1,721,277 research outputs found
Insight into the Mechanism of Hydrolysis of Meropenem by OXA-23 Serine-β-lactamase Gained by Quantum Mechanics/Molecular Mechanics Calculations
No full textThe fast and constant development of drug resistant bacteria represents a serious medical emergency. To overcome this problem, the development of drugs with new structures and modes of action is urgently needed. In this work, we investigated, at the atomistic level, the mechanisms of hydrolysis of Meropenem by OXA-23, a class D β-lactamase, combining unbiased classical molecular dynamics and umbrella sampling simulations with classical force field-based and quantum mechanics/molecular mechanics potentials. Our calculations provide a detailed structural and dynamic picture of the molecular steps leading to the formation of the Meropenem-OXA-23 covalent adduct, the subsequent hydrolysis, and the final release of the inactive antibiotic. In this mechanistic framework, the predicted activation energy is in good agreement with experimental kinetic measurements, validating the expected reaction path
Design, synthesis and pharmacological properties of alkylbisammonio bitopic ligands of muscarinic acetylcholine receptors
No full textOver the past two decades, novel opportunities for drug discovery have risen from a greater understanding of the complexity of GPCR signaling. A striking example of this is the appreciation that GPCRs possess functional allosteric binding sites.[1] The five muscarinic acetylcholine receptor (mAChR) subtypes bind their physiological transmitter in the highly conserved orthosteric site within the transmembrane domain of the receptors. Orthosteric muscarinic agonists have negligible binding selectivity and poor signaling specificity. A less conserved allosteric site has been also characterized at the extracellular entrance of the binding pocket of mAChRs. Our interest in the research field on mAChR ligands has been recently extended to the study of derivatives designed to simultaneously interact with the orthosteric and the allosteric site (bitopic ligands) of these receptors, thus exploiting the complementary characteristics of the two different binding sites by a single ligand molecule.[2,3] This approach is a variation of the more traditional bivalent ligand concept and shares some of the same challenges, including the choice and role of the linker between the two pharmacophores and the validation of mechanism of action.[4] The most interesting bitopic compounds which emerged from our investigation (represented by the general molecular skeleton A in Figure 1) are alkylbisammonio derivatives incorporating a) iperoxo, an oxotremorine-related unselective muscarinic superagonist, b) a polymethylene spacer chain, and c) a heteroaromatic fragment targeting the allosteric site.
The synthetic approach of target compounds and the most relevant results of their pharmacological investigation will be presented. In particular, the analgesic effects observed for a group of the compounds under study will be illustrated in detail.
References
1. Wang, L.; Martin, B.; Brenneman, R.; Luttrell, L. M.; Maudsley, S. Allosteric Modulators of G Protein-Coupled Receptors: Future Therapeutics for Complex Physiological Disorders. J. Pharmacol. Exp. Ther. 2009, 331, 340-348
2. Antony, J.; Kellershohn, K.; Disingrini, T.; Dallanoce, C.; Tränkle, C.; Christopoulos, A.; Barocelli, E.; De Amici, M.; Holzgrabe, U.; Mohr, K. et al. Dualsteric GPCR targeting: a novel route to binding and signaling pathway selectivity. FASEB J. 2009, 23, 442-450
3. Bock, A.; Merten, N.; Schrage, R.; Dallanoce, C.; Matera, C.; Hoffmann, C.; De Amici, M.; Holzgrabe, U.; Kostenis, E.; Mohr, K. et al. The allosteric vestibule of a seven transmembrane helical receptor controls G-protein coupling. Nat. Commun. 2012, 3, 1044
4. Valant, C.; Lane, J. R.; Sexton, P. M.; Christopoulos, A. The Best of Both Worlds? Bitopic Orthosteric/Allosteric Ligands of G Protein-Coupled Receptors. Annu. Rev. Pharmacol. Toxicol. 2012, 52, 153-17
Allosteric modulators and selective agonists of muscarinic receptors
No full textAllosteric modulators of ligand-receptor interactions are found for a variety of receptors (Christopoulos, 2002). Allosteric agents attach to a binding site being topographically distinct from the site for conventional (orthosteric) agonists or antagonists. In the case of the muscarinic receptor, a huge selection of structurally divergent modulators has been described for different receptor subtypes (Mohr et al., 2003). Alkane-bisammonio-type compounds carrying lateral phthalimido substituents are known to have a high affinity for the common allosteric binding site of the muscarinic acetylcholine M2 receptor (mAChR M2), which is already occupied by the orthosteric antagonist N-methylscopolamine (NMS). The resulting allosteric inhibition of the dissociation of [3H]NMS from the M2 receptors in porcine cardiac homogenates served to indicate binding of the test compounds to the allosteric site. Additionally, allosteric modulators can strongly influence equilibrium binding of the orthosteric ligand: Its binding can be reduced, left unaltered or elevated, and encoded as negative, neutral, and positive cooperativity, respectively (Christopoulos and Kenakin, 2002). The cooperativity is strongly dependent on the pair of allosteric/orthosteric ligands and on the receptor subtyp
Bifunctional dopaminergic/nicotinic agonists: novel pharmacological tools to study the D3R/β2*nAChRs heteromeric complex
No full textBifunctional derivatives have gained a relevant interest in the medicinal chemistry research as potentially innovative therapeutic agents.[1] Indeed, bifunctional drug candidates may concomitantly regulate two biological targets instead of blocking or activating, for example, only one dysfunctional receptor system at a time. As a first contribution in the field, we recently reported the synthesis of new bifunctional derivatives and their affinity/efficacy profiles at D2/non-α7 nAChRs.[2] In this framework, the recent demonstration that D3 dopaminergic and β2-subunit-containing (β2*) nAChRs may assemble in a heteromeric receptor complex [3] has provided the rationale for the investigation of bifunctional compounds targeting such receptor heterodimers. Our study focused on the design and synthesis of novel compounds, which incorporate in a common molecular skeleton two substructures, i.e., the pharmacophoric moiety of the D3 agonist Ropinirole and the fragment of the selective, highly potent α4β2 agonist A-84543 (Figure 1). The synthetic approach and the details of the pharmacological investigation will be illustrated and discussed. Figure 1. Model compounds and target bifunctional derivatives In particular, our findings extend the current understanding of the molecular mechanisms regulating the neuronal plasticity and provide an example of the importance of G protein-coupled receptor and ligand-gated ion channel heteromerization for synaptic efficacy and intrinsic neural properties. Increasing evidence suggests that D2R/D3R agonists may slow the progression of Parkinson’s disease (PD) and that nicotine has neuroprotective effects on dopaminergic neurons. Therefore, the D3/β2*nAChR heteromeric complex may represent a novel therapeutic
target for neuroprotection and, accordingly, bifunctional compounds which activate this complex could provide a new pharmacological approach to the treatment of PD.
References
1. Wang, M.; Wong, A. H.; Liu, F. Interactions between NMDA and dopamine receptors: a potential therapeutic target. Brain Res. 2012, 1476, 154-163.
2. Matera, C.; Pucci, L.; Fiorentini, C.; Fucile, S.; Missale, C.; Grazioso, G.; Clementi, F.; Zoli, M.; De Amici, M.; Gotti, C.; Dallanoce, C. Bifunctional compounds
targeting both D2 and non-α7 nACh receptors: design, synthesis and pharmacological characterization. Eur. J. Med. Chem. 2015, in press.
3. Missale, C. et al., manuscript in preparation
CONVERSION OF ISOXAZOLINES TO BETA-HYDROXY ESTERS - SYNTHESIS OF 2-DEOXY-D-RIBOSE
No full textA simple and effficient preparation of β-hydroxy esters with a well-defined stereochemistry has been developed using 3-bromoisoxazolines as key-intermidiates. A synthesis of 2-decxy-D-ribose is also reported
CHEMOENZYMATIC SYNTHESIS OF CHIRAL ISOXAZOLE DERIVATIVES
No full textThe synthesis of the two enantiomers of 1-(3-bromo-5-isoxazolyl)-2-(tert-butylamino)ethanol (1), a potent and selective β2-adrenergic stimulant, has been efficiently accomplished by enzyme-catalyzed transformations. The absolute configurations are attributed to (+)- and (-)-1 by correlation with (S)-3-butyn-2-ol. The S enantiomer was prepared in >98% enantiomeric excess by reducing α-bromo ketone 4 in the presence of alcohol dehydrogenase from Thermoanaerobium brockii and the R enantiomer was obtained in 97% ee through a kinetic resolution of the racemic bromohydrin (±)-5, in organic solvents, catalyzed by lipase P from Pseudomonas fluorescens. The experimental conditions for the lipase-catalyzed asymmetric transesterifications were optimized in order to improve reaction rates and the enantiomeric excess of the products
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