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T Solmajer

Publications and source records attributed to T Solmajer.

14 recordsLinked to original sources
PubMed2004

Prediction of selectivity of alpha1-adrenergic antagonists by counterpropagation neural network (CP-ANN).

A quantitative structure-selectivity relationships of series of structurally diverse alpha1-adrenergic antagonists was performed by using counter-propagation neural network (CP-ANN). The theoretical molecular descriptors have been calculated and selected using CODESSA program. The results obtained for a highly non-congeneric set of molecules have confirmed the potential of use of CP-ANN approach in prediction of relative activity (selectivity) of alpha1-adrenergic antagonists.

Adrenergic alpha-Antagonists↗
PubMed2001

Design and structure-activity relationship of thrombin inhibitors with an azaphenylalanine scaffold: potency and selectivity enhancements via P2 optimization.

Theoretical and structural studies followed by the directed synthesis and in vitro biological tests lead us to novel noncovalent thrombin pseudopeptide inhibitors. We have incorporated an azapeptide scaffold into the central part of the classical tripeptide D-Phe-Pro-Arg inhibitor structure thus eliminating one stereogenic center from the molecule. A series of compounds has been designed to optimize the occupancy of the S2 pocket of thrombin. Increased hydrophobicity at P2 provides an enhanced fit into this active site S2 pocket. In the present paper, we also report on the structure of these inhibitors in solution and conformational analysis of inhibitors in the active site in order to asses the consequences of the replacement of the central alpha-CH by a nitrogen functionality. In vitro biological testing of the designed inhibitors shows that elimination of R, S stereoisomerism and restriction of conformational freedom influences the binding of inhibitors in a favorable fashion.

Antithrombins↗
PubMed2001

Kinetic study of two novel enantiomeric tricyclic beta-lactams which efficiently inactivate class C beta-lactamases.

A detailed kinetic study of the interaction between two ethylidene derivatives of tricyclic carbapenems, Lek 156 and Lek 157, and representative beta-lactamases and D-alanyl-D-alanine peptidases (DD-peptidases) is presented. Both compounds are very efficient inactivators of the Enterobacter cloacae 908R beta-lactamase, which is usually resistant to inhibition. Preliminary experiments indicate that various extended-spectrum class C beta-lactamases (ACT-1, CMY-1, and MIR-1) are also inactivated. With the E. cloacae 908R enzyme, complete inactivation occurs with a second-order rate constant, k(2)/K', of 2 x 10(4) to 4 x 10(4) M(-1) s(-1), and reactivation is very slow, with a half-life of >1 h. Accordingly, Lek 157 significantly decreases the MIC of ampicillin for E. cloacae P99, a constitutive class C beta-lactamase overproducer. With the other serine beta-lactamases tested, the covalent adducts exhibit a wide range of stabilities, with half-lives ranging from long (>4 h with the TEM-1 class A enzyme), to medium (10 to 20 min with the OXA-10 class D enzyme), to short (0.2 to 0.4 s with the NmcA class A beta-lactamase). By contrast, both carbapenems behave as good substrates of the Bacillus cereus metallo-beta-lactamase (class B). The Streptomyces sp. strain R61 and K15 extracellular DD-peptidases exhibit low levels of sensitivity to both compounds.

Ampicillin↗
PubMed2000

Conformational analysis of 7-oxoacyl-L-alanyl-D-isoglutamines.

In a recent article (Planinsek, O., Srcic, S., 1999. Int. J. Pharm. 87, 199-207) some interesting physicochemical properties of a series N-(7-oxoacyl)-L-alanyl-D-isoglutamines with n=0-6 methylene groups between the terminal methyl and 7-oxo group were measured. In view of the practical importance of these N-acetylmuramyldipeptide(MDP) immunomodulator analogues and their interesting biological properties a detailed conformational analysis was undertaken for the series with n=3-6 methylene spacers between the 7-oxo and terminal methyl groups. The puzzle posed by the reversal of the measured water solubility and lipophylicity could be resolved by using the Monte Carlo approach to searching the conformational space of the molecules in this series. We have found that the increase in water solubility and drop in lipophylicity when the number of methylene groups is increased from 5 to 6 can be attributed to the change in predominant conformation in the conformational family as described by the Boltzmann distribution of conformations. Notwithstanding this, we point out the changes in biological response coupled to the nonlinearity of the physicochemical behaviour in the series.

Adjuvants, Immunologic↗
PubMed1991

Electrostatic effects in proteins: comparison of dielectric and charge models.

Two approaches for calculating electrostatic effects in proteins are compared and ana analysis is presented of the dependence of calculated properties on the model used to define the charge distribution. Changes in electrostatic free energy have been calculated using a screened Coulomb potential (SCP) with a distance-dependent effective dielectric permittivity to model bulk solvent effects and a finite difference approach to solve the Poisson-Boltzmann (FDPB) equation. The properties calculated include shifts in dissociation constants of ionizable groups, the effect of annihilating surface charges on the binding of metals, and shifts in redox potentials due to changes in the charge of ionizable groups. In the proteins considered the charged sites are separated by 3.5-12 A. It is shown that for the systems studied in this distance range the SCP yields calculated values which are at least as accurate as those obtained from solution of the FDPB equation. In addition, in the distance range 3-5 A the SCP gives substantially better results than the FDPB equation. Possible sources of this difference between the two methods are discussed. Shifts in binding constants and redox potentials were calculated with several standard charge sets, and the resulting values show a variation of 20-40% between the 'best' and 'worst' cases. From this study it is concluded that in most applications, changes in electrostatic free energies can be calculated economically and reliably using an SCP approach with a single functional form of the screening function.

Bacterial Proteins↗
PubMed1991

Electrostatic screening in molecular dynamics simulations.

The screened Coulombic potential has been shown to describe satisfactorily equilibrium properties like pK shifts, the effects of charged groups on redox potentials and binding constants of metal ions. To test how well the screening of the electrostatic potential describes the dynamical trajectory of a macromolecular system, a series of comparative simulations have been carried out on a protein system which explicitly included water molecules and a system in vacuo. For the system without solvent the results of using (i) the standard potential form were compared with results of (ii) the potential where the Coulomb term was modified by the inclusion of a distance dependent dielectric, epsilon (r), to model the screening effect of bulk water, and (iii) standard potential modified by reducing the charge on ionized residue side chains. All molecular dynamics simulations have been carried out on bovine pancreatic trypsin inhibitor. Comparisons between the resulting trajectories, averaged structures, hydrogen bonding patterns and properties such as solvent accessible surface area and radius of gyration are described. The results show that the dynamical behaviour of the protein calculated with a screened electrostatic term compares more favourably with the time-dependent structural changes of the full system with explicitly included water than the standard vacuum simulation.

Animals↗
PubMed1990

Design of biologically active, conformationally constrained GnRH antagonists.

The introduction of conformational constraints into a flexible peptide hormone can be exploited to develop models for the conformation required for receptor binding and activity. In this review, we illustrate this approach to analog design using our work on antagonists of gonadotropin-releasing hormone (GnRH). Design of a conformationally constrained, competitive antagonist of GnRH, cyclo[delta 3,4 Pro-D4ClPhe-DTrp-Ser-Tyr-DTrp-NMeLeu-Arg-Pro-bet a Ala] led to the prediction of its bioactive conformation. Template forcing experiments show that this conformation is accessible to other active GnRH analogs. Two-dimensional NMR studies verified the predicted conformation in solution. The predicted binding conformation has recently been used to design two new analogs incorporating side chain-side chain linkages suggested by the conformational model: Ac-delta 3,4Pro-D4FPhe-DTrp-Dap-Tyr-DTrp-Leu-Arg-Asp-Gly- NH2 and Ac-delta 3,4Pro-D4FPhe-DTrp-Dap-Tyr-D2Nal-Leu-Arg-Pro-Asp -NH2. These analogs were synthesized and the one predicted to be most similar to the parent conformation had equivalent potency while the second, designed to refine the conformational hypothesis, was found to exhibit enhanced potency, thus confirming the original binding conformation hypothesis. These compounds and their derivatives now provide a new class of GnRH antagonists possessing both high biological potency and limited conformational flexibility, thus making them ideal for both biophysical and structure-activity studies.

Amino Acid Sequence↗
PubMed1990

Design of a novel thymopoietin analogue based on conformational analyses.

A novel cyclic peptide c(Arg-Pro-Asp-D-Val-Tyr) related to thymopentin--the immunostimulant pentapeptide contained in thymic hormones--was designed on the basis of theoretical computer modeling. We applied molecular dynamics/energy minimization techniques and restrained molecular dynamics to determine the preferred conformation of this peptide. The linear precursor of the peptide is biologically active and probably exists in a highly motile dynamical equilibrium of different conformations. Our calculations show that the cyclic peptide consists of a single conformational family containing a beta turn at position Pro 2. Experimental support for this conclusion was derived from 2-D NOE data in aqueous solution for the closely related analogue c(Arg-Lys-Glu-D-Val-Tyr). Synthesis and biological testing of the cyclic peptide is therefore indicated.

Amino Acid Sequence↗
PubMed1982

Correlation between affinity toward adrenergic receptors and approximate electrostatic potentials of phenylethylamine derivatives. 1. Effects of the side chain.

The molecular electrostatic potential (VN) in the region of the nitrogen lone pair of a series of substituted propylamines is used in a correlation with the dissociation constants of parent phenylethylamine-type ligands obtained on beta-adrenoceptors by Bilezikian et al. It is shown that VN is a more effective index for quantitative structure-activity relationship studies than an optimal set of substituent constants used in additive, linear models. No significant correlation between the total electronic charge on the nitrogen and the binding potencies was obtained in the examined series. Protonation energies of the propylamines have been computed, but no meaningful correlation with the dissociation constants was obtained.

Chemical Phenomena↗
PubMedDate not supplied

Quantitative structure-activity relationship of flavonoid analogues. 3. Inhibition of p56lck protein tyrosine kinase.

Quantitative structure-activity relationship (QSAR) studies on 104 flavonoid derivatives as p56lck protein tyrosine kinase (PTK) inhibitors were performed, using a large number of molecular descriptors calculated by CODESSA software. Multiple linear regression and orthogonalization of descriptors were applied to generate models for the prediction of biological activities for binding flavonoids to PTK. The obtained results demonstrate in detail the importance of electrostatic and quantum chemical descriptors for the interaction of flavonoids with the specific p56lck enzymatic active site environment. In particular, the maximal total interaction for a C-O bond is the most important factor in regression. Use of orthogonalization in regression models provides a valuable improvement for the interpretative and predictive capacity of structure-activity relationships found.

Enzyme Inhibitors↗
PubMedDate not supplied

Prediction of enzyme binding: human thrombin inhibition study by quantum chemical and artificial intelligence methods based on X-ray structures.

Thrombin is a serine protease which plays important roles in the human body, the key one being the control of thrombus formation. The inhibition of thrombin has become a target for new antithrombotics. The aim of our work was to (i) construct a model which would enable us to predict Ki values for the binding of an inhibitor into the active site of thrombin based on a database of known X-ray structures of inhibitor-enzyme complexes and (ii) to identify the structural and electrostatic characteristics of inhibitor molecules crucially important to their effective binding. To retain as much of the 3D structural information of the bound inhibitor as possible, we implemented the quantum mechanical/molecular mechanical (QM/MM) procedure for calculating the molecular electrostatic potential (MEP) at the van der Waals surfaces of atoms in the protein's active site. The inhibitor was treated quantum mechanically, while the rest of the complex was treated by classical means. The obtained MEP values served as inputs into the counter-propagation artificial neural network (CP-ANN), and a genetic algorithm was subsequently used to search for the combination of atoms that predominantly influences the binding. The constructed CP-ANN model yielded Ki values predictions with a correlation coefficient of 0.96, with Ki values extended over 7 orders of magnitude. Our approach also shows the relative importance of the various amino acid residues present in the active site of the enzyme for inhibitor binding. The list of residues selected by our automatic procedure is in good correlation with the current consensus regarding the importance of certain crucial residues in thrombin's active site.

Algorithms↗
PubMedDate not supplied

Enzyme binding selectivity prediction: alpha-thrombin vs trypsin inhibition.

In the present work we explore the possibility of an in-depth computational analysis of available experimental X-ray structures in the specific case of a series of alpha-thrombin and trypsin complexes with their respective inhibitors for the development of a novel scoring function based on molecular electrostatic potential computed at the contact surface in the enzyme-inhibitor molecular complex. We subsequently employ the chemometrical approach to determine which are the interactions in the large volume of data that determine the resulting experimental binding constant between ligand and receptor. The results of the model evaluated with molecules in the independent validation set show that a reasonable average error of 1.30 log units of the difference between experimental and calculated binding constants was achieved in the system thrombin-trypsin, which is comparable with those of methods from the literature. Furthermore, by a careful preparation of the Kohonen top layer in the artificial neural network approach that is normally perceived as a "black box device", we have been able to follow the implications of the structure of the inhibitor-enzyme complex for the inhibitor's binding constant. The method appears to be suitable for evaluation of selectivity in structurally similar enzymatic systems, which is currently an important problem in drug design.

Algorithms↗
PubMedDate not supplied

Conformational study of catecholamines in solution.

Conformations of noradrenaline, dopamine and ephedrine have been studied in aqueous solutions using high resolution PMR spectroscopy. We found that for dopamine the mole fraction of trans rotamer is increased if pH is changed from acidic to basic while for noradrenaline and ephedrine the opposite trend is observed: gauche rotamer forms of the side chain become more populated. These changes are discussed in relation to the role of the benzylic hydroxyl group for conformation and/or binding to a receptor site in the biophase.

Dopamine↗