Vladimir Sukalovic

Theoretical insight into sulfur–aromatic interactions with extension to D2 receptor activation mechanism

Contacts between aromatic rings and sulfur-containing amino acids are frequent in proteins. However, little is known about the nature of their interactions particularly if substituents are present on aromatic ring. In this paper, DFT quantum chemical calculations were used to study substituted benzenes in complex with hydrogen sulfide (H2S), methanethiol (CH3SH), and (Methylsulfanyl)methane (CH3SCH3). It was found that SH···π interaction is more stabilizing than the S···π interaction in the case of benzene, but this is changed with increasing electronegativity of the substituent on benzene ring. Although the change of energy of SH···π and S···π interaction follows the conventional model of substituent effect, where S···π interactions are maximized and SH···π interactions are diminished with electron-withdrawing substituent on benzene as a result of changes in the aryl π-system, it was found that it is mainly a consequence of direct electrostatic interaction between substituent and the sulfur-containing molecule. We also investigated the model system of Cys···Trp interaction, adjacent to a cluster of aromatic amino acids, in proteins, using explicit membrane molecular dynamics simulations results of D3 dopamine receptor crystal structure as starting point. It was found that fluorination in aromatic cluster enhances the Cys···Trp interaction. The effect is maximized when transferred through the rest of aromatic system suggesting possible explanation for frequent contacts between sulfur-containing and aromatic amino acids in proteins and their effects on protein folding and stabilization.

Molecular Modeling of 5HT2A Receptor – Arylpiperazine Ligands Interactions

In this paper, we report the molecular modeling of the 5HT2A receptor and the molecular docking of arylpiperazine‐like ligands. The focus of the research was on explaining the effects the ligand structure has on the binding properties of the 5HT2A receptor and on the key interactions between the ligands and the receptor‐binding site. To see what the receptor–ligand interactions were, various substituents were introduced in one part of the ligand, keeping the rest unchanged. In this way, using a docking analysis on the proposed 5HT2A receptor model, we identified key receptor–ligand interactions and determined their properties. Those properties were correlated with experimentally determined binding affinities in order to determine the structure to activity relationship of the examined compounds.

Interactions of N-{[2-(4-phenyl-piperazin-1-yl)-ethyl]-phenyl}-2-aryl-2-yl-acetamides and 1-{[2-(4-phenyl-piperazin-1-yl)-ethyl]-phenyl}-3-aryl-2-yl-ureas with dopamine D2 and 5-hydroxytryptamine 5HT1A receptors

It is suggested that the ratio of dopamine D(2) to 5-hydroxytryptamine 5-HT(1A) activity is an important parameter that determines the efficiency of antipsychotic drugs. Here we present the synthesis of N-{[2-(4-phenyl-piperazin-1-yl)-ethyl]-phenyl}-2-aryl-2-yl-acetamides and 1-{[2-(4-phenyl-piperazin-1-yl)-ethyl]-phenyl}-3-aryl-2-yl-ureas and their structure-activity relationship studies on dopamine D(2) and 5-hydrohytryptamine 5-HT(1A) receptors. It was shown that ligand selectivity and affinity strongly depends on their topology and the presence of a pyridyl group in the head of molecules. Molecular modeling studies using homology modeling and docking simulation revealed a rational explanation for the ligand behavior. The observed binding modes and receptor-ligand interactions provided us with a clue for optimizing the optimal selectivity towards 5-HT(1A) receptors.

Synthesis, biological evaluation and docking analysis of substituted piperidines and (2-methoxyphenyl)piperazines

A series of sixteen novel substituted piperidines and (2-methoxyphenyl)piperazines were synthesized, starting from the key intermediates 1-(2-methoxyphenyl)-4-(piperidin-4-yl)piperazine and 1-(2-methoxyphenyl)-4-(piperidin-4-ylmethyl)piperazine. Biological evaluation of the synthesized compounds was pointed out seven compounds, of which 1-(2-methoxyphenyl)-4-{[1-(2-nitrobenzyl)piperidin-4-yl]methyl}piperazine has the highest affinity for the dopamine D 2 receptor. For all seven selected compounds docking analysis was performed in order to establish their structure-to-activity relationship.

Identification of NQO1 and ferrochelatase as interaction partners for neuroprotective N-{[2-(4-phenyl-piperazin-1-yl)-ethyl]-phenyl}-arylamides

Affinity chromatography was used to identify potential cellular targets that are responsible for neuroprotective activity of N‐{[2‐(4‐phenyl‐piperazin‐1‐yl)‐ethyl]‐phenyl}‐arylamides. Active and inactive representatives of N‐{[2‐(4‐phenyl‐piperazin‐1‐yl)‐ethyl]‐phenyl}‐arylamides bearing an extended linker were synthesized and immobilized on an agarose‐based matrix. This was followed by the identification of specifically bound proteins isolated out of the whole rat brain extract. Inducible flavoprotein NAD(P)H:quinone oxidoreductase (NQO1) was identified as candidates for cellular targets.

Synthesis, Biological, and Computational Evaluation of Substituted 1-(2-Methoxyphenyl)-4-(1-phenethylpiperidin-4-yl)piperazines and 1-(2-Methoxyphenyl)-4-[(1-phenethylpiperidin-4-yl)methyl]piperazines as Dopaminergic Ligands.

Sixteen new 1‐(2‐methoxyphenyl)‐4‐(1‐phenethylpiperidin‐4‐yl)piperazines and 1‐(2‐methoxyphenyl)‐4‐[(1‐phenethylpiperidin‐4‐yl)methyl]piperazines were synthesized to be used as probes for mapping the dopamine D2 receptor (D2DAR) arylpiperazine binding site. All compounds were evaluated for their affinity toward D2DAR in an in vitro competitive displacement assay. The most active one was 1‐(2‐methoxyphenyl)‐4‐{[1‐(3‐nitrophenethyl)piperidin‐4‐yl]methyl}piperazine (25) with an affinity of Ki = 54 nM. Docking analysis was conducted on all herein described compounds, whereas molecular dynamic simulation was performed on ligand 25 to establish its mode of interaction with D2DAR. Two possible docking orientations are proposed; the one with a salt bridge between the piperidine moiety and Asp114 of D2DAR is more stable.