Is it possible docking and scoring new ligands with few experimental data? Preliminary results on estrogen receptor as a case study.

Estrogens are steroid hormones playing critical roles in several physiological processes, which bind the estrogen receptors ERalpha and ERbeta. Aim of this work is to analyze, by different docking experiments, the behavior of a set of compounds, mimicking estrogens activity, in order to understand the relationship between ERalpha and such new ligands. Main goal is to verify, using a widely tested scoring software procedure applied on a set of 10 compounds, the possibility to produce new lead candidate molecules in lack of, or with few experimental data. Our preliminary results reveal the significance of HINT software as a scoring function in docking methodology and specifically, as a mean for assessing the consistency of docking solutions.

Self-assembly and anion encapsulation properties of cavitand-based coordination cages.

Two novel classes of cavitand-based coordination cages 7a--j and 8a--d have been synthesized via self-assembly procedures. The main factors controlling cage self-assembly (CSA) have been identified in (i) a P--M--P angle close to 90 degrees between the chelating ligand and the metal precursor, (ii) Pd and Pt as metal centers, (iii) a weakly coordinated counterion, and (iv) preorganization of the tetradentate cavitand ligand. Calorimetric measurements and dynamic (1)H and (19)F NMR experiments indicated that CSA is entropy driven. The temperature range of the equilibrium cage-oligomers is determined by the level of preorganization of the cavitand component. The crystal structure of cage 7d revealed the presence of a single triflate anion encapsulated. Guest competition experiments revealed that the encapsulation preference of cages 7b,d follows the order BF(4)(-) > CF(3)SO(3)(-) >> PF(6)(-) at 300 K. ES-MS experiments coupled to molecular modeling provided a rationale for the observed encapsulation selectivities. The basic selectivity pattern, which follows the solvation enthalpy of the guests, is altered by size and shape of the cavity, allowing the entrance of an ancillary solvent molecule only in the case of BF(4)(-).

Database of C-glycosylporphyrins in Web fashion.

The aim of this work was to organize chemical data in a client-server environment using Database Management System and Web fashion for the client interface. To solve this ancient problem (for us) merging text data, reaction schemes, tridimensional structures, and NMR, CD, and UV spectra images, we have based our implementation on a few fundamental points: no cost for the user, availability of data via the Internet, standard and freeware software, and a Web browser for the database inquiry. These functions are delivered in a platform-independent manner via the Internet and are used by computational experts and nonexperts alike. C-Glycosylporphyrins is the class of compounds chosen to test our applications. These results can be exportable for many other classes of chemical compounds.

HINT predictive analysis of binding between retinol binding protein and hydrophobic ligands.

The interaction between the retinol binding protein and four ligands was evaluated using HINT, a software based on experimental LogP values of individual atoms. A satisfactory correlation was found between the HINT scores and the experimental dissociation constants of three of the ligands, fenretinide, N-ethylretinamide and all-trans retinol, despite their hydrophobic nature. A prediction is made for the binding affinity of the fourth ligand, axerophtene, not yet determined in solution.

Novel allosteric effectors of the tryptophan synthase alpha(2)beta(2) complex identified by computer-assisted molecular modeling.

Tryptophan synthase is a pyridoxal 5'-phosphate-dependent alpha(2)beta(2) complex catalyzing the formation of L-tryptophan. The functional properties of one subunit are allosterically regulated by ligands of the other subunit. Molecules tailored for binding to the alpha-active site were designed using as a starting model the three-dimensional structure of the complex between the enzyme from Salmonella typhimurium and the substrate analog indole-3-propanol phosphate. On the basis of molecular dynamics simulations, indole-3-acetyl-X, where X is glycine, alanine, valine and aspartate, and a few other structurally related compounds were found to be good candidates for ligands of the alpha-subunit. The binding of the designed compounds to the alpha-active site was evaluated by measuring the inhibition of the alpha-reaction of the enzyme from Salmonella typhimurium. The inhibition constants were found to vary between 0.3 and 1.7 mM. These alpha-subunit ligands do not bind to the beta-subunit, as indicated by the absence of effects on the rate of the beta-reaction in the isolated beta(2) dimer. A small inhibitory effect on the activity of the alpha(2)beta(2) complex was caused by indole-3-acetyl-glycine and indole-3-acetyl-aspartate whereas a small stimulatory effect was caused by indole-3-acetamide. Furthermore, indole-3-acetyl-glycine, indole-3-acetyl-aspartate and indole-3-acetamide perturb the equilibrium of the catalytic intermediates formed at the beta-active site, stabilizing the alpha-aminoacrylate Schiff base. These results indicate that (i) indole-3-acetyl-glycine, indole-3-acetyl-aspartate and indole-3-acetamide bind to the alpha-subunit and act as allosteric effectors whereas indole-3-acetyl-valine and indole-3-acetyl-alanine only bind to the alpha-subunit, and (ii) the terminal phosphate present in the already known allosteric effectors of tryptophan synthase is not strictly required for the transmission of regulatory signals.

H3-receptor antagonists: conformational analysis of thioperamide and x-ray crystal structure of the analog N-cyclohexyl-4-methylpiperidine-1-carbothioamide.

Thioperamide (N-cyclohexyl-4-[4(5)-imidazolyl]piperidine-1-carbothioamide) is a potent H3-receptor antagonist, the low conformational flexibility of which could be a favourable feature in the design of new H3-receptor antagonists using its structure as a template. Minimum-energy conformations of thioperamide were studied with the molecular mechanics approach, integrated by X-ray crystallography on an analogue, N-cyclohexyl-4-methylpiperidine-1-carbothioamide (1). Compound 1 was synthesized, and its structure has been solved by X-ray diffraction in order to verify the conformation of the piperidine-1-carbothioamide fragment, and to compare the crystallographic results with those of molecular mechanics. Conformational analysis on the free-rotating bonds of thioperamide was performed with different search methods in order to find the minimum-energy conformations and to estimate rotational barriers. For steric reasons, the rotation around the bond connecting the cyclohexane ring with the carbothioamide nitrogen is more hampered than that around the bond connecting imidazole with piperidine. The rotation around the first bond presents two symmetrical energy minima separated from a third minimum by an energy barrier of 40 KJ/mol. The spatial disposition of compound 1 in the crystal and the common part of thioperamide in one of its minimum-energy conformations are very similar. The minimum-energy conformations of thioperamide calculated by molecular mechanics are therefore reliable and they can be used for structural comparisons with other H3-receptor antagonists.

(E)-(methyloxyimino)acetamides as analogues of neuroleptic benzamides: synthesis and D2-dopaminergic binding affinity.

Some type C (E)-(methyloxyimino)acetamides were synthesised as analogues of type A neuroleptic and antipsychotic benzamides, in which the aromatic group is substituted by a methyloxyiminomethyl moiety with the E configuration (CH2ON = CH, E-MOIMM). Type C compounds were tested for their D2-dopaminergic binding affinity in order to obtain an indication of their potential neuroleptic and antipsychotic properties. Biological results showed that only a few aryl-substituted E-MOIM derivatives possess a certain affinity for the D2-dopaminergic receptor, at least one order of magnitude lower than that of metoclopramide and sulpiride.