1), a well-known chiral building block, is investigated.

Theoretical study on the 5-exo/6-endo selectivity in the cyclization of electrophilic radicals

Abstract A theoretical study on the cyclization of electrophilic radicals was carried out. Transition state geometries were obtained by MNDO semiempirical calculations and the calculated properties (orbital energies, orbital coefficients, charge distributions and energy partition) were analysed. Observed regioselectivities can be rationalised on the basis of SOMO-HOMO and SOMO-LUMO orbital interactions.