Erratum: Lipase-catalyzed regioselective acylation of resorcin[4]arenes (Journal of Molecular Catalysis B: Enzymatic (2002) 16 (24-247) PII: S1381117701000686)

10Immobilized lipase from Mucor miehei (RML) catalyzed the regioselective acylation of the C-2 side-chain of the C-alkyl resorcin[4]arene tetra-alcohol 1 in the 1,2-alternate form in organic solvents using vinyl acetate as acylating reagent. The influence of reaction parameters and solvent choice were also studied. Docking simulations allowed the determination of the binding geometry of 1, revealing the importance of Trp88 residue in stabilizing the Michaelis–Menten complex between enzyme and substrate.reservedmixedBotta, Bruno; Zappia, Giovanni; Tafi, Andrea; Botta, Maurizio; Manetti, Fabrizio; Cernia, Enrico; Milana, Giuliana; Palocci, Cleofe; Soro, Simonetta; Delle Monache, GiulianoBotta, Bruno; Zappia, Giovanni; Tafi, Andrea; Botta, Maurizio; Manetti, Fabrizio; Cernia, Enrico; Milana, Giuliana; Palocci, Cleofe; Soro, Simonetta; Delle Monache, Giulian

0365: Non-peptidic prokineticin receptor 1 agonist as a novel cardioprotective therapeutic

ObjectiveProkineticins are potent angiogenic peptides that bind to two G protein-coupled receptors to initiate their biological effects. We previously have shown that prokineticin receptor-1 (PKR1) signaling contributes to cardiomyocyte survival or repair in myocardial infarction. Here, we discovered the first non-peptidic PKR1 agonists and examined their effects in mice model of heart diseases.Methods and resultsHerein we identify a selective PKR1 agonist both in vitro and in vivo, utilizing GPCR structure-based virtual screening approach. High Throughput Docking was carried out by GOLD using homology model of PKR1. Asinex gold collection 3D chemical databese (250,000 compounds) was screened by the docking protocol. We provided a strategy with a high potential for in silico identifying one agonist hit. We present here IS20, the first synthetic PKR1 agonist that induces angiogenesis in the presence of PKR1 on the endothelial cells seeded on matrigel. IS20 reduced doxorubicin cytotoxicity in H9C2 cells. IS20 promotes mouse epicardial progenitor cell differentiation into endothelial cells. In vivo IS20 activates Akt in mice heart. IS20 treatment of mice after coronary ligation reduces mortality by 30%.ConclusionThis study identifies a non-peptidic PKR1 agonist as therapeutic target holding promise for treatment of heart diseases

Pharmacophore Modelling: A Forty Year Old Approach and its Modern Synergies

A pharmacophore represents a simple and intuitive concept that can be used in many different drug discovery applications. Ligand-based and structure-based pharmacophore models continue to play a pivotal role in hit discovery and may guide lead optimization. Moreover, owing to the versatility of the pharmacophore concept, pharmacophore modelling has been routinely used in combination with other molecular modelling techniques. The synergistic use of different tools in drug discovery workflows may allow to fully exploit the advantages, while compensating for some of the intrinsic limitations, of each methodology. This review will focus on the synergistic combination of pharmacophore modelling with other molecular modelling approaches such as the hot spot analysis of protein binding sites, molecular dynamics, and docking

CONFORMATIONAL EFFECTS ON THE STEREOCHEMICAL COURSE OF THE NABH4 REDUCTION OF SUBSTITUTED BICYCLO[3.3.1]NONAN-2-ONES

Molecular mechanics calculations for the 1-substituted bicyclo[3.3.1]nonan-2-ones 2a-d show that the amount of the chair-boat conformation increases as the size of the substituent at C1 increases. This result sharply fits with the stereochemical course of NaBH4 reductions of ketones 2a-d if axial attack on the chair-boat conformation and equatorial attack on the chair-chair one are assumed to be preferential

Molecular modeling as a powerful technique for understanding small-large molecules interactions

In the present review we summarize recent work, aimed at a better understanding of the interactions in macromolecule-ligand complexes, performed by means of computational tools such as pseudoreceptor generation, molecular docking, conformational search and energy minimization. While the first approach has been applied when the three-dimensional structural properties of the biological target were unknown, the remaining protocols exploited the knowledge of the overall structure of the involved macromolecules and their active sites. Molecular modeling techniques were used in the cases reported to study and propose macromolecular binding sites and to predict their interactions with bioactive conformers of the ligand

Desymmetrisation of meso-Methylcyclooctanones. Highly Enantioselective Synthesis of C8 syn-Isoprenoid and syn,syn-Deoxypropionate Subunits from a Bicyclo[3.3.1]nonane Precursor.

The methyl esters of 3R, 7S-dimethyl- and 3R, 5R, 7S-trimethyl-8-hydroxyoctanoic acids have been prepared in good yields and with ee > 98% by chemical elaboration of the known exo, exo-3,7-dimethylbicyclo[3.3.1]nonan-9-one, the key step involving the desymmetrisation of the intermediate meso-ketones cis-3,7-dimethyl- and cis,cis-3,5,7-trimethyl-cyclooctanone through the corresponding chiral enolates generated by the lithium amide of the (+) bis[(R)-(1-phenylethylamine)]. The very high enantioselectivity observed might be related to the conformational features of the eight-membered ring.

3D-QSAR using pharmacophore-based alignment and virtual screening for discovery of novel MCF-7 cell line inhibitors

The development of a novel approach for the prediction of antiestrogenic activity is described, bringing up to date a previous pharmacophore study. Software Phase has been used to derive a 3D-QSAR model based, as alignment rule, on a pharmacophore built on three compounds highly active against MCF-7 cell line. Five features comprised the pharmacophore: two hydrogen-bond acceptors, one hydrogen-bond donor, and two aromatic rings. The sequential 3D-QSAR yielded a test set q(2) equal to 0.73 and proved to be predictive with respect to an external test set of 21 compounds (r(2) = 0.69). The model was used to detect new MCF-7 inhibitors through 3D-database searching and identified fourteen compounds that were subsequently tested in vitro against the MCF-7 human breast adenocarcinoma cell line. Eleven out of the fourteen compounds exhibited inhibitory activity with IC50 values ranging between 30 and 186 μM. The results of the study confirmed the fundamental validity of the chosen approach as a hit discovery tool

Chair-boat equilibrium as driving force in epimerization of 3,7-dimethylbicyclo[3.3.1]nonan-2,9-dione derivatives. Stereocontrolled synthesis of 3-exo,7-exo- and 3-endo,7-exo-3,7-dimethylbicyclo[3.3.1]nonan-9-ones

Molecular mechanics calculations and experimental 1H NMR data are in close agreement and show that the epimerization equilibrium at C3 of 3,7-dimethylbicyclo[3.3.1]nonan-2,9-diones is shifted toward the 3-endo-epimer in order to reach the lowest energy chair-boat conformation. Introduction of a 1,3-dioxolane moiety at C9 results in reversal of the equilibrium, in protic solvents, leading mainly to the 3-exo-epimer in the most stable chair-chair conformation. These results have been applied to the stereocontrolled synthesis of the title compounds

Desymmetrisation of meso-methylcyclooctanones. Highly Enantioselective Synthesis of C8 syn-Isoprenoid and syn,syn-Deoxypropionate Subunits from a Bicyclo[3.3.1]nonane Precursor

The methyl esters of 3R,7S-dimethyl- and 3R,5R,7S-trimethyl-8-hydroxyoctanoic acids have been prepared in good yields and with e.e. >98% by chemical elaboration of the known exo,exo-3,7-dimethylbicyclo[3.3.1]nonan-9-one, the key step involving the desymmetrisation of the intermediate meso-ketones cis-3,7-dimethyl- and cis,cis-3,5,7-trimethyl-cyclooctanone through the corresponding chiral enolates generated by the lithium amide of the (+)bis[(R)-(1-phenylethylamine)]. The very high enantioselectivity observed might be related to the conformational features of the eight-membered ring