Biomedical subjects

I Iriepa

Publications and source records attributed to I Iriepa.

5 recordsLinked to original sources

PubMed2002

Ligand-receptor interaction at the neural nicotinic acetylcholine binding site: a theoretical model.

Recent mutagenesis experiments have identified some of the functional amino acids that are essential in the interaction of nicotinic agents with the binding site of the neural nicotinic acetylcholine receptor (nAChR). Although this receptor is one of the best studied and characterized the lack of detailed experimental information regarding its quaternary structure has turned it into a challenge for computational chemistry. We have previously reported [J. Comput. Aided Mol. Design 13 (1999) 57-68] a computational protocol based on molecular mechanics and molecular dynamics (MD) where SER82, ASP83, TRP86, ASP89, TYR93, TYR190, TYR198 and ARG209 were placed around selected agonists and antagonists aided by stereoelectronic criteria. Explicit water molecules were used with the double goal of simulating aqueous environment and keeping the system from falling apart. The protocol was stable enough to allow the ligands to evolve to their thermodynamically most probable structure while maintaining the key interactions. In this communication we use the average model for the agonists (one average structure for each agonist) to calculate quantum mechanically the interactions of the binding site with one neurotransmitter acetylcholine (ACh, 1), as well as with two of the most potent agonists described so far [nicotine (2) and epibatidine (3)] and the modeled binding site. A wide variety of methods as well as basis sets were used in order to rationalise the best way to treat the problem. In this limited set of compounds, a good correlation between total interaction energies and biological affinity is observed.

Acetylcholine↗

PubMed2002

The 5-HT(3) and nACh ionotropic receptors: a perspective from the computational chemistry point of view.

Recent contributions applying Computational Chemistry to serotonin-3 and nicotinic acetylcholine ionotropic receptors are reviewed. These two receptors constitute a good example for the examination of the computational protocols that have been used to understand how they work. On the one hand, (5-HT(3)R) receptor mapping techniques have been mostly employed in its study and very few examples of receptor fitting have been appeared. On the other hand, (nAChR) has been studied mainly from the receptor fitting point of view, although many contributions using receptor mapping exist. In the first case, antagonists seems to be more important that agonists, so more works are devoted to them. In the second case, agonist development is the main issue. Although far for being complete, in either of the cases we have working pharmacophores as well as 3D models for their binding sites that are ready to be used as a starting guess to design potential drugs. It is noteworthy that the absence of crystallographic structure for these receptors has motivated the interest in their study, constituting an interesting and challenging field. Mutagenesis experiments have allowed the establishment of main amino acids that are essential in the receptor functioning and then, interaction models have been postulated. Although most of the models are speculative in nature, some of them have been proved to be valuable tools for drug design. This scientific field is already open and many areas are still unexplored. Computational tools for treating these issues exist in a wide variety and their rational application would produce the answers to the structure and functioning of these receptors.

Animals↗

PubMed2001

Superimposition-based protocol as a tool for determining bioactive conformations. I. Application to ligands of the glycinergic receptor (GlyR).

The natural templates (NT) approach, which is a superimposition-based protocol that has been successfully employed in several studies, is here applied to ligands of the glycine ligand-gated ion channel receptor. Bioactive conformations for glycine and its analogs were obtained using strychnine (a natural and specific competitive antagonist) as template. Experimental evidence was used to guide the superimposition protocol. Three essential regions have been defined in strychnine's structure that serve as a pharmacophore for agonist and antagonist activities. Reasonable alignments of known ligands were found in the majority of the cases. Molecular mechanics (i.e., conformational searches for the relatively flexible ligands) and molecular dynamics (for relatively rigid ligands such as strychnine and 5,6,7,8-tetrahydro-4H-isoxazolo[3,4-d]azepin-3-ol) were used to assess the energetic accessibility of the proposed bioactive conformations.

Amino Acids↗

PubMed2001

Superimposition-based protocol as a tool for determining bioactive conformations. II. Application to the GABA(A) receptor.

The natural templates (NT) superimposition method is used to determine the pharmacophoric requirements of the A subtype of the gamma-aminobutyric acid (GABA) receptor. Bioactive conformations for antagonists and agonists are found by superimposing them on a relatively rigid alkaloid bicuculline, which itself is a competitive antagonist at this ligand-gated ion channel receptor. As has been usual in the application of this modeling method, consideration of available experimental data is the cornerstone for obtaining realistic models. The identification of two substructural fragments of bicuculline permitted classification of the ligands. Analysis of the antagonists and agonists with respect to the two substructural fragments revealed two bioactive conformations of the highly flexible GABA molecule, one of which is extended with the nonhydrogenic atoms roughly coplanar torsional angles of -37 and -179 degrees at N-C-C-C and C-C-C-C (carboxyl), respectively. The second bioactive compound is clearly non planar (torsional angles of -81 and -109 degrees at N-C-C-C and C-C-C-C (carboxyl), respectively).

Bicuculline↗

PubMed1995

Synthesis and structural, conformational, biochemical, and pharmacological study of new compounds derived from tropane-3-spiro-4'(5')-imidazoline as potential 5-HT3 receptor antagonists.

A series of tropane-3-spiro-4'(5')-imidazolines was synthesized and studied by 1H and 13C NMR spectroscopy, and the crystal structure of 2'-(1H-indol-3-yl)tropane-3-spiro-4'(5')-imidazoline hydrochloride 5(6)f was determined by X-ray diffraction. In CD3OD solution, compounds 5(6)a-f display the same preferred conformation. The pyrrolidine and piperidine rings adopt an envelope conformation flattened at N8 and a distorted chair conformation puckered at N8 and flattened at C3, respectively, with the N-substituent in the equatorial position with respect to the piperidine ring. This conformation is similar to that observed for compound 5(6)f in the solid state. From binding studies on the compounds synthesized, compound 5(6)d demonstrated the ability to efficiently displace the binding of [3H]GR65630 to bovine brain area postrema membranes to an extent comparable to MDL 72222. In the von Bezold-Jarisch reflex, compound 5(6)d was equipotent with metoclopramide. It is, therefore, likely that the imidazoline ring may provide a useful bioisosteric replacement for the carbonyl group in 5-HT3 antagonists.

Animals↗