Biomedical subjects

Antonio Chana

Publications and source records attributed to Antonio Chana.

7 recordsLinked to original sources

PubMed2006

Virtual screening for aryl hydrocarbon receptor binding prediction.

The overall goal of this study has been to validate computational models for predicting aryl hydrocarbon receptor (AhR) binding. Due to the unavailability of the AhR X-ray crystal structure we have decided to use QSARs models for the binding prediction virtual screening. We have built up CoMFA, Volsurf, and HQSAR models using as a training set 84 AhR ligands. Additionally, we have built a hybrid model combining two of the final selected models in order to give a single operational system. The results show that CoMFA, VolSurf, HQSAR, and the hybrid models gives good results (R(2) equal to 0.91, 0.79, 0.85, and 0.82 and q(2) 0.62, 0.58, 0.62, and 0.70, respectively). Since the techniques analyzed show a good correlation and good prediction also for an external test set, particularly the HQSAR and the hybrid model, we can conclude that these models can be used for predicting AhR binding in virtual screening.

Dioxins↗

PubMed2004

Induction of cytochrome P4501A (CYP1A) by clotrimazole, a non-planar aromatic compound. Computational studies on structural features of clotrimazole and related imidazole derivatives.

The classical pathway for induction of cytochrome P4501A (CYP1A) by xenobiotics is ligand binding to the aryl hydrocarbon receptor (AhR). High-affinity AhR ligands are planar polyaromatic molecules such as the prototypic ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The present work investigated the ability of the imidazole derivative, clotrimazole [1-(2'chlorotrityl)imidazole, CLO], to induce CYP1A in cultured rainbow trout (Oncorhynchus mykiss) hepatocytes at the catalytic activity (determined as 7-ethoxyresorufin-O-deethylase, EROD) and at the transcriptional level. CLO resulted in a significant increase of hepatocyte EROD activity and CYP1A mRNA at a concentration of 1.56 microM. Computational studies on the molecular structure of CLO show that CLO is unlikely to take a planar conformation. Further indications that CLO does not behave like a planar AhR ligand come from the experimental observation that co-incubation of trout hepatocytes with CLO and the AhR antagonist, alpha-naphthoflavone (alpha-NF), did not result in an inhibition of CLO induction of CYP1A mRNA, whereas alpha-NF was able to inhibit CYP1A induction by the prototpyic, planar AhR ligand, beta-naphthoflavone. The experimental findings on CLO agree with previous results obtained for another non-planar imidazole derivative, 1-benzylimidazole (BIM). Further, computational studies showed that the non-planar imidazoles, BIM and CLO, are highly similar with respect to some electrostatic properties, namely the dipole moment and the molecular electrostatic potential (MEP). Overall our experimental and computational studies suggest that transcriptional activation of CYP1A by the imidazole derivatives CLO and BIM is mediated by a mechanism different to that of prototypic CYP1A inducers such as the planar AhR-ligands.

Animals↗

PubMed2004

Synthesis and nematocide activity of S-glycopyranosyl-6,7-diarylthiolumazines.

6,7-Diaryl derivatives of mono and di-S-glycopyranosylthiolumazine derivatives 5-8 were prepared to test their nematocide activity. In vitro tests against Caenorhabditis elegans were performed and it was found that monosubstituted derivatives 5-7 showed higher activity than the corresponding unsubstituted 2-thiolumazines 1-3, whilst 2-S,4-S-di-glycopyranosylpteridine derivative 8 was inactive in contrast to unsubstituted derivative 4. In order to check whether the lack of activity of 8 was due to the two bulky substituents of the pteridine nucleus, 2-S,4-S-dimethyl derivative 9 was synthesized and assayed showing also lack of activity. A theoretical study on the stability of the different possible tautomers of compound 4 was carried out in an attempt to explain some, in appearance, anomalous (13)C NMR data of this compound.

Animals↗

PubMed2004

Studies on aromatic compounds: inhibition of calpain I by biphenyl derivatives and peptide-biphenyl hybrids.

With the objective to understand structural features responsible for the biological activity, novel nonelectrophilic biphenyl derivatives and peptide-biphenyl hybrids have been synthesized and evaluated as calpain I inhibitors. The preliminary results indicate that the presence of additional aromatic rings (besides the biphenyl system) makes these compounds potent calpain inhibitors with IC50 values in the nanomolar range.

Biphenyl Compounds↗

PubMed2004

Peptide-biphenyl hybrids as calpain inhibitors.

Calpain is a cysteine protease that is activated by Ca2+. The over-activation of calpain, which occurs on increasing Ca2+ concentration, causes a variety of diseases. This paper reports experimental results on the inhibition of calpain I (mu-calpain) by peptide-biphenyl hybrids. We have found that some peptide-biphenyl hybrids, with aromatic amino acids in the peptide chains, inhibit calpain with IC50 values in the nanomolar range. Since the peptide-biphenyl hybrids reported in the present paper do not possess a reactive electrophilic functionality, we hypothesize that they interfere with the activation of calpain by Ca2+, and present experimental and computational results on the binding of peptide-biphenyl hybrids to Ca2+.

Biphenyl Compounds↗

PubMed2003

Induction of CYP1A by the N-imidazole derivative, 1-benzylimidazole.

Xenobiotics can induce cytochrome P4501A (CYP1A) by ligand binding to the aryl hydrocarbon receptor (AhR). Typical AhR ligands are polycyclic aromatic compounds with planar molecular conformation. The present work investigated the ability of the N-imidazole derivative, 1-benzylimidazole (BIM), to induce CYP1A in rainbow trout hepatocytes. Benzylimidazole increased hepatocellular CYP1A catalytic activity (determined as 7-ethoxyresorufin-O-deethylase [EROD] activity) and CYP1A mRNA in a concentration-dependent way. Computational studies on the molecular structure of BIM indicated that the energetically most stable BIM conformer has the imidazole ring and the phenyl ring in different planes, i.e., does not take a planar conformation. This property of BIM does not agree with the structural requirements of a typical AhR ligand. In line with this observation, we found that the AhR antagonist, alpha-naphthoflavone (alphaNF), was not able to inhibit BIM induction of EROD activity and CYP1A mRNA, although it inhibited the induction of CYP1A by the prototypic AhR ligand, beta-naphthoflavone (betaNF). The results suggest that transcriptional activation of CYP1A by the N-imidazole derivative, BIM, is not mediated through direct ligand binding to the AhR.

Animals↗

PubMed2002

Computational studies on biphenyl derivatives. Analysis of the conformational mobility, molecular electrostatic potential, and dipole moment of chlorinated biphenyl: searching for the rationalization of the selective toxicity of polychlorinated biphenyls (PCBs).

With the objective to understand how the pattern and degree of chlorination influence on the properties of the title molecules, a computational study on biphenyl and all the chlorinated biphenyls (from 1 to 10 chlorine atoms, 209 congeners) has been undertaken. The study includes conformational searches (and further refinement by molecular dynamics simulations) and the ab initio calculation of the molecular electrostatic potential (MEP) and the dipole moments for all the congeners. The most significant property is the MEP, finding a good correlation between the MEPs and the substitution pattern on chlorinated biphenyls. The most toxic congeners possess highly positive values of electrostatic potential on the aromatic rings and highly negative values of electrostatic potential on the chlorine atoms. Additionally, we have found that the toxic congeners possess conformations with low dipole moments, a fact that may be linked to the ready accumulation on the adipose tissue. The results on the geometry and electrostatic properties of chlorinated biphenyls can be useful to rationalize their selective toxicities.

Computer Simulation↗