Biomedical subjects

Simona Golic Grdadolnik

Publications and source records attributed to Simona Golic Grdadolnik.

10 recordsLinked to original sources

PubMed2006

Comparison of proposed putative active conformations of myelin basic protein epitope 87-99 linear altered peptide ligands by spectroscopic and modelling studies: the role of positions 91 and 96 in T-cell receptor activation.

This work proposes a structural motif for the inhibition of experimental autoimmune encephalomyelitis (EAE) by the linear altered peptide ligands (APLs) [Ala91,96] MBP87-99 and [Arg91,Ala96] MBP87-99 of myelin basic protein. Molecular dynamics was applied to reveal distinct populations of EAE antagonist [Ala91,96] MBP87-99 in solution, in agreement with NOE data. The combination of the theoretical and experimental results led to the identification of a putative active conformation. This approach is of value as no crystallographic data is available for the APL-receptor complex. TCR contact residue Phe89 has an altered topology in the putative bioactive conformations of both APLs with respect to the native peptide, as found via crystallography; it is no longer prominent and solvent exposed. It is proposed that the antagonistic activity of the APLs is due to their binding to MHC, preventing the binding of self-myelin epitopes, with the absence of an immunologic response as the loss of some interactions with the TCR hinders activation of T-cells.

Epitopes↗

PubMed2006

Biophysical characterization of an indolinone inhibitor in the ATP-binding site of DNA gyrase.

Fighting bacterial resistance is a challenging task in the field of medicinal chemistry. DNA gyrase represents a validated antibacterial target and has drawn much interest in recent years. By a structure-based approach we have previously discovered compound 1, an indolinone derivative, possessing inhibitory activity against DNA gyrase. In the present paper, a detailed biophysical characterization of this inhibitor is described. Using mass spectrometry, NMR spectroscopy, and fluorescence experiments we have demonstrated that compound 1 binds reversibly to the ATP-binding site of the 24 kDa N-terminal fragment of DNA gyrase B from Escherichia coli (GyrB24) with low micromolar affinity. Based on these data, a plausible molecular model of compound 1 in the active site of GyrB24 was constructed. The predicted binding mode explains the competitive inhibitory mechanism with respect to ATP and forms a useful basis for further development of potent DNA gyrase inhibitors.

Adenosine Triphosphate↗

PubMed2006

Synthesis, conformation, and stereodynamics of a salt of 2-{[2-(3,4-dichlorophenyl)- ethyl]propylamino}-1-pyridin-3-ylethanol.

[reaction: see text] A novel synthetic route was developed for 2-{[2-(3,4-dichlorophenyl)ethyl]propylamino}-1-pyridin-3-ylethanol (4). A dynamic process due to nitrogen inversion at the central amine nitrogen has been identified by NMR spectroscopy for the dihydrobromide salt of this compound. The conformational properties of the diastereomeric pair were determined by analysis of NOE connectivities and MO calculations.

Ethanol↗

PubMed2006

Intrinsic backbone preferences are fully present in blocked amino acids.

The preferences of amino acid residues for ,psi backbone angles vary strikingly among the amino acids, as shown by the backbone angle found from the (3)J(H(alpha),H(N)) coupling constant for short peptides in water. New data for the (3)J(H(alpha),H(N)) values of blocked amino acids (dipeptides) are given here. Dipeptides exhibit the full range of coupling constants shown by longer peptides such as GGXGG and dipeptides present the simplest system for analyzing backbone preferences. The dipeptide coupling constants are surprisingly close to values computed from the coil library (conformations of residues not in helices and not in sheets). Published coupling constants for GGXGG peptides agree closely with dipeptide values for all nonpolar residues and for some polar residues but not for X = D, N, T, and Y, which are probably affected by polar side chain-backbone interactions in GGXGG peptides. Thus, intrinsic backbone preferences are already determined at the dipeptide level and remain almost unchanged in GGXGG peptides and are strikingly similar in the coil library of conformations from protein structures. The simplest explanation for the backbone preferences is that backbone conformations are strongly affected by electrostatic dipole-dipole interactions in the peptide backbone and by screening of these interactions with water, which depends on nearby side chains. Strong backbone electrostatic interactions occur in dipeptides. This is shown by calculations both of backbone electrostatic energy for different conformers of the alanine dipeptide in the gas phase and by electrostatic solvation free energies of amino acid dipeptides.

Alanine↗

PubMed2005

Structure elucidation and conformational study of V8: a novel synthetic non peptide AT(1) antagonist.

AT(1) antagonists constitute the most recent class of antihypertensive drugs which act through the Renin Angiotensin System (RAS). In an effort to comprehend their stereoelectronic features, a study was initiated to compare the conformational properties of drugs already marketed for the treatment of hypertension with synthetic ones, possessing common structural characteristics. In this study, the synthetic AT(1) antagonist V8 is structurally elucidated and its conformational properties are studied through a combination of NMR spectroscopy and computational analysis. Its conformational properties are compared with those of the structurally similar prototype AT(1) antagonist losartan.

Angiotensin II Type 1 Receptor Blockers↗

PubMed2005

In silico fragment-based discovery of indolin-2-one analogues as potent DNA gyrase inhibitors.

We describe here the fragment-based design of potent DNA gyrase inhibitors. Using the tools of virtual screening and NMR spectroscopy we identified the binding of two low-molecular weight fragments (2-aminobenzimidazole and indolin-2-one) to the 24kDa N-terminal fragment of DNA gyrase B. Further in silico optimization of indolin-2-one led to the discovery of potent DNA gyrase inhibitors.

Computer Simulation↗

PubMed2003

Structural elucidation and conformational properties of the toxin paralysin beta-Ala-Tyr.

Larval extracts of the homotetabolous insects (i.e., Neobelleria Bullata-Insecta Diptera), cause paralysis followed by death when injected into adult flesh flies. The reason for causing these lethal effects is because the extracts contain endogenous toxins widely spread over the class of insects. Since their major effect is the paralysis they are called paralysins and are present through all the development stages. Their concentration gradually increases from larvae stage over pupation to late pharate adults indicating that paralysins have an active role in the metamorphosis. The prototype pharmacologically important dipeptide beta-alanine-tyrosine was synthesized and submitted to conformational analysis studies in hydrophilic and amphoteric environments in order to reveal the stereoelectronic properties responsible for its activity.

Animals↗

PubMed2003

Antileishmanial ring-substituted ether phospholipids.

Three series of ring-substituted ether phospholipids were synthesized carrying N,N,N-trimethylammonium, N-methylpiperidino, or N-methylmorpholino headgroups. The first series is substituted by 2-cyclohexyloxyethyl or 2-(4-alkylidenecyclohexyloxy)ethyl groups, the second series by cyclohexylidenealkyl or adamantylidenealkyl moieties, and the third series by 2-aryloxyethyl or 6-aryloxyhexyl groups in the alkyl portion of the molecule. The antileishmanial activity of the new compounds was evaluated in vitro against the promastigote forms of L. donovani and L. infantum using an MTT (3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide)-based microassay as a marker of cell viability. Analogues 12, 15, 24, 30, 32, 41, 43, and 45 were more potent than the control compound miltefosine (hexadecylphosphocholine) against both L. donovani and L. infantum while, derivatives 13 and 42 were equipotent to miltefosine. Analogues 16, 17, 19, 20 were more potent than miltefosine against L. infantumand compounds 27, 31, 44 were more active than miltefosine against L. donovani. Differential scanning calorimetry (DSC) was used to probe the role of individual ether phospholipids on the physicochemical properties of model membranes. The DSC scans showed that the active compounds have a more profound effect on the thermotropic properties of model membrane bilayers than the less active ones.

Animals↗

PubMed2002

Design, synthesis and biological evaluation of cyclic angiotensin II analogues with 3,5 side-chain bridges. Role of C-terminal aromatic residue and ring cluster for activity and implications in the drug design of AT1 non-peptide antagonists.

The novel amide linked angiotensin II (ANG II) cyclic analogues: gamma, epsilon -cyclo(3, 5)-[Sar(1)-Glu(3)-Lys(5)-Ile(8)] ANG II (I) and gamma, epsilon -cyclo(3, 5)-[Sar(1)-Glu(3)-Lys(5)-Phe(8)] ANG II (II) have been designed, synthesized and bioassayed in anesthetized rabbits in order to unravel structural ring cluster characteristics important for receptor activation. Analogue I with Ile at position 8 was an inhibitor of Angiotensin II while analogue II with Phe at position 8 was found to be an agonist. Similar results were reported for cyclic compounds that have reversed the linking between positions 3 and 5. The overall results show that positions 3 and 5 do not govern the biological activity of the synthetic analogues. It also appears that the aromatic ring cluster (Tyr-His-Phe) in agonist peptides is an essential stereo-electronic feature for Angiotensin II to exert its biological activity. A non-peptide mimetic of ANG II, 1-[2'-[(N-benzyl)tetrazol-5-yl]biphenyl-4-yl]methyl]-2-hydroxymethylbenzimidazole (BZI8) has been designed and synthesized. This molecule is more rigid and much less active than AT(1) non-peptide mimetic losartan probably because it lacks to mimic the orientation of tetrazole and the pharmacophore segments of butyl chain and imidazole ring.

Angiotensin II↗

PubMed2002

Structure elucidation and conformational properties of eprosartan, a non peptide angiotensin II AT1 antagonist.

A novel approach to treat hypertension is to interfere with the Renin-Angiotensin system (RAS) by blocking the binding of vasoconstrictive hormone Angiotensin II to the AT(1) receptor site. This approach led to the beneficial drug losartan (COZAAR) and other similar in structure to the antihypertensive drugs (sartans). In an effort to compare the stereoelectronic features of pharmacophoric segments of the different sartans, a research activity was initiated in our laboratory related to the conformational properties of these drugs. In a previous study, the structural features which determine the pharmacophoric segments of losartan were examined. In this study, the conformational properties of eprosartan (TEVETEN), a drug with fewer side effects, were examined. In addition, the superimposition ability of losartan and eprosartan with the peptide antagonist sarmesin was studied.

Acrylates↗