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A Macchiarulo

Publications and source records attributed to A Macchiarulo.

17 recordsLinked to original sources
PubMed2001

Design, synthesis and preliminary evaluation of novel 3'-substituted carboxycyclopropylglycines as antagonists at group 2 metabotropic glutamate receptors.

Two novel 3'-substituted carboxycylopropylglycines, (2S,1'S,2'S,3'R)-2-(3'-xanthenylmethyl-2'-carboxycyclopropyl)glycine (8a) and (2S,1'S,2'S,3'R)-2-(3'-xanthenylethyl-2'-carboxycyclopropyl)glycine (8b), were synthesized and evaluated as mGluR ligands. Compound 8b showed to be a potent group II antagonist with submicromolar activity.

Animals↗
PubMed2001

Modeling of poly(ADP-ribose)polymerase (PARP) inhibitors. Docking of ligands and quantitative structure-activity relationship analysis.

Poly(ADP-ribose)polymerase-1 (PARP-1) is a nuclear enzyme that has recently emerged as an important player in the mechanisms leading to postischemic neuronal death, and PARP inhibitors have been proposed as potential neuroprotective agents. With the aim of clarifying the structural basis responsible for PARP inhibition, we carried out a computational study on 46 inhibitors available through the literature. Our computational approach is composed of three parts. In the first one, representative PARP inhibitors have been docked into the crystallographic structure of the catalytic domain of PARP by using the Autodock 2.4 program. The docking studies thus carried out have provided an alignment scheme that has been instrumental for superimposing all the remaining inhibitors. Upon the basis of this alignment scheme, a quantitative structure-activity relationship (QSAR) analysis has been carried out after electrostatic and steric interaction energies have been computed with the RECEPTOR program. The QSAR analysis yielded a predictive model able to explain much of the variance of the 46-compound data set. The inspection of the QSAR coefficients revealed that the major driving force for potent inhibition is given by the extension of the contact surface between enzyme and inhibitors while electrostatic energy and hydrogen bonding capability play a minor role. Finally, the projection of the QSAR coefficients back onto the X-ray structure of the catalytic domain of PARP provides insights into the role played by specific amino acid residues. This information will be useful to address the design of new selective and potent PARP inhibitors.

Catalytic Domain↗
PubMed2001

QSAR and molecular modeling studies of baclofen analogues as GABA(B) agonists. Insights into the role of the aromatic moiety in GABA(B) binding and activation.

An integrated QSAR/molecular modeling study is carried out on a series of baclofen analogues with the aim of addressing the role of their aromatic moiety in GABA(B) receptor binding and activation. The strong correlation found between electronic descriptors (HOMO and LUMO orbital energies) and the biological activity expressed as receptor binding is discussed also on the basis of available experimental mutagenesis data and of the results obtained from homology modeling of GABA(B) receptor. In particular, it can be inferred from the QSAR analysis that the ability of being involved in aromatic-aromatic pi interaction is the distinctive feature of the p-chlorophenyl moiety of baclofen. This conclusion is confirmed by homology modeling and docking studies which indicate that the p-chlorophenyl moiety of baclofen is disposed into a pocket formed by Tyr366 and Tyr395. These results are discussed in terms of mechanism of GABA(B) activation promoted by baclofen or GABA.

Baclofen↗
PubMed2001

Conformational analysis of carboxyphenylglycine (CPG) derivatives: insight into bioactive and bioselective conformations of group-I mGluRs antagonists.

A series of carboxyphenylglycine (CPG) derivatives, endowed with diverse activity and selectivity at metabotropic glutamate receptors (mGluRs), were subjected to an extensive conformational analysis by employing molecular mechanics, semiempirical and ab initio methods. The comparison of the conformational profiles of active and inactive CPGs suggests a possible bioactive conformation characterized by a value of 10 degrees for the N-Calpha-C1Ph-C2Ph angle, with this conformation characterized by ammonium group of the amino acid moiety lying on the plane defined by the aromatic ring.

Glycine↗
PubMed2001

Homology model of the closed, functionally active, form of the amino terminal domain of mGlur1.

The amino terminal domain (ATD) of metabotropic glutamate receptors (mGluRs) contains the neurotransmitter binding site and is related in sequence to leucine/isoleucine/valine binding proteins (LIVBP). It has been proposed that the ATD of mGluRs shares with periplasmic binding proteins a common mechanism of ligand binding and processing which involves the equilibrium between closed and open forms. The availability of the X-ray structure of LIVBP in its open, unliganded form, has allowed the construction of homology models of the ATD of mGluR1 which have been instrumental in clarifying the mode of binding of agonists and antagonists. We propose in this paper the use of the X-ray structure of AmiC. the controller of transcription antitermination in the amidiase operon of Pseudomonas aerugimosa as suitable template for the construction of the closed form of the ATD of mGluR1. The resulting model of the closed form of the ATD of mGluR1 indicates that several interdomain hydrogen bonds and salt bridges may be formed upon domain contraction and that the ligand directly participates to this interdomain network.

Amino Acid Sequence↗
PubMed1999

Modeling of amino-terminal domains of group I metabotropic glutamate receptors: structural motifs affecting ligand selectivity.

On the basis of a new sequence alignment between the amino terminal domains of mGlu1 and mGlu5 receptor subtypes and leucine/isoleucine/valine binding protein (LIVBP), three-dimensional models of the binding sites of the two group I metabotropic glutamate receptor subtypes were constructed. The 3D-models thus obtained showed a high degree of similarity. In the region of the putative binding site, identified by Ser165 and Thr188 (mGlu1) or Ser152 and Thr175 (mGlu5), the only nonconserved residue is Pro369 (mGlu1), which is substituted by Gln356 in mGlu5. Although not directly involved in ligand binding, these residues may provide a subtle difference in the steric environment of the two active sites that may account for the observed subgroup selectivity of recently reported ligands.

Amino Acid Sequence↗
PubMed1999

Pharmacophore models of group I and group II metabotropic glutamate receptor agonists. Analysis of conformational, steric, and topological parameters affecting potency and selectivity.

A wide variety of conformationally constrained glutamate analogues, active as group I or group II metabotropic glutamate receptor agonists, were employed in a molecular modeling study aimed at the definition of group I and group II agonist pharmacophoric models. The results of this study can be summarized as follows: (i) Recognition sites of both group I and group II mGluRs can adequately be described by five-point pharmacophores. (ii) An extended conformation of glutamate is required for interaction with both group I and group II mGluRs. Group I receptors, however, can also be activated by a more folded conformation if only four pharmacophore points are considered. (iii) Conformational preferences are, however, not sufficient to explain the potency and selectivity of the whole set of ligands. Volume comparison analysis allowed us to define steric environments for group I and group II mGluRs. Group I mGluRs are characterized by a region of allowed volume in proximity of the distal acidic function, whereas group II mGluRs are characterized by a small polar pocket whose occupancy confers high potency and selectivity. Finally, our study points out the necessity of a careful analysis of the energetic requirements needed to attain the putative bioactive conformations and of explicitly considering the conformational mobility of carboxylate groups.

Excitatory Amino Acid Agonists↗
PubMed1989

[Orthodontic card: a compilation proposal].

In relation to particular specialist filing of orthodontic patients and with reference to the need for pointing out peculiar data during diagnosis and treatment, it is necessary to have a suitable clinical card, which, if filed, may represent a reliable and valid document for case reports. Such a card has also been conceived for its likely insertion into a computer database.

Cephalometry↗