320 research outputs found
Partition and distribution coefficients of aryloxypropanolamine β-adrenoceptor antagonists
No full textAbstract
n-Octanol/water partition and distribution coefficients of fifteen β-blockers have been measured and the relationships between log P (neutral species), log Pi (fully ionized species) and log D7·4 have been examined. A strict correlation exists among these three parameters, suggesting that the ionization exerts similar effects on the partition behaviour of these drugs.</jats:p
Hydrophobic Properties of Chromones and Flavones. Relationships Between Octanol/Water Partition Coefficients and RP‐HPLC Capacity Factors
No full textThe octanol/water partition coefficient (P) and the RP‐HPLC capacity factors (k′) at four different concentrations of organic modifier (methanol) in the mobile phase have been measured. The observed log P values of the polar substituted compounds show good consistency, if the interactions among the polar groups are taken into account on the basis of the Leo‐Fujita theory. Log P and log k′ are linearly correlated at the four methanol concentrations examined and at the extrapolated 0% methanol concentration. The phenolic compounds deviate from the correlation and this is recognized as a characteristic behaviour of the C‐18/ MeOH‐H2O chromatographic system. Copyright © 1987 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinhei
Comparative molecular field analysis of non-steroidal aromatase inhibitors related to fadrozole
No full textA series of non-steroidal inhibitors of aromatase, structurally related to fadrozole (2) , was investigated with the aim of developing a 3D QSAR model using the Comparative Molecular Field Analysis (CoMFA) technique. The alignment of the molecules was performed following two approaches (atomby-atom and field fit) , both starting from an initial hypothesis of superimposition of fadrozole to a steroidal inhibitor (3) . From a number of CoMFA models built with different characteristics, one was recognized as the most statistically relevant; this one is discussed in detail. The features of the 3D QSAR model are consistent with those of other 3D and QSAR models of aromatase and its inhibitors. © 1996 ESCOM Science Publishers B.V
Looking for selectivity among cytochrome P450s inhibitors
No full textCytochrome P450s 19 and 17 are very important pharmacological targets in two different fields of cancer chemotherapy. We present here a theoretical study aimed at explaining the molecular basis of inhibitor affinity and selectivity for either P450 19 or P450 17. Docking simulations of two compounds pointed out the major physicochemical features associated with inhibitory activity. Our results, in agreement with site-directed mutagenesis experiments, could be of relevant utility when designing new P450 19 and P450 17 inhibitors
Acetylcholinesterase inhibitors in the context of therapeutic strategies to combat alzheimer's disease
No full textAcetylcholinesterase inhibitors (AChEIs) are a class of drugs useful in the treatment of Alzheimer's disease (AD) as a result of their indirect cholinomimetic effect. In this review, patents claiming AChEIs that have appeared from the late 1990s (after the marketing of second generation compounds) to the present day will be discussed. The patents filed in this period fall into two categories of AChEIs, new products and combinations of drugs. Most of the new compounds are modifications of known drugs, although some novel structures have been claimed. The association of AChEIs with other pharmacological agents is hoped to improve efficacy of treatment by combining effects from the different pharmacological mechanisms of action. To put this discussion of AChEIs into perspective, some observations on the clinical uses of the anticholinesterases are also briefly summarised
Modeling the hERG potassium channel and its interactions with drugs
No full textThe human ether-à-go-go-related gene (HERG) was isolated in 1994, and shown to encode a six trans-membrane protein that assembles in a tetrameric complex to form the hERG potassium channel. The hERG K+ channel was then demonstrated to conduct the rapid delayed rectifier current (IKr), which is a component of the repolarization phase of the action potential of cardiomyocytes. In recent years, a large amount of evidence has accumulated that drugs belonging to different pharmacological classes may unintentionally block hERG channels, thus causing a prolongation of the action potential duration resulting in the so-called long QT syndrome (LQTS). Drug-induced LQTS predisposes individuals to a potentially lethal form of arrhythmia named torsades de pointes (TdP), and it is therefore not surprising that nowadays in the drug design and development process a great emphasis is cast on methods aimed at an early identification of the hERG blockade potential of new molecules. Several in vitro and in vivo models are currently available for the assessment of the proarrhythmic potential of new chemical entities, but anyway, prediction of drug-induced LQTS is still problematic. On the molecular side, many efforts have been devoted to understanding the determinants
of hERG block by drugs, and site-directed mutagenesis combined with the voltage-clamp technique is continuously providing increased and precise information. In silico methods have recently been proposed as a means to increase the capability of predicting hERG liability, and indeed several ligand-based QSAR models have recently appeared in the literature showing good accuracy in assessing the potential for hERG blockade. On the other hand, a parallel development of targetbased studies has been partly hampered by the lack of a sound experimental basis, on which to build a fully reliable model of the channel complex. Nevertheless, in the most recent times, some drug/hERG docking models of increasing quality have started to appear, and despite the limitations imposed by the homology modeling approach, they promise to become useful tools for predicting the hERG binding affinity and interpreting the hERG blockade by small molecules
Comparative molecular field analysis of non-steroidal aromatase inhibitors: an extended model for two different structural classes
No full textAromatase is a cytochrome P450 isozyme, whose inhibition is known to be therapeutically relevant in the treatment of the breast cancer. A comparative molecular field analysis (CoMFA) has been carried out on a series of non- steroidal aromatase inhibitors belonging to two different structural classes. One subset of compounds consists of fadrozole analogues and was studied in a previous work, from which a 'local' 3-D quantitative structure-activity relationship (QSAR) model for the inhibition of aromatase was obtained. In the present paper, that model is extended to include a second subset of compounds bearing a tetralone nucleus and acting at the same enzyme site with the same mechanism as the azoles. The critical alignment step has been solved by using two different steroidal inhibitors of aromatase as rigid templates, on which the non-steroidal compounds have been superimposed. The final 3-D QSAR models are discussed in terms of predictivity and some implications regarding the steric and electronic requirements of steroidal and non- steroidal inhibitors are pointed out
Strategie innovative per la scoperta di lead antitumorali: identificazione di nuovi composti attivi su sistemi molecolari di controllo del ciclo cellulare e della trascrizione genica
No full textNel presente progetto di ricerca biennale mirato alla scoperta di lead antitumorali innovativi, si intende realizzare una piattaforma sperimentale che unisce la sintesi di nuove molecole, lo studio computazionale dei sistemi bersaglio e la determinazione attraverso opportuni saggi delle proprietà biologiche dei nuovi composti. I principali obiettivi che il progetto si pone sono:
a) l’identificazione di nuovi candidati lead antitumorali attivi su sistemi di controllo del ciclo cellulare e della trascrizione genica;
b) l’identificazione di nuove molecole utili come sonde chimiche per lo studio degli stessi sistemi;
c) l’acquisizione di nuove conoscenze sugli aspetti molecolari delle interconnessioni esistenti tra i meccanismi di controllo del ciclo cellulare e quelli della trascrizione genica;
d) una valutazione dell’applicabilità di approcci innovativi alla ricerca di nuovi candidati lead.
Il contesto biologico all’interno del quale si inserisce la ricerca è quello riguardante i sistemi di controllo del ciclo cellulare e della trascrizione genica. I bersagli molecolari che si prenderanno inizialmente in considerazione in questo progetto sono proteine chiave per il funzionamento di questi sistemi, e, specificamente, le chinasi ciclina-dipendenti Cdk1, Cdk2 e Cdk7 coinvolte in processi regolatori del ciclo cellulare (tutte) e della trascrizione (Cdk7), enzimi quali istone deacetilasi (HDAC), acetiltransferasi (HAT) e metiltransferasi (HMT) responsabili assieme ad altri del rimodellamento cromatinico, e topoisomerasi I e II (Topo I/II), enzimi necessari per il controllo dello stato topologico del DNA e coinvolti anch’essi nelle modificazioni cromatiniche.
Date le comprovate interconnessioni esistenti non solo tra i sistemi biologici di cui sopra, ma anche tra singole macromolecole o complessi proteici appartenenti ad uno o all’altro dei sistemi, questo progetto si propone di riunire e coordinare le ricerche che vari gruppi portano avanti in questo campo, in modo da ottimizzare il lavoro di ciascuna unità e inserirlo in un contesto di conoscenze più ampio nel quale possa essere più efficacemente sfruttato e valorizzato.
Verranno sintetizzati sia derivati di lead noti all’interno delle unità di ricerca, che nuovi composti mirati a colpire determinati target e a svolgere azioni specifiche all’interno della cellula. Inoltre, saranno preparate librerie di molecole per le quali saranno prefissate soltanto caratteristiche generali (struttura simil-naturale o polieterociclica) e si cercherà di ottenere il massimo della diversità dei composti utilizzando adatti protocolli sintetici.
Le attività computazionali saranno mirate sia alla progettazione di nuove molecole che allo studio delle caratteristiche strutturali 3D di bersagli molecolari complessi (complessi CDK/ciclina), con particolare riguardo all’interfaccia proteina-proteina.
Le nuove molecole saranno saggiate per la loro abilità sia di colpire il bersaglio molecolare (saggi sui target in soluzione), che di dare i classici end point cellulari (citotossicità, apoptosi, differenziazione). Inoltre, si cercherà di indagare il modo d’azione dei composti più interessanti non soltanto in funzione della loro interazione con un singolo bersaglio molecolare, ma in un’ottica di biologia di sistema, cioè considerando anche l’insieme di relazioni che questo target intrattiene con altri partecipanti al sistema biologico. Questo permetterà sia di ottenere suggerimenti su come migliorare la potenza e la selettività delle molecole, che di avere indicazioni sul funzionamento del sistema studiato con la possibilità di identificare nuovi bersagli molecolari da colpire per modularlo
Density functional study of the enzymatic reaction catalyzed by a cyclin-dependent kinase
No full textDensity functional theory (DFT) calculations were carried out to study the molecular mechanism of the phosphoryl transfer reaction catalyzed by cyclin-dependent kinases (CDKs). The DFT study presented here shows that CDKs catalyze the phosphoryl transfer reaction from ATP to the serine substrate through a single step mechanism with a SN2-like transition state. © 2003 The Royal Society of Chemistry
- …
