V Soskić

Proteosys AG, Mayence, Rheinland-Pfalz, Germany

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Publications (41)69.07 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: There is an urgent need for surrogate biomarkers in clinical diagnostics but also preclinical in toxicology of chemicals and efficacy testing of pharmaceuticals. On the background of the emerging fields of systems biology and theranostics, the importance of time scales and the synchronization of complex biological readouts become increasingly obvious. Systemic effects such as responses to stimuli, medical intervention, cellular stress, or toxicity elicit immediate molecular changes on the protein level. Early events include phosphorylation and oxidation of proteins. These posttranslational modifications have a direct impact on enzyme activities and protein-protein interactions. Only at downstream stages is gene transcription activated. Here we outline the analytical and statistical requirements dealing with complex patterns of protein expression and the extraction of protein surrogate biomarkers defining specific early stages of biological responses. We also present successful examples from research on aging and discuss prerequisites and necessary considerations while moving candidates to validation.
    Annals of the New York Academy of Sciences 06/2010; 1197:118-28. · 4.38 Impact Factor
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    ABSTRACT: ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
    ChemInform 01/2010; 28(6).
  • [Show abstract] [Hide abstract]
    ABSTRACT: ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
    ChemInform 01/2010; 29(46).
  • V. Soskic, Jelena Joksimovic
    ChemInform 01/2010; 30(11).
  • ChemInform 01/2010; 33(3).
  • [Show abstract] [Hide abstract]
    ABSTRACT: ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
    ChemInform 01/2010; 27(7).
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    ABSTRACT: Regarding toxicity and efficacy tests of pharmacological and chemical substances (REACH legislation in Europe), there is a strong need to develop alternative methods for animal in vivo studies, in particular for human in vitro models. Here we present results from early phases of projects exploring the potential of embryonic stem cell models, with a special emphasis on embryo toxicity and neuronal stress.We have been able to demonstrate key functional read-outs of neural hESC models, in addition to representing mechanistic aspects which are characteristic for ischemia or excitotoxicity. There is agreement that these mechanisms underlie a variety of human neurodegenerative diseases. We discuss the possibilities to develop more precise endpoints on the molecular level and present an example of a protein biomarker signature emerging from a European FP6 project about embryo toxicity (www.reprotect.eu), employing murine and human embryonic stem cell models.
    Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz 10/2008; 51(9):1033-8. · 0.72 Impact Factor
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    ABSTRACT: In a drug reprofiling attempt, we explored novel neuroprotective properties of 4-azasteroids by synthesizing chemical affinity tags capturing adenine nucleotide translocator-1, as a potential target. Dutasteride inhibits the mitochondrial transition pore and induces an increase of autophagosomal structures in human cell lines. In vivo, a surprising reduction of the beta-amyloid plaque load in a model for cerebral amyloidosis appears to connect release of neurotoxic peptides, mitochondrial apoptosis and autophagy.
    Journal of Proteome Research 07/2008; 7(6):2262-9. · 5.06 Impact Factor
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    ABSTRACT: One of the most fundamental molecular aspects of aging is accumulating oxidative damage caused by reactive oxygen species (ROS) as proposed by the free radical theory of aging. These unwanted chemical side products of normal metabolism lead to the formation of altered, less active and potentially toxic species of DNA, RNA, proteins, lipids, and small molecules. Due to gradually accumulating small contributions of irreversible reactions during ageing, uncatalyzed chemical side reactions occur with increasing frequencies and repair functions decline. Eventually key biochemical pathways are impaired by increasingly less efficient cellular stress management. In this review, we describe the chemical nature of nonenzymatic age-related modifications of proteins and provide an overview of related analytical challenges and approaches, with a focus on mass spectrometry. We include the description of a strategy to rapidly exploit the wealth of mass spectrometric information from standard MALDI-TOF peptide fingerprints for the characterisation of age-related oxidative amino acid modifications.
    Experimental Gerontology 05/2008; 43(4):247-57. · 3.91 Impact Factor
  • Source
    André Schrattenholz, Vukić Soskić
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    ABSTRACT: The complexity and flexibility of cellular architectures is increasingly recognized by impressive progress on the side of molecular analytics, i.e. proteomics, genomics and metabolomics. One of the messages from systems biology is that the number of molecular species in cellular networks is orders of magnitude bigger than anticipated by genomic analysis, in particular by fast posttranslational modifications of proteins. The requirements to manage external signals, integrate spatiotemporal signal transduction inside an organism and at the same time optimizing networks of biochemical and chemical reactions result in chemically extremely fine tuned molecular entities. Chemical side reactions of enzymatic activity, like e.g. random oxidative damage of proteins by free radicals during aging constantly introduce epigenetic alterations of protein targets. These events gradually and on an individual stochastic scale, keep modifying activities of these targets, and their affinities and selectivities towards biological and pharmacological ligands. One further message is that many of the key reactions in living systems are essentially based on interactions of low affinities and even low selectivities. This principle is responsible for the enormous flexibility and redundancy of cellular circuitries. So, in complex disorders like cancer or neurodegenerative diseases, which are rooted in relatively subtle and multimodal dysfunction of important physiologic pathways, drug discovery programs based on the concept of high affinity/high specificity compounds ("one-target, one-disease"), which still dominate the pharmaceutical industry increasingly turn out to be unsuccessful. Despite improvements in rational drug design and high throughput screening methods, the number of novel, single-target drugs fell much behind expectations during the past decade and the treatment of "complex diseases" remains a most pressing medical need. Currently a change of paradigm can be observed with regard to a new focus on agents that modulate multiple targets simultaneously. Targeting cellular function as a system rather than on the level of the single protein molecule significantly increases the size of the drugable proteome and is expected to introduce novel classes of multi-target drugs with fewer adverse effects and toxicity. Multiple target approaches have recently been used to design medications against atherosclerosis, cancer, depression, psychosis and neurodegenerative diseases. A focussed approach towards "systemic" drugs will certainly require the development of novel computational and mathematical concepts for appropriate modelling of complex data and extraction of "screenable" information from biological systems essentially ruled by deterministic chaotic processes on a background of individual stochasticity.
    Current Medicinal Chemistry 02/2008; 15(15):1520-8. · 3.72 Impact Factor
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    ABSTRACT: In this publication we are describing synthesis, binding properties, and receptor docking of 4-halo-6-[2-(4-arylpiperazin-1-yl)ethyl]-1H-benzimidazoles, a new compounds with potential antipsychotics properties. Affinity towards the dopamine D(1)-like and D(2)-like, and serotonin 5-HT(1A) receptors was evaluated using the radioligand binding assays. All compounds tested had affinity for the D(2)-like and 5-HT(1A) receptors, but were inactive towards the D(1)-like receptor. Halogenated 6-[2-(4-arylpiperazin-1-yl)ethyl]-1H-benzimidazoles showed higher affinity compared to their nonhalogenated congeners. In silico docking analysis of selected ligands was performed in order to explain the results of binding assays. Our analysis suggests that stabilizing interactions between the halogen atom at the benzimidazole ring and the Ser-122 of the D(2)-like and Trp-358 of the 5-HT(1A) receptor. Energy contributions for these interactions were calculated using the ab initio method.
    European Journal of Medicinal Chemistry 11/2007; 43(8):1696-705. · 3.50 Impact Factor
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    ABSTRACT: Clinical properties of atypical antipsychotics are based on their interaction with D(2) dopamine receptor and serotonin 5-HT(1A) and 5-HT(2A) receptors. As a part of our research program on new antipsychotics, we synthesized various derivatives of 1-cinnamyl-4-(2-methoxyphenyl)piperazines, and evaluated their affinities for D(2), 5-HT(1A), 5-HT(2A), and adrenergic (alpha(1)) receptors using radioligand-binding assays. In addition, we performed docking analysis using models for the D(2) and 5-HT(1A) receptors. All compounds exhibited low to moderate affinity to 5-HT(1A) and 5-HT(2A) receptors, high affinity to the D(2 )receptor and large variability in affinities for the alpha(1) receptor. Docking analysis indicated that the binding to D(2) and 5-HT(1A) receptors is based on (i) interaction between protonated N1 of the piperazine ring and various aspartate residues, (ii) hydrogen bonds between various moieties of the ligand and the residues of threonine, serine, histidine or tryptophane, and (iii) edge-to-face interactions of the aromatic ring of the arylpiperazine moiety with phenylalanine or tyrosine residues. Docking data for the D(2) receptor can account for the binding properties obtained in binding assays, suggesting that the model is reliable and robust. However, docking data for the 5-HT(1A) receptor cannot account for actual binding properties, suggesting that further refinement of the model is required.
    Archiv der Pharmazie 10/2007; 340(9):456-65. · 1.54 Impact Factor
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    ABSTRACT: 5-[3-(4-Arylpiperazin-1-yl)propyl]-1H-benzimidazoles and 5-[2-(4-arylpiperazin-1-yl)ethoxy]-1H-benzimidazoles were synthesized and their affinity for the D1, D2 and 5-HT1A receptors examined. They expressed a rather high affinity for the D2 dopamine receptor. The main features of ligand-D2 receptor interactions revealed by docking analyses were: salt bridge between piperazine ring protonated N1 and Asp 86, hydrogen bonds of ligand bezimidazole part with Ser 141, Ser 122 and His 189, edge-to-face interactions of arylpiperazine aromatic ring with Phe 178, Tyr 216 and Trp 182 and hydrogen bond between ethereal oxygen in ethylenoxy ligands and hydrogen of Phe 185 or Trp 115. The most active 5-[2-[4-(2-methoxyphenyl)-piperazin-1-yl]ethoxy]-1,3-dihydro-2H-benzimidazole-2-thione (27) has a maximal number of attractive interactions. A satisfactory correlation between docking of the compounds into the D2 receptor and competition binding results was observed.
    European Journal of Medicinal Chemistry 06/2005; 40(5):481-93. · 3.50 Impact Factor
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    ABSTRACT: The docking of several 1-benzyl-4-arylpiperazines to the dopamine receptor (DAR) D2 was examined. The results demonstrated that the interaction of protonated N1 of the piperazine ring with Asp 86 (III.32) and edge-to-face interactions of the aromatic ring of the arylpiperazine part of the ligand with Phe 178 (VI.44), Trp 182 (VI.48) and Tyr 216 (VII.58) of the receptor, represent the major stabilizing forces. Besides, the hydrogen bond acceptor group in position 2 of the phenylpiperazine aromatic ring could build one more hydrogen bond with Trp 182 (VI.48). Bulky substituents in position 4 were not tolerated due to the unfavorable sterical interaction with Phe 178 (VI.44). Substituents in position 2 and 3 were found to be sterically well tolerated. Introduction of electron attractive -NO2 group in position 3 of aryipiperazines decreased, while electron donors (-OMe) and the second aromatic ring (naphthyl) increased the binding affinity comparing to that of the phenylpiperazine 1. This can be explained in terms of favoured edge-to-face interactions in ligands with a high negative electrostatic surface potential (ESP) in the centre of aromatic residue of arylpiperazines. Thus, besides the salt bridges and hydrogen bonds, edge-to-face interactions significantly contribute to arylpiperazine ligands to form complexes with the DAR D2. Phe 178 (VI.44), Trp 182 (VI.48) and Tyr 216 (VII.58) can be considered as a part of the ancillary DAR D2 pocket preserved in most G protein-coupled receptors of the A class and obviously, the arylpiperazine structural motif represents one of the privileged structures that bind to this pocket.
    Arzneimittel-Forschung 02/2005; 55(3):145-52. · 0.56 Impact Factor
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    ABSTRACT: For Abstract see ChemInform Abstract in Full Text.
    ChemInform 01/2005; 36(1).
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    ABSTRACT: Docking of several 1-[2-[5-(1H-benzimidazole-2-thione)]ethyl]-4- and 1-benzyl-arylpiperazines to the D(2) dopamine receptor (DAR) was examined. The binding pocket of the D(2) DAR defined according to Teeter and DuRand [1] was extended using the Insight II software. It was found that (i) the interaction of the protonated N1 of the piperazine ring with Asp86, (ii) the hydrogen bond formation between the benzimidazole part of the ligand and Ser141, as well as Ser122, and (iii) the edge-to-face interactions of the aromatic ring or arylpiperazine part of the ligand with Phe178, Tyr216 and Trp182 of the receptor represent the mayor stabilizing forces. Besides, the hydrogen bond acceptor group in position 2 of the phenylpiperazine aromatic ring could form one more hydrogen bond with Trp182. Bulky substituents in position 4 are not tolerated, due to the unfavorable sterical interaction with Phe178. Substituents in positions 2 and 3 are sterically well tolerated. Electron-attractive groups (F, Cl, CF(3), and NO(2)) decreased, while electron donors (-OMe) and the second aromatic ring (naphthyl) increased the binding affinity, as compared to that of the parent compound 1. This can be explained by strong edge-to-face interactions of negative electrostatic surface potential (ESP) in the center of aromatic residues of the ligand with positive-ESP protons in the aromatic residues of the receptor. Thus, besides the salt bridges and hydrogen bonds, edge-to-face interactions significantly contribute to arylpiperazine ligands forming complexes with the D(2) DAR.
    Archiv der Pharmazie 10/2004; 337(9):502-12. · 1.54 Impact Factor
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    ABSTRACT: We examined the effects of the electron density distribution (electrostatic surface potential; ESP) of several new benzimidazole-type ligands on their binding affinity for the D(1) and D(2) dopamine receptors (DAR). Receptors were prepared from synaptosomal membranes of bovine caudate nuclei. [(3)H]SCH 23390 and [(3)H]spiperone were used as specific radiolabels for the D(1) and D(2) receptors, respectively. The ESP of these compounds was calculated using Gaussian 98 W software. Calculations performed with known dopaminergic ligands showed that the electron density charge in the aromatic ring of these compounds favors a higher binding affinity for the D(2) DAR. This was confirmed by the synthesis of halogenated analogues of several known dopaminergic ligands. Halogenation resulted in an increase in the positive charge of the aromatic part of the molecule. None of the newly synthesized compounds was efficient in displacing [(3)H]SCH 23390 from the D1 DAR. The introduction of chlorine into the molecule led to a higher binding affinity for the D(2) DAR of the new ligands in comparison to both parent compounds and brominated ligands. This difference probably originates from the difference in the sizes of chlorine and bromine atoms, which could influence the interaction of a ligand with the receptor binding site. However, among the new ligands with bromine as a substituent, two compounds (8b and 10b) expressed a higher binding affinity and two of them (9b and 11b) a lower binding affinity for the D(2) DAR, when compared to unsubstituted parent compounds. These results indicate that the electrostatic surface potential of a ligand is an important factor in its interaction with the D(2) DAR and that this should be taken into account during design and synthesis of dopaminergic compounds.
    Archiv der Pharmazie 08/2004; 337(7):376-82. · 1.54 Impact Factor
  • Pharmazie 10/2003; 58(9):677-8. · 0.96 Impact Factor
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    ABSTRACT: 1-(2-Heteroarylalkyl)-4-phenylpiperazines containing methyl group in either the alpha- or the beta-position of the side alkyl chain were synthesized as racemic mixtures. They were evaluated for in vitro binding affinity at the D1 and D2 dopamine and 5-HT1A serotonin receptors using synaptosomal membranes of the bovine caudate nucleus and hippocampus, respectively, as a source of the corresponding receptors. Tritiated SCH 23390 (D1 receptor-selective), spiperone (D2 receptor-selective), and 8-OH-DPAT (5-HT1A receptor-selective) were employed as the radioligands. None of the new compounds expressed significant affinity for the D1 receptor. Introduction of the methyl group into the beta-position of the parent molecules increased the affinity for the D2 receptor (10b-13b), and decreased the affinity for the 5-HT1A receptor with the exception of imidazole (11b) which was a rather efficient displacer of 8-OH-DPAT. Most potent of the newly synthesized compounds in [3H]spiperone assay were compounds (+/-)6-[1-methyl-2- (4-phenylpiperazin-1-yl)-ethyl]-1,4-dihydroquinoxaline-2,3-dione (10b), Kd = 6.0 nM and (+/-)5-[1-methyl-2-(4-phenylpiperazin-1-yl)-ethyl]-1,3-dihydrobenzoimidazol- 2-thione (13b), Kd = 5.3 nM. However, compounds containing methyl group in alpha-position (10a-13a) of the parent molecules expressed a decreased affinity for the D2 receptor, while the affinity for the 5-HT1A receptor remained in the same range of concentrations as that of closely related achiral parent compounds (14-17) run in the same binding assays as references.
    Archiv der Pharmazie 01/2002; 334(12):375-80. · 1.54 Impact Factor
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    ABSTRACT: Eight novel N-heteroarylalkyl-N-phenylpiperazines have been synthesized, chemically characterized and evaluated for in vitro binding affinity at the dopamine and serotonin receptors. Synaptosomal membranes of fresh bovine caudate nuclei (D1 and D2), the membranes of COS-7 cells (D4.4) and those prepared from fresh bovine hippocampi (5-HT1A) were used as a source of the corresponding receptor subtypes. [3H]SCH 23390 (D1-selective), [3H]spiperone (D2- and D4.4-selective) and [3H]-8-OH-DPAT (5-HT1A-selective) served as radioligands. None of the compounds expressed the affinity for the binding at the D1 subtype receptor. Compounds 7-9 containing a single methylene group serving as a bridge between heteroaryl- and N-phenylpiperazine part of the molecule were inactive [3H]spiperone and [3H]-8-OH-DPAT competitors. Ligands 15-19 (three methylene groups connecting heteroaryl- and N-phenylpiperazine part of the molecule) acted as moderate competitors of [3H]spiperone binding at the D2 receptor subtype, with the exception of 15 (a thione) which expressed a high binding affinity at the D2 receptor subtype. Compounds 15-19 behaved as moderate displacers of 8-OH-[3H]DPAT. Among all eight novel ligands only compound 15 expressed a moderate binding affinity at the D4.4 receptor subtype.
    Pharmazie 11/2001; 56(10):803-7. · 0.96 Impact Factor

Publication Stats

111 Citations
69.07 Total Impact Points

Institutions

  • 2005–2008
    • Proteosys AG
      Mayence, Rheinland-Pfalz, Germany
  • 1987–2002
    • University of Belgrade
      • • Faculty of Chemistry
      • • Department of Chemistry
      • • Institute of Chemistry in Medicine
      Belgrade, SE, Serbia
  • 1994–1998
    • Institute of Chemistry, Technology and Metallurgy
      Beograd, Central Serbia, Serbia
  • 1997
    • Institute for Medical Research - Belgrade
      Beograd, Central Serbia, Serbia