Biomedical subjects

Ferenc Otvös

Publications and source records attributed to Ferenc Otvös.

5 recordsLinked to original sources

PubMed2005

Ligand-based prediction of active conformation by 3D-QSAR flexibility descriptors and their application in 3+3D-QSAR models.

A conceptionally new 3D molecular descriptor type and methodology are deduced by simple statistical thermodynamic reasoning, based on the free energy change encountered during a transformation of a conformational ensemble of the ligand to an active conformation. The performance of the descriptor was first tested on 37 endomorphin analogues with mu-opiate activity. The method resulted in predictive 3D-QSAR models, and the active conformation was also predicted. Generally, the methodology can be combined with the traditional 3D-QSAR techniques in a 3+3D-QSAR manner. This feature was tested on a series of 38 PGF2alphaprostaglandin analogues with antinidatory activity; the extent to which the molecular flexibility explains the variation in the biological activity was estimated and the active conformation was predicted. The novel descriptors in combination with the grid-based SOMFA descriptors resulted in 3+3D-QSAR models with good levels of predictivity leading to the approach of separation of the effect of the molecular interaction field of the active conformation and the effect of the conformational free energy loss.

Amino Acids↗

PubMed2003

Conformational analysis of endomorphin-2 by molecular dynamics methods.

Endomorphin-2 (EM2, H-Tyr-Pro-Phe-Phe-NH(2)) is a highly potent and selective mu-opioid receptor agonist. A conformational analysis of EM2 was carried out by simulated annealing (SA) and molecular dynamics (MD) methods. Molecular modeling was conducted on both neutral (N-terminal NH(2)) and charged (N-terminal NH(3) (+)) molecules. Based on the results of NMR investigations showing an equilibrium mixture of cis and trans Tyr(1)-Pro(2) peptide bonds for EM2 in solution, simulations were performed with restrained cis-Pro and trans-Pro peptide bonds, too. A separate SA study with unrestrained Pro peptide bonds was also conducted. Preferred conformational states are presented in Ramachandran plots. The g(+), g(-), and trans populations of the aromatic amino acid residue side chains were determined in chi(1) space. The distances between the N-terminal N atom and the other backbone N and O atoms, and the distances between the centers of the aromatic rings and the Pro(2) ring, were determined. The energy distribution of the structures obtained by SA was calculated. The preferred secondary structural elements were different kinds of beta-turns, an inverse gamma-turn located in the N-terminal region, and regular and inverse gamma-turns located in the C-terminal region. These turns were stabilized by intramolecular H-bonds and bifurcated H-bonds.

Amino Acid Sequence↗

PubMed2003

Binding characteristics of [3H]14-methoxymetopon, a high affinity mu-opioid receptor agonist.

The highly potent micro -opioid receptor agonist 14-methoxymetopon (4,5alpha-epoxy-3-hydroxy-14beta-methoxy-5beta,17-dimethylmorphinan-6-one) was prepared in tritium labelled form by a catalytic dehalogenation method resulting in a specific radioactivity of 15.9 Ci/mmol. Opioid binding characteristics of [3H]14-methoxymetopon were determined using radioligand binding assay in rat brain membranes. [3H]14-Methoxymetopon specifically labelled a single class of opioid sites with affinity in low subnanomolar range (Ki = 0.43 nm) and maximal number of binding sites of 314 fmol/mg protein. Binding of [3H]14-methoxymetopon was inhibited by ligands selective for the micro -opioid receptor with high potency, while selective kappa-opioids and delta-opioids were weaker inhibitors. 14-Methoxymetopon increased guanosine-5'-O-(3-[35S]thio)-triphosphate ([35S]GTPgammaS) binding with an EC50 of 70.9 nm, thus, providing evidence for the agonist character of this ligand. The increase of [35S]GTPgammaS binding was inhibited by naloxone and selective micro -opioid antagonists, indicating a micro -opioid receptor-mediated action. [3H]14-Methoxymetopon is one of the few nonpeptide mu-opioid receptor agonists available in radiolabelled form up to now. Due to its high affinity and selectivity, high stability and extremely low nonspecific binding (<10%), this radioligand would be an important and useful tool in probing mu-opioid receptor mechanisms, as well as to promote a further understanding of the opioid system at the cellular and molecular level.

Animals↗

PubMed2002

A specific binding site for a fragment of the B-loop of epidermal growth factor and related peptides.

Fragments of the B-loop of the epidermal growth factor family of peptides are reported to have mitogenic and angiogenic properties but appear to fail to compete with radioiodinated EGF in receptor binding. In this study, 11 analogs of a fragment of the B-loop of EGF-related peptides from several species were synthesized to study binding to A431 human epidermoid carcinoma using both 125I-EGF and [3'4'-3H-Tyr(22,29), Abu(20,31)]EGF(20-31)-NH(2). Specific binding sites were found for the human fragment and 8 analogs at a density five times higher than that of the EGF receptors. Analogs did not compete with 125I-EGF for binding to the EGF receptor. The novel binding site may mediate the biological effects of the fragments. The primary rather than secondary structure of the fragments appears to determine affinity.

Amino Acid Sequence↗

PubMedDate not supplied

Development of a chirality-sensitive flexibility descriptor for 3+3D-QSAR.

Multidimensional QSAR methodologies can be used to predict the active conformation encoded in the conformational preferences of molecules in an active series by utilizing conformational sampling. In the 3+3D-QSAR approach, the conformational free energy loss is modeled with internal coordinate-based flexibility descriptors. While the pharmacophore point pair distance descriptors introduced earlier proved useful in the construction of QSAR models and in the prediction of important features of the active conformation, they are inherently incapable of describing the chiral arrangement of the pharmacophores. As an improvement, a chirality-sensitive flexibility (CSF) descriptor is now introduced, which is based on the distance between a pharmacophore point and a plane defined by three pharmacophore points. The performance of the CSF descriptor was tested on two active series: 37 endomorphin analogues with opiate activity and 38 PGF2alpha analogues with antinidatory activity. The newly devised descriptor resulted in improved QSAR models in terms of both prediction accuracy and precision of the chiral geometric features of the predicted active conformations.

Drug Design↗