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2.
Cell ; 184(24): 5886-5901.e22, 2021 11 24.
Artículo en Inglés | MEDLINE | ID: mdl-34822784

RESUMEN

Current therapies for Alzheimer's disease seek to correct for defective cholinergic transmission by preventing the breakdown of acetylcholine through inhibition of acetylcholinesterase, these however have limited clinical efficacy. An alternative approach is to directly activate cholinergic receptors responsible for learning and memory. The M1-muscarinic acetylcholine (M1) receptor is the target of choice but has been hampered by adverse effects. Here we aimed to design the drug properties needed for a well-tolerated M1-agonist with the potential to alleviate cognitive loss by taking a stepwise translational approach from atomic structure, cell/tissue-based assays, evaluation in preclinical species, clinical safety testing, and finally establishing activity in memory centers in humans. Through this approach, we rationally designed the optimal properties, including selectivity and partial agonism, into HTL9936-a potential candidate for the treatment of memory loss in Alzheimer's disease. More broadly, this demonstrates a strategy for targeting difficult GPCR targets from structure to clinic.


Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Diseño de Fármacos , Receptor Muscarínico M1/agonistas , Anciano , Anciano de 80 o más Años , Envejecimiento/patología , Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/patología , Secuencia de Aminoácidos , Animales , Presión Sanguínea/efectos de los fármacos , Células CHO , Inhibidores de la Colinesterasa/farmacología , Cricetulus , Cristalización , Modelos Animales de Enfermedad , Perros , Donepezilo/farmacología , Electroencefalografía , Femenino , Células HEK293 , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Masculino , Ratones Endogámicos C57BL , Modelos Moleculares , Simulación de Dinámica Molecular , Degeneración Nerviosa/complicaciones , Degeneración Nerviosa/patología , Primates , Ratas , Receptor Muscarínico M1/química , Transducción de Señal , Homología Estructural de Proteína
3.
Nat Commun ; 12(1): 5475, 2021 09 16.
Artículo en Inglés | MEDLINE | ID: mdl-34531380

RESUMEN

Acetylcholine release in the hippocampus plays a central role in the formation of new memory representations. An influential but largely untested theory proposes that memory formation requires acetylcholine to enhance responses in CA1 to new sensory information from entorhinal cortex whilst depressing inputs from previously encoded representations in CA3. Here, we show that excitatory inputs from entorhinal cortex and CA3 are depressed equally by synaptic release of acetylcholine in CA1. However, feedforward inhibition from entorhinal cortex exhibits greater depression than CA3 resulting in a selective enhancement of excitatory-inhibitory balance and CA1 activation by entorhinal inputs. Entorhinal and CA3 pathways engage different feedforward interneuron subpopulations and cholinergic modulation of presynaptic function is mediated differentially by muscarinic M3 and M4 receptors, respectively. Thus, our data support a role and mechanisms for acetylcholine to prioritise novel information inputs to CA1 during memory formation.


Asunto(s)
Acetilcolina/metabolismo , Región CA1 Hipocampal/fisiología , Corteza Entorrinal/fisiología , Potenciales Postsinápticos Excitadores/fisiología , Retroalimentación Fisiológica/fisiología , Transmisión Sináptica/fisiología , Animales , Región CA1 Hipocampal/citología , Carbacol/farmacología , Agonistas Colinérgicos/farmacología , Corteza Entorrinal/citología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Retroalimentación Fisiológica/efectos de los fármacos , Interneuronas/metabolismo , Interneuronas/fisiología , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Técnicas de Placa-Clamp , Células Piramidales/metabolismo , Células Piramidales/fisiología , Receptor Muscarínico M3/genética , Receptor Muscarínico M3/metabolismo , Transmisión Sináptica/efectos de los fármacos
4.
Heliyon ; 7(6): e07201, 2021 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-34189291

RESUMEN

The identification of cannabinoid ligands Cannabidiol and O-1918 as inverse agonists of the orphan receptor GPR52 is reported. Detailed characterisation of GPR52 pharmacology and modelling of the proposed receptor interaction is described. The identification of a novel and further CNS pharmacology for the polypharmacological agent and marketed drug Cannabidiol is noteworthy.

5.
Adv Pharmacol ; 88: 35-58, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32416871

RESUMEN

The metabotropic glutamate (mGlu) receptors are a family of eight class C G protein-coupled receptors (GPCRs) which modulate cell signaling and synaptic transmission to the major excitatory neurotransmitter l-glutamate (l-glutamic acid). Due to their role in modulating glutamate response, their widespread distribution in the central nervous system (CNS) and some evidence of dysregulation in disease, the mGlu receptors have become attractive pharmacological targets. As the orthosteric (glutamate) binding site is highly conserved across the eight mGlu receptors, it is difficult not only to generate ligands with subtype selectivity but, due to the nature of the binding site, with suitable drug-like properties to allow oral bioavailability and CNS penetration. Selective pharmacological targeting of a single receptor subtype can be achieved by targeting alternative (allosteric) binding sites. The nature of the allosteric binding pockets allows ligands to be developed that have good physical chemical properties as evidenced by several allosteric modulators of mGlu receptors entering clinical trials. The first negative allosteric modulators of the metabotropic glutamate 5 (mGlu5) receptor were discovered from high throughput screening activities. An alternative approach to drug discovery is to use structural knowledge to enable structure-based drug design (SBDD), which allows the design of molecules in a more rational, rather than empirical, fashion. Here we will describe the process of SBDD in the discovery of the mGlu5 negative allosteric modulator HTL0014242 and describe how knowledge of receptor structure can also be used to gain insights into the receptor activation mechanisms.


Asunto(s)
Descubrimiento de Drogas , Receptor del Glutamato Metabotropico 5/química , Receptor del Glutamato Metabotropico 5/metabolismo , Regulación Alostérica , Sitio Alostérico , Animales , Humanos , Terapia Molecular Dirigida , Receptor del Glutamato Metabotropico 5/genética , Relación Estructura-Actividad
6.
J Med Chem ; 63(4): 1528-1543, 2020 02 27.
Artículo en Inglés | MEDLINE | ID: mdl-31860301

RESUMEN

The orexin system, which consists of the two G protein-coupled receptors OX1 and OX2, activated by the neuropeptides OX-A and OX-B, is firmly established as a key regulator of behavioral arousal, sleep, and wakefulness and has been an area of intense research effort over the past two decades. X-ray structures of the receptors in complex with 10 new antagonist ligands from diverse chemotypes are presented, which complement the existing structural information for the system and highlight the critical importance of lipophilic hotspots and water molecules for these peptidergic GPCR targets. Learnings from the structural information regarding the utility of pharmacophore models and how selectivity between OX1 and OX2 can be achieved are discussed.


Asunto(s)
Antagonistas de los Receptores de Orexina/metabolismo , Receptores de Orexina/metabolismo , Sitios de Unión , Simulación por Computador , Cristalografía por Rayos X , Células HEK293 , Humanos , Enlace de Hidrógeno , Interacciones Hidrofóbicas e Hidrofílicas , Ligandos , Antagonistas de los Receptores de Orexina/química , Receptores de Orexina/química
7.
Methods Mol Biol ; 1705: 207-232, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29188565

RESUMEN

The following chapter examines some of the current "state-of-the-art" tools for predicting, scoring, and examining explicit water molecules in proteins and protein/ligand complexes, highlighting some of the ways information can be readily examined in a manner that is useful in a drug discovery process.


Asunto(s)
Modelos Moleculares , Receptores Acoplados a Proteínas G/química , Agua/química , Algoritmos , Descubrimiento de Drogas/métodos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Unión Proteica , Relación Estructura-Actividad Cuantitativa , Programas Informáticos
8.
Nature ; 545(7652): 112-115, 2017 05 04.
Artículo en Inglés | MEDLINE | ID: mdl-28445455

RESUMEN

Protease-activated receptors (PARs) are a family of G-protein-coupled receptors (GPCRs) that are irreversibly activated by proteolytic cleavage of the N terminus, which unmasks a tethered peptide ligand that binds and activates the transmembrane receptor domain, eliciting a cellular cascade in response to inflammatory signals and other stimuli. PARs are implicated in a wide range of diseases, such as cancer and inflammation. PARs have been the subject of major pharmaceutical research efforts but the discovery of small-molecule antagonists that effectively bind them has proved challenging. The only marketed drug targeting a PAR is vorapaxar, a selective antagonist of PAR1 used to prevent thrombosis. The structure of PAR1 in complex with vorapaxar has been reported previously. Despite sequence homology across the PAR isoforms, discovery of PAR2 antagonists has been less successful, although GB88 has been described as a weak antagonist. Here we report crystal structures of PAR2 in complex with two distinct antagonists and a blocking antibody. The antagonist AZ8838 binds in a fully occluded pocket near the extracellular surface. Functional and binding studies reveal that AZ8838 exhibits slow binding kinetics, which is an attractive feature for a PAR2 antagonist competing against a tethered ligand. Antagonist AZ3451 binds to a remote allosteric site outside the helical bundle. We propose that antagonist binding prevents structural rearrangements required for receptor activation and signalling. We also show that a blocking antibody antigen-binding fragment binds to the extracellular surface of PAR2, preventing access of the tethered ligand to the peptide-binding site. These structures provide a basis for the development of selective PAR2 antagonists for a range of therapeutic uses.


Asunto(s)
Receptor PAR-2/química , Receptor PAR-2/metabolismo , Regulación Alostérica/efectos de los fármacos , Sitio Alostérico/efectos de los fármacos , Anticuerpos Bloqueadores/química , Anticuerpos Bloqueadores/farmacología , Bencimidazoles/química , Bencimidazoles/farmacología , Benzodioxoles/química , Benzodioxoles/farmacología , Alcoholes Bencílicos/química , Alcoholes Bencílicos/farmacología , Cristalografía por Rayos X , Humanos , Imidazoles/química , Imidazoles/farmacología , Fragmentos Fab de Inmunoglobulinas/química , Fragmentos Fab de Inmunoglobulinas/farmacología , Cinética , Ligandos , Modelos Moleculares , Receptor PAR-2/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos
9.
Curr Top Med Chem ; 17(1): 71-78, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-27448651

RESUMEN

Class C G protein-coupled receptors encompass a range of promising therapeutic targets for a variety of diseases, yet to date only two members of this sub-family of GPCRs have been drugged. Recent advances in structural biology have revealed the X-ray crystallographic structures of allosteric ligands bound to two Class C metabotropic glutamate (mGlu) receptors, mGlu1 and mGlu5. Herein, we review how this information can be leveraged to help understand some of the historical challenges of mGlu receptor allosteric modulator drug discovery, and discuss how the structural enablement can be prospectively used for structurebased drug discovery approaches across Class C GPCR targets in general.


Asunto(s)
Diseño de Fármacos , Receptores Acoplados a Proteínas G/efectos de los fármacos , Regulación Alostérica , Cristalografía por Rayos X , Conformación Proteica , Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/metabolismo
10.
Curr Opin Pharmacol ; 30: 8-13, 2016 10.
Artículo en Inglés | MEDLINE | ID: mdl-27400445

RESUMEN

Recent developments in receptor stabilisation have facilitated major advances in G protein-coupled receptor (GPCR) research, notably structural biology, over the past eight years. Here we review the application of fragment, structure and biophysical techniques using stabilised GPCRs (StaR proteins), and their impact in the drug discovery process. These techniques have, most recently, been utilised in the discovery of the non-alkyne mGlu5 negative allosteric modulator HTL14242, in addition to the dual orexin receptor antagonist HTL6641, with differentiated residence time kinetics.


Asunto(s)
Diseño de Fármacos , Descubrimiento de Drogas/métodos , Receptores Acoplados a Proteínas G/química , Regulación Alostérica/efectos de los fármacos , Humanos , Antagonistas de los Receptores de Orexina/farmacología , Conformación Proteica , Estabilidad Proteica , Piridinas/farmacología , Pirimidinas/farmacología , Receptor del Glutamato Metabotropico 5/efectos de los fármacos , Receptor del Glutamato Metabotropico 5/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Temperatura
11.
J Chem Inf Model ; 56(4): 642-51, 2016 04 25.
Artículo en Inglés | MEDLINE | ID: mdl-26958710

RESUMEN

Virtual screening is routinely used to discover new ligands and in particular new ligand chemotypes for G protein-coupled receptors (GPCRs). To prepare for a virtual screen, we often tailor a docking protocol that will enable us to select the best candidates for further screening. To aid this, we created GPCR-Bench, a publically available docking benchmarking set in the spirit of the DUD and DUD-E reference data sets for validation studies, containing 25 nonredundant high-resolution GPCR costructures with an accompanying set of diverse ligands and computational decoy molecules for each target. Benchmarking sets are often used to compare docking protocols; however, it is important to evaluate docking methods not by "retrospective" hit rates but by the actual likelihood that they will produce novel prospective hits. Therefore, docking protocols must not only rank active molecules highly but also produce good poses that a chemist will select for purchase and screening. Currently, no simple objective machine-scriptable function exists that can do this; instead, docking hit lists must be subjectively examined in a consistent way to compare between docking methods. We present here a case study highlighting considerations we feel are of importance when evaluating a method, intended to be useful as a practitioners' guide.


Asunto(s)
Simulación del Acoplamiento Molecular , Receptores de Adenosina A2/química , Receptores de Adenosina A2/metabolismo , Benchmarking , Bases de Datos de Proteínas , Evaluación Preclínica de Medicamentos , Ligandos , Conformación Proteica , Interfaz Usuario-Computador , Agua/metabolismo
12.
Sci Rep ; 5: 13869, 2015 Sep 11.
Artículo en Inglés | MEDLINE | ID: mdl-26359761

RESUMEN

The metabotropic glutamate receptors have a wide range of modulatory functions in the central nervous system. They are among the most highly pursued drug targets, with relevance for several neurological diseases, and a number of allosteric modulators have entered clinical trials. However, so far this has not led to a marketed drug, largely because of the difficulties in achieving subtype-selective compounds with desired properties. Very recently the first crystal structures were published for the transmembrane domain of two metabotropic glutamate receptors in complex with negative allosteric modulators. In this analysis, we make the first comprehensive structural comparison of all metabotropic glutamate receptors, placing selective negative allosteric modulators and critical mutants into the detailed context of the receptor binding sites. A better understanding of how the different mGlu allosteric modulator binding modes relates to selective pharmacological actions will be very valuable for rational design of safer drugs.


Asunto(s)
Ligandos , Mutación , Receptores de Glutamato Metabotrópico/química , Receptores de Glutamato Metabotrópico/genética , Regulación Alostérica , Sitio Alostérico , Sitios de Unión , Humanos , Modelos Moleculares , Conformación Molecular , Unión Proteica , Receptores de Glutamato Metabotrópico/metabolismo , Relación Estructura-Actividad
13.
J Med Chem ; 58(16): 6653-64, 2015 Aug 27.
Artículo en Inglés | MEDLINE | ID: mdl-26225459

RESUMEN

Fragment screening of a thermostabilized mGlu5 receptor using a high-concentration radioligand binding assay enabled the identification of moderate affinity, high ligand efficiency (LE) pyrimidine hit 5. Subsequent optimization using structure-based drug discovery methods led to the selection of 25, HTL14242, as an advanced lead compound for further development. Structures of the stabilized mGlu5 receptor complexed with 25 and another molecule in the series, 14, were determined at resolutions of 2.6 and 3.1 Å, respectively.


Asunto(s)
Piridinas/síntesis química , Piridinas/farmacología , Pirimidinas/síntesis química , Pirimidinas/farmacología , Receptor del Glutamato Metabotropico 5/efectos de los fármacos , Receptores Acoplados a Proteínas G/efectos de los fármacos , Regulación Alostérica , Animales , Células CACO-2 , Perros , Diseño de Fármacos , Descubrimiento de Drogas , Células HEK293 , Humanos , Ligandos , Modelos Moleculares , Conformación Molecular , Piridinas/farmacocinética , Pirimidinas/farmacocinética , Ratas , Relación Estructura-Actividad
14.
Br J Pharmacol ; 171(13): 3132-45, 2014 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-24628305

RESUMEN

Class B GPCRs of the secretin family are important drug targets in many human diseases including diabetes, neurodegeneration, cardiovascular disease and psychiatric disorders. X-ray crystal structures for the glucagon receptor and corticotropin-releasing factor receptor 1 have now been published. In this review, we analyse the new structures and how they compare with each other and with Class A and F receptors. We also consider the differences in druggability and possible similarity in the activation mechanisms. Finally, we discuss the potential for the design of small-molecule modulators for these important targets in drug discovery. This new structural insight allows, for the first time, structure-based drug design methods to be applied to Class B GPCRs.


Asunto(s)
Diseño de Fármacos , Receptores Acoplados a Proteínas G/química , Receptores de la Hormona Gastrointestinal/química , Animales , Cristalografía por Rayos X , Descubrimiento de Drogas/métodos , Humanos , Terapia Molecular Dirigida , Conformación Proteica , Receptores de Hormona Liberadora de Corticotropina/química , Receptores Acoplados a Proteínas G/efectos de los fármacos , Receptores Acoplados a Proteínas G/metabolismo , Receptores de la Hormona Gastrointestinal/efectos de los fármacos , Receptores de la Hormona Gastrointestinal/metabolismo , Receptores de Glucagón/química
15.
Pharmacol Ther ; 143(1): 51-60, 2014 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-24561131

RESUMEN

Several new pairs of active and inactive GPCR structures have recently been solved enabling detailed structural insight into the activation process, not only of rhodopsin but now also of the ß2 adrenergic, M2 muscarinic and adenosine A2A receptors. Combined with structural analyses they have enabled us to examine the different recent theories proposed for GPCR activation and show that they are all indeed parts of the same process, and are intrinsically related through their effect on the central hydrophobic core of GPCRs. This new unifying general process of activation is consistent with the identification of known constitutively active mutants and an in-depth conservational analysis of significant residues implicated in the process.


Asunto(s)
Receptores Acoplados a Proteínas G/fisiología , Animales , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Receptores Acoplados a Proteínas G/química , Relación Estructura-Actividad
16.
J Med Chem ; 56(9): 3446-55, 2013 May 09.
Artículo en Inglés | MEDLINE | ID: mdl-23517028

RESUMEN

Biophysical fragment screening of a thermostabilized ß1-adrenergic receptor (ß1AR) using surface plasmon resonance (SPR) enabled the identification of moderate affinity, high ligand efficiency (LE) arylpiperazine hits 7 and 8. Subsequent hit to lead follow-up confirmed the activity of the chemotype, and a structure-based design approach using protein-ligand crystal structures of the ß1AR resulted in the identification of several fragments that bound with higher affinity, including indole 19 and quinoline 20. In the first example of GPCR crystallography with ligands derived from fragment screening, structures of the stabilized ß1AR complexed with 19 and 20 were determined at resolutions of 2.8 and 2.7 Å, respectively.


Asunto(s)
Fenómenos Biofísicos , Diseño de Fármacos , Piperazinas/química , Piperazinas/metabolismo , Receptores Adrenérgicos beta 1/metabolismo , Evaluación Preclínica de Medicamentos , Células HEK293 , Humanos , Simulación del Acoplamiento Molecular , Piperazina , Unión Proteica , Conformación Proteica , Receptores Adrenérgicos beta 1/química , Resonancia por Plasmón de Superficie
17.
Mol Pharmacol ; 83(5): 949-58, 2013 May.
Artículo en Inglés | MEDLINE | ID: mdl-23429888

RESUMEN

Using isolated receptor conformations crystal structures of the adenosine A2A receptor have been solved in active and inactive states. Studying the change in affinity of ligands at these conformations allowed qualitative prediction of compound efficacy in vitro in a system-independent manner. Agonist 5'-N-ethylcarboxamidoadenosine displayed a clear preference to bind to the active state receptor; inverse agonists (xanthine amine congener, ZM241385, SCH58261, and preladenant) bound preferentially to the inactive state, whereas neutral antagonists (theophylline, caffeine, and istradefylline) demonstrated equal affinity for active and inactive states. Ligand docking into the known crystal structures of the A2A receptor rationalized the pharmacology observed; inverse agonists, unlike neutral antagonists, cannot be accommodated within the agonist-binding site of the receptor. The availability of isolated receptor conformations opens the door to the concept of "reverse pharmacology" whereby the functional pharmacology of ligands can be characterized in a system-independent manner by their affinity for a pair (or set) of G protein-coupled receptor conformations.


Asunto(s)
Agonistas del Receptor de Adenosina A2/farmacología , Antagonistas del Receptor de Adenosina A2/farmacología , Receptor de Adenosina A2A/química , Receptor de Adenosina A2A/metabolismo , Animales , Sitios de Unión , Células CHO , Línea Celular , Cricetinae , Ligandos , Conformación Molecular , Receptores Acoplados a Proteínas G/metabolismo , Relación Estructura-Actividad
18.
J Med Chem ; 55(5): 1898-903, 2012 Mar 08.
Artículo en Inglés | MEDLINE | ID: mdl-22220592

RESUMEN

Potent, ligand efficient, selective, and orally efficacious 1,2,4-triazine derivatives have been identified using structure based drug design approaches as antagonists of the adenosine A(2A) receptor. The X-ray crystal structures of compounds 4e and 4g bound to the GPCR illustrate that the molecules bind deeply inside the orthosteric binding cavity. In vivo pharmacokinetic and efficacy data for compound 4k are presented, demonstrating the potential of this series of compounds for the treatment of Parkinson's disease.


Asunto(s)
Antagonistas del Receptor de Adenosina A2/síntesis química , Antiparkinsonianos/síntesis química , Piridinas/síntesis química , Receptor de Adenosina A2A/metabolismo , Triazinas/síntesis química , Antagonistas del Receptor de Adenosina A2/farmacocinética , Antagonistas del Receptor de Adenosina A2/farmacología , Administración Oral , Animales , Antiparkinsonianos/farmacocinética , Antiparkinsonianos/farmacología , Cristalografía por Rayos X , Diseño de Fármacos , Humanos , Modelos Moleculares , Conformación Proteica , Piridinas/farmacocinética , Piridinas/farmacología , Ensayo de Unión Radioligante , Ratas , Relación Estructura-Actividad , Resonancia por Plasmón de Superficie , Triazinas/farmacocinética , Triazinas/farmacología
19.
J Med Chem ; 54(13): 4312-23, 2011 Jul 14.
Artículo en Inglés | MEDLINE | ID: mdl-21661720

RESUMEN

A new approach to generating information on ligand receptor interactions within the binding pocket of G protein-coupled receptors has been developed, called Biophysical Mapping (BPM). Starting from a stabilized receptor (StaR), minimally engineered for thermostability, additional single mutations are then added at positions that could be involved in small molecule interactions. The StaR and a panel of binding site mutants are captured onto Biacore chips to enable characterization of the binding of small molecule ligands using surface plasmon resonance (SPR) measurement. A matrix of binding data for a set of ligands versus each active site mutation is then generated, providing specific affinity and kinetic information (K(D), k(on), and k(off)) of receptor-ligand interactions. This data set, in combination with molecular modeling and docking, is used to map the small molecule binding site for each class of compounds. Taken together, the many constraints provided by these data identify key protein-ligand interactions and allow the shape of the site to be refined to produce a high quality three-dimensional picture of ligand binding, thereby facilitating structure based drug design. Results of biophysical mapping of the adenosine A(2A) receptor are presented.


Asunto(s)
Antagonistas del Receptor de Adenosina A2/química , Diseño de Fármacos , Modelos Moleculares , Receptor de Adenosina A2A/química , Sitios de Unión/genética , Ligandos , Mutación , Pirimidinas/química , Receptor de Adenosina A2A/genética , Bibliotecas de Moléculas Pequeñas , Triazinas/química , Triazoles/química , Xantinas/química
20.
Antivir Ther ; 9(2): 149-60, 2004 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-15134177

RESUMEN

The antiviral treatment of chronic hepatitis B is limited by the selection of antiviral resistance mutations. Primary resistance to lamivudine occurs at rtM2041/V in the C Domain of the polymerase. Recently, resistance to adefovir has also been described in the D Domain at rtN236T. The treatment of patients with resistant virus without complete suppression can lead to the further selection of compensatory mutations. Thus, to gain an understanding of the hepatitis B virus (HBV) polymerase and also mutations associated with resistance, a three-dimensional model of the HBV reverse transcriptase core region based on homology with human immunodeficiency virus (HIV) was created. A comparative analysis of the HIV polymerase and the model of HBV polymerase was performed. In addition, the antiviral resistance mutations including potential compensatory mutations were mapped to determine their effect on the HBV polymerase model, especially in the nucleotide binding site.


Asunto(s)
Farmacorresistencia Viral , Transcriptasa Inversa del VIH/química , Virus de la Hepatitis B/enzimología , Mutación , ADN Polimerasa Dirigida por ARN/química , Secuencia de Aminoácidos , Animales , Antivirales/farmacología , Secuencia de Bases , Transcriptasa Inversa del VIH/genética , Virus de la Hepatitis B/efectos de los fármacos , Virus de la Hepatitis B/genética , Hepatitis B Crónica/virología , Humanos , Modelos Moleculares , Datos de Secuencia Molecular , ADN Polimerasa Dirigida por ARN/genética
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