Oxidation sensitivity may be a useful tool for the detection of the hematotoxic potential of newly developed molecules: application to antipsychotic drugs.

Some antipsychotic agents have been found to produce agranulocytosis and aplastic anemia. The oxidation phenomena and/or the formation of free radicals has been suggested to be causally related to various hematological disorders, e.g., agranulocytosis. Using five experimental conditions, we tested the oxidative potential of compounds with and without a history of hematological side effects, e.g., agranulocytosis and aplastic anemia. A statistical analysis was undertaken for each experimental condition and a multivariate analysis combining all results was performed. Two peroxidase-induced free radical models did not successfully discriminate between drugs with and without a history of causing hematologic problems (<70%). The lipid peroxidation system provided even less satisfactory discrimination, with only 56.25% correct classification. However, an 87.5% correct classification was obtained when using the oxidation potentials of these drugs determined at pH 4.7 and at pH 7.4. A multivariate analysis taking into account the five variables provided 87.5% success in classification. The two clusters were better discriminated in terms of a "distance coefficient." In a second analysis, the putative antipsychotic pyridobenzodiazepine analogues (JL5, JL8, JL18, and JL25) were classified in the cluster of toxic compounds, while the oxa- and thiazepine analogues (JL2, JL3, and JL13) were classified as nontoxic compounds. On the other hand, a few metabolites of clozapine and fluperlapine were classified in the toxic compound group. The procedure described herein is, to our knowledge, the first which classifies molecules of different structures as well as different pharmacological profiles according to their hematotoxic potential. Such a procedure could be used to predict drug-induced hematological side effects.     

The application of a 3D-QSAR (autoMEP/PLS) approach as an efficient pharmacodynamic-driven filtering method for small-sized virtual library: application to a lead optimization of a human A3 adenosine receptor antagonist

We have recently reported that the combination of molecular electrostatic potential (MEP) surface properties (autocorrelation vectors) with the conventional partial least squares (PLS) analysis can be used to produce a robust ligand-based 3D structure-activity relationship (autoMEP/PLS) for the prediction of the human A3 receptor antagonist activities. Here, we present the application of the 3D-QSAR (autoMEP/PLS) approach as an efficient and alternative pharmacodynamic filtering method for small-sized virtual library. For this purpose, a small-sized combinatorial library (841 compounds) was derived from the scaffold of the known human A3 antagonist pyrazolo-triazolo-pyrimidines. The most interesting analogues were further prioritized for synthesis and pharmacological characterization. Remarkably, we have found that all the newly synthetized compounds are correctly predicted as potent human A3 antagonists. In particular, two of them are correctly predicted as sub-nanomolar inhibitors of the human A3 receptor.     

Lipase-catalysed synthesis of new acetylcholinesterase inhibitors: N-benzylpiperidine aminoacid derivatives

New acetylcholinesterase inhibitors were synthetized via a lipase-mediated regioselective amidation using Candida antarctica lipase B as a biocatalyst in the key step. The new compounds have two different structural fragments: a N-benzylpiperidine moiety to anchor the enzyme active site and a dicarboxylic aminoacid to act as a biological carrier. Some analogues of N-benzylpiperazine were also synthesised and studied but they did not display AChE inhibitor activity. A preliminary structure activity relationship study was performed employing some computational techniques as similarity indices and electrostatic potential maps.     

Similarities of pharmacophoric patterns revealed by the MEP of metoclopramide,molindone and piquindone,a subgroup of dopamine D-2 receptor antagonists

Molecular electrostatic potential (MEP) calculations based on ab initio wave functions have been used to compare three compounds belonging to two distinct chemical series (substituted benzamides (metoclopramide) and indolones (piquindone and molindone)). These compounds have highly similar pharmacological properties at the receptor level (antagonists binding selectively to the dopamine D₂ receptor and in a sodium-dependent manner). The MEPs of these compounds show close similarities and form a common pharmacophoric pattern.     

Advancement in the development of heterocyclic nucleosides for the treatment of cancer - A review

Abstract

Cancer diseases are widely recognised as an important medical problem and killing millions of people in a year. Chemotherapeutic drugs are successful against cancer in many cases and different compounds, including the analogues of natural substances, may be used for anticancer agents. Nucleoside analogues also have become a necessity for the treatment of cancer diseases. Nucleoside, nucleotide and base analogues have been utilised for decades for the treatment of viral pathogens, neoplasms and in anticancer chemotherapy. This review focuses on the different types of nucleosides and their potential role as anticancer agents. It also discusses the nucleoside analogues approved by FDA and in process of approval. The effect of the substitution on the nucleoside analogues and their pharmacological role is also discussed in the review. Owing to the advances in computational chemistry, it concludes with the future advancement and possible outcome of the nucleoside analogues. Also, it depicts the development of heterocyclic nucleoside analogues, explores the QSAR of the synthesised compounds and discusses the 3?D QSAR pharmacophore modelling in order to examine their potential anti-cancer activities.     

The use of the electrostatic potential at the molecular surface in recognition interactions: Dibenzo-p-dioxinsand related systems

An ab initio self-consistent-field molecular orbital approach was used to compute the electrostatic potentials of dibenzo-p-dioxin, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), two analogues of the latter, and two isomeric benzoflavones on a three-dimensional molecular surface corresponding to the contour of constant electronic density equal to 0.002 electrons/bohr³. The results are discussed in relation to the biological activities of the respective molecules. It is shown that the electrostatic potential graphically depicted on the molecular surface is well suited for the study of recognition interactions, such as are believed to be involved in the initial receptor-mediated step leading to toxicity in the dibenzo-p-dioxins. The surface potential has the advantage of clearly showing steric features that may play a role in understanding the recognition process being investigated.     

Hydrazino-aza and N-azapeptoids with therapeutic potential as anticancer agents

The ubiquitin-proteasome-mediated degradation pathway plays an important role in regulating protein turnover in eucaryotic cells and, consequently, regulates both cell proliferation and cell death. The proteasome influences many cellular regulatory signals and is thus a potential target for pharmacological agents. The study of proteasome function has led to the identification of several natural and synthetic compounds that can act as tumor cell growth inhibitors. In this study, we have developed a series of hydrazino-aza and N-azapeptoids, analogues of Ac-Leucyl-Leucyl-Norleucinal (ALLN) a non-specific peptidyl aldehyde inhibitor of the proteasome. These peptide analogues share a common backbone and bear different C- and N-terminal functions. Their antiproliferative activity on murine leukemia L1210 cells is reported here.     

Comparison of structurally different allosteric modulators of muscarinic receptors by self-organizing neural networks

Similarities in the molecular structure and surface properties of the allosteric modulators of muscarinic receptors, alcuronium, gallamine, tubocurarine, and the hexamethonium compound W84, a well-known pharmacological tool, are explored. The analysis of the molecular electrostatic potential (MEP) as well as of the shape of the molecular surface is performed by self-organizing neural networks. A distorted sandwich conformation of W84 is suggested to be the active form. The importance of the MEP for binding of these compounds could be established.     

Comparison of pharmacological properties of rubidomycine and its newly synthesized derivatives DR-22 and DR-27 in animals

The effect of two newly synthesized 5-amino modified analogues of rubidomycine was submitted to preliminary pharmacological and histological investigations in healthy Albino Swiss mice. The results showed a similarity of the tested properties of the new compounds and commercial rubidomycine, suggesting the same spectrum undesired side-effects after acute administration. Of the two novel compounds DR-22 was found to be less toxic, while much potent in its action on the haematopoietic system in comparison to rubidomycine, in prolonged treatment. DR-22 is a candidate for further, more detailed investigations.     

AChE inhibitor: a regio- and stereo-selective 1,3-dipolar cycloaddition for the synthesis of novel substituted 5,6-dimethoxy spiro[5.3']-oxindole-spiro-[6.3″]-2,3-dihydro-1H-inden-1″-one-7-(substituted aryl)-tetrahydro-1H-pyrrolo[1,2-c][1,3]thiazole

Pyrrolothiazolyloxindole analogues share vital pharmacological properties, considered useful in Alzheimer's disease (AD). The aim of this study was synthesis and evaluate pyralothiazolyloxindole analogues if possess acetyl cholinesterase (AChE) inhibitory activity. The easily accessible one-pot synthesis of these compounds resulted to be significantly less difficult and expensive than that of donepezil. Several compounds possess anti-cholinesterase activity in the order of micro and sub-micromolar. Particularly, compound was the most potent inhibitors of the series against acetyl cholinesterase enzyme with IC(50) 0.11μmol/L.     

青蒿素及其类似物抗疟构效关系的DFT研究

为了从原子水平上揭示青蒿素及其类似物的结构与抗疟活性之间的关系,运用密度泛函理论DFT方法,在B3LYP/6-31G*水平上对青蒿素及其类似物二氢青蒿素、蒿甲醚和青蒿琥酯的结构和性质进行了理论计算。从分子的平衡构型、Wiberg键级、溶剂化能、偶极矩和静电势等方面分析了青蒿素及其类似物的抗疟构效关系。结果表明,青蒿素及其类似物结构中七元环上的过氧桥键、醚氧键以及六元环上的内酯结构是其抗疟作用的关键活性位,过氧桥键处负的静电势越多,青蒿素与血红素的相互作用越强,分子的抗疟活性越强。理论预测四个药物分子的抗疟活性顺序为:青蒿素<二氢青蒿素<蒿甲醚<青蒿琥酯,与实验活性结果一致。     

Rational screening of oligonucleotide combinatorial libraries for drug discovery.

Combinatorial strategies offer the potential to generate and screen extremely large numbers of compounds and to identify individual molecules with a desired binding specificity or pharmacological activity. We describe a combinatorial strategy for oligonucleotides in which the library is generated and screened without using enzymes. Freedom from enzymes enables the use of oligonucleotide analogues. This dramatically extends the scope of both the compounds and the targets that may be screened. We demonstrate the utility of the method by screening 2'-O-Methyl and phosphorothioate oligonucleotide analogue libraries. Compounds have been identified that bind to the activated H-ras mRNA and that have potent antiviral activity against the human herpes simplex virus.     

Automated on-like dialysis, trace enrichment and high-performance liquid chromatography Inhibition of interaction with the dialysis membrane and disruption of protein binding in the determination of clozapine in human plasma

Problems related to interaction of drugs with the dialysis membrane and to protein binding must be overcome in order to develop automated methods for drug analysis based on on-line dialysis, trace enrichment and HPLC. In order to study these problems, clozapine and its active metabolite N-desmethylclozapine were chosen as model compounds because they were found to interact with the dialysis membrane, and clozapine is highly protein bound. Addition of a cationic surfactant, dodecylethyldimethyl ammonium bromide, to the donor solution and to the plasma samples was found to inhibit interaction of the drugs with surfaces. The protein binding in plasma was disrupted prior to dialysis by lowering the pH with hydrochloric acid and the plasma proteins were solubilised with glycerol. The results obtained were used to develop a fully automated method for the determination of clozapine and N-desmethylclozapine in human plasma. More than 100 samples could be analysed within 24 h. The limit of detection in human plasma was 0.050 μmol/1 for clozapine and 0.055 μmol/1 for N-desmethylclozapine. Linearity was found for drug concentrations between 0.25–3 μmol/1. The relative standard deviations were between 1.2–6.7% and the method was applicable for therapeutic drug monitoring.     

Hydration effects on the electrostatic potential around tuftsin

The electrostatic potential and component dielectric constants from molecular dynamics (MD) trajectories of tuftsin, a tetrapeptide with the amino acid sequence Thr–Lys–Pro–Arg in water and in saline solution are presented. The results obtained from the analysis of the MD trajectories for the total electrostatic potential at points on a grid using the Ewald technique are compared with the solution to the Poisson–Boltzmann (PB) equation. The latter was solved using several sets of dielectric constant parameters. The effects of structural averaging on the PB results were also considered. Solute conformational mobility in simulations gives rise to an electrostatic potential map around the solute dominated by the solute monopole (or lowest order multipole). The detailed spatial variation of the electrostatic potential on the molecular surface brought about by the compounded effects of the distribution of water and ions close to the peptide, solvent mobility, and solute conformational mobility are not qualitatively reproducible from a reparametrization of the input solute and solvent dielectric constants to the PB equation for a single structure or for structurally averaged PB calculations. Nevertheless, by fitting the PB to the MD electrostatic potential surfaces with the dielectric constants as fitting parameters, we found that the values that give the best fit are the values calculated from the MD trajectories. Implications of using such field calculations on the design of tuftsin peptide analogues are discussed. © 1999 John Wiley & Sons, Inc. Biopoly 50: 133–143, 1999     

Investigating protein-protein interaction surfaces using a reduced stereochemical and electrostatic model

A method of calculating the electrostatic potential energy between two molecules, using finite difference potential, is presented. A reduced charge set is used so that the interaction energy can be calculated as the two static molecules explore their full six-dimensional configurational space. The energies are contoured over surfaces fixed to each molecule with an interactive computer graphics program. For two crystal structures (trypsin-trypsin inhibitor and anti-lysozyme Fab-lysozyme), it is found that the complex corresponds to highly favourable interacting regions in the contour plots. These matches arise from a small number of protruding basic residues interacting with enhanced negative potential in each case. The redox pair cytochrome c peroxidase-cytochrome c exhibits an extensive favourably interacting surface within which a possible electron transfer complex may be defined by an increased electrostatic complementarity, but a decreased electrostatic energy. A possible substrate transfer configuration for the glycolytic enzyme pair glyceraldehyde phosphate dehydrogenase-phosphoglycerate kinase is presented.     

Efficacy of S-adenosylhomocysteine hydrolase inhibitors, D-eritadenine and (S)-DHPA, against the growth of Cryptosporidium parvum in vitro

D-eritadenine and (S)-DHPA are aliphatic adenosine analogues known to target S-adenosylhomocysteine hydrolase (SAHH) and potent antiviral compounds. In the present study, we demonstrate that these two compounds also display efficacy against recombinant SAHH enzyme of the protozoan parasite Cryptosporidium parvum, as well as inhibition of parasite growth in vitro. Our data confirm that SAHH could serve as a rational drug target in cryptosporidial infection and antiviral adenosine analogues are potential candidates for drug development against cryptosporidiosis.     

Effect of branching in 4-alkylpyrazoles on liver alcohol dehydrogenase inhibition: A shape analysis study

Shape analysis methodology is applied to the study of 4-alkylpyrazoles which are known inhibitors of liver alcohol dehydrogenase. Elongation of the alkyl chain increases the inhibitory power, whereas branching of the chain diminishes the activity. These two counterpoised effects are studied simultaneously in a selected set of 4-alkylpyrazoles. A systematic conformational analysis followed by topological characterization of the van der Waals surfaces of all the local minima restricts the conformational space to potential bioactive structures. The analysis of the interrelation between the molecular electrostatic potential and van der Waals surfaces provides certain shape codes characteristic of each 4-alkylpyrazole. In both topological analyses van der Waals surfaces and molecular electrostatic potential van der Waals surface interrelations) graphical representations and analytical methods were used. A good correlation between the shape codes and the inhibitory activity is found for the linear derivatives. For branched pyrazoles, a tendency in their inhibitory power is predicted. Isopentylpyrazole is suggested to have the same inhibitory profile as 4-butylpyrazole, the linear derivative with one less carbon atom.     

Synthesis of proline analogues as potent and selective cathepsin S inhibitors

Cathepsin S is a potential target of autoimmune disease. A series of proline derived compounds were synthesized and evaluated as cathepsin S inhibitors. We discovered potent cathepsin S inhibitors through structure–activity relationship studies of proline analogues. In particular, compound 19-(S) showed promising in vitro/vivo pharmacological activities and properties as a selective cathepsin S inhibitor.     

Relation between the molecular electrostatic potential and activity of some FF-MAS related sterol compounds

Follicular Fluid-Meiosis Activating Sterol (FF-MAS) is a compound important for maturation of gametes in mammals. Therefore, it may serve as a lead compound for a novel method of contraception. We studied the Molecular Electrostatic Potential of a series of active and inactive analogues of FF-MAS. We find that double bond configurations required for activity result in a local negative electrostatic potential which is larger as well as more dense compared to those of inactive molecules. We therefore hypothesize that the interaction energy of the double bond system of the MAS compounds with its receptor substantially contributes to the overall interaction energy. This notion is supported by interaction studies of the electrostatic potential originating from the double bonds in crystal structures of cholesterol and four MAS-derived Delta(8,14) structures synthesized and crystallized by us. In addition, we were able to derive a pharmacophore model that relates the local average ESP and its distance to the 3beta-OH oxygen atom to the activity of the molecules.     

The effect of lipid demixing on the electrostatic interaction of planar membranes across a salt solution

We study the effect of lipid demixing on the electrostatic interaction of two oppositely-charged membranes in solution, modeled here as an incompressible two-dimensional fluid mixture of neutral and charged mobile lipids. We calculate, within linear and nonlinear Poisson-Boltzmann theory, the membrane separation at which the net electrostatic force between the membranes vanishes, for a variety of different system parameters. According to Parsegian and Gingell, contact between oppositely-charged surfaces in an electrolyte is possible only if the two surfaces have exactly the same charge density (sigma(1) = -sigma(2)). If this condition is not fulfilled, the surfaces can repel each other, even though they are oppositely charged. In our model of a membrane, the lipidic charge distribution on the membrane surface is not homogeneous and frozen, but the lipids are allowed to freely move within the plane of the membrane. We show that lipid demixing allows contact between membranes even if there is a certain charge mismatch, /sigma(1)/ not equal /sigma(2)/, and that in certain limiting cases, contact is always possible, regardless of the value of sigma(1)/sigma(2) (if sigma(1)/sigma(2) < 0). We furthermore find that of the two interacting membranes, only one membrane shows a major rearrangement of lipids, whereas the other remains in exactly the same state it has in isolation and that, at zero-disjoining pressure, the electrostatic mean-field potential between the membranes follows a Gouy-Chapman potential from the more strongly charged membrane up to the point of the other, more weakly charged membrane.