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1.
Annu Rev Biochem ; 93(1): 389-410, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38594926

RESUMEN

Molecular docking has become an essential part of a structural biologist's and medicinal chemist's toolkits. Given a chemical compound and the three-dimensional structure of a molecular target-for example, a protein-docking methods fit the compound into the target, predicting the compound's bound structure and binding energy. Docking can be used to discover novel ligands for a target by screening large virtual compound libraries. Docking can also provide a useful starting point for structure-based ligand optimization or for investigating a ligand's mechanism of action. Advances in computational methods, including both physics-based and machine learning approaches, as well as in complementary experimental techniques, are making docking an even more powerful tool. We review how docking works and how it can drive drug discovery and biological research. We also describe its current limitations and ongoing efforts to overcome them.


Asunto(s)
Descubrimiento de Drogas , Simulación del Acoplamiento Molecular , Unión Proteica , Proteínas , Ligandos , Descubrimiento de Drogas/métodos , Humanos , Proteínas/química , Proteínas/metabolismo , Aprendizaje Automático , Sitios de Unión , Diseño de Fármacos
2.
Cell ; 187(3): 521-525, 2024 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-38306979

RESUMEN

High-quality predicted structures enable structure-based approaches to an expanding number of drug discovery programs. We propose that by utilizing free energy perturbation (FEP), predicted structures can be confidently employed to achieve drug design goals. We use structure-based modeling of hERG inhibition to illustrate this value of FEP.


Asunto(s)
Diseño de Fármacos , Descubrimiento de Drogas , Termodinámica , Entropía
3.
Cell ; 187(9): 2194-2208.e22, 2024 Apr 25.
Artículo en Inglés | MEDLINE | ID: mdl-38552625

RESUMEN

Effective treatments for complex central nervous system (CNS) disorders require drugs with polypharmacology and multifunctionality, yet designing such drugs remains a challenge. Here, we present a flexible scaffold-based cheminformatics approach (FSCA) for the rational design of polypharmacological drugs. FSCA involves fitting a flexible scaffold to different receptors using different binding poses, as exemplified by IHCH-7179, which adopted a "bending-down" binding pose at 5-HT2AR to act as an antagonist and a "stretching-up" binding pose at 5-HT1AR to function as an agonist. IHCH-7179 demonstrated promising results in alleviating cognitive deficits and psychoactive symptoms in mice by blocking 5-HT2AR for psychoactive symptoms and activating 5-HT1AR to alleviate cognitive deficits. By analyzing aminergic receptor structures, we identified two featured motifs, the "agonist filter" and "conformation shaper," which determine ligand binding pose and predict activity at aminergic receptors. With these motifs, FSCA can be applied to the design of polypharmacological ligands at other receptors.


Asunto(s)
Quimioinformática , Diseño de Fármacos , Polifarmacología , Animales , Ratones , Humanos , Quimioinformática/métodos , Ligandos , Receptor de Serotonina 5-HT2A/metabolismo , Receptor de Serotonina 5-HT2A/química , Receptor de Serotonina 5-HT1A/metabolismo , Receptor de Serotonina 5-HT1A/química , Masculino , Sitios de Unión
4.
Cell ; 187(6): 1460-1475.e20, 2024 Mar 14.
Artículo en Inglés | MEDLINE | ID: mdl-38428423

RESUMEN

Apelin is a key hormone in cardiovascular homeostasis that activates the apelin receptor (APLNR), which is regarded as a promising therapeutic target for cardiovascular disease. However, adverse effects through the ß-arrestin pathway limit its pharmacological use. Here, we report cryoelectron microscopy (cryo-EM) structures of APLNR-Gi1 complexes bound to three agonists with divergent signaling profiles. Combined with functional assays, we have identified "twin hotspots" in APLNR as key determinants for signaling bias, guiding the rational design of two exclusive G-protein-biased agonists WN353 and WN561. Cryo-EM structures of WN353- and WN561-stimulated APLNR-G protein complexes further confirm that the designed ligands adopt the desired poses. Pathophysiological experiments have provided evidence that WN561 demonstrates superior therapeutic effects against cardiac hypertrophy and reduced adverse effects compared with the established APLNR agonists. In summary, our designed APLNR modulator may facilitate the development of next-generation cardiovascular medications.


Asunto(s)
Receptores de Apelina , Fármacos Cardiovasculares , Diseño de Fármacos , Receptores de Apelina/agonistas , Receptores de Apelina/química , Receptores de Apelina/ultraestructura , Microscopía por Crioelectrón , Proteínas de Unión al GTP/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Transducción de Señal , Humanos , Fármacos Cardiovasculares/química
5.
Cell ; 185(19): 3533-3550.e27, 2022 09 15.
Artículo en Inglés | MEDLINE | ID: mdl-36113427

RESUMEN

Integrins are validated drug targets with six approved therapeutics. However, small-molecule inhibitors to three integrins failed in late-stage clinical trials for chronic indications. Such unfavorable outcomes may in part be caused by partial agonism, i.e., the stabilization of the high-affinity, extended-open integrin conformation. Here, we show that the failed, small-molecule inhibitors of integrins αIIbß3 and α4ß1 stabilize the high-affinity conformation. Furthermore, we discovered a simple chemical feature present in multiple αIIbß3 antagonists that stabilizes integrins in their bent-closed conformation. Closing inhibitors contain a polar nitrogen atom that stabilizes, via hydrogen bonds, a water molecule that intervenes between a serine residue and the metal in the metal-ion-dependent adhesion site (MIDAS). Expulsion of this water is a requisite for transition to the open conformation. This change in metal coordination is general to integrins, suggesting broad applicability of the drug-design principle to the integrin family, as validated with a distantly related integrin, α4ß1.


Asunto(s)
Diseño de Fármacos , Integrina alfa4beta1 , Conformación Proteica , Serina , Agua
6.
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
7.
Cell ; 181(1): 151-167, 2020 04 02.
Artículo en Inglés | MEDLINE | ID: mdl-32243788

RESUMEN

Off-target effects of systemically administered drugs have been a major hurdle in designing therapies with desired efficacy and acceptable toxicity. Developing targeting strategies to enable site-specific drug delivery holds promise in reducing off-target effects, decreasing unwanted toxicities, and thereby enhancing a drug's therapeutic efficacy. Over the past three decades, a large body of literature has focused on understanding the biological barriers that hinder tissue-specific drug delivery and strategies to overcome them. These efforts have led to several targeting strategies that modulate drug delivery in both the preclinical and clinical settings, including small molecule-, nucleic acid-, peptide-, antibody-, and cell-based strategies. Here, we discuss key advances and emerging concepts for tissue-specific drug delivery approaches and their clinical translation.


Asunto(s)
Sistemas de Liberación de Medicamentos , Diseño de Fármacos , Preparaciones Farmacéuticas/química , Humanos
8.
Cell ; 181(1): 81-91, 2020 04 02.
Artículo en Inglés | MEDLINE | ID: mdl-32243800

RESUMEN

Structures of 70 unique G protein-coupled receptors (GPCRs) have been determined, with over 370 structures in total bound to different ligands and the receptors in various conformational states. Structure-based drug design has been applied to an increasing number of GPCR targets over the past decade and now a few of these drug candidates have entered clinical trials. Given the length of time required for a drug to reach the market, there are no documented examples of licensed drugs being developed with the aid of a structure, but this is likely to change as current efforts come to fruition.


Asunto(s)
Diseño de Fármacos , Descubrimiento de Drogas , Receptores Acoplados a Proteínas G/química , Humanos , Ligandos , Conformación Molecular , Estructura Molecular
9.
Nat Rev Mol Cell Biol ; 23(1): 21-39, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34824452

RESUMEN

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has killed millions of people and continues to cause massive global upheaval. Coronaviruses are positive-strand RNA viruses with an unusually large genome of ~30 kb. They express an RNA-dependent RNA polymerase and a cohort of other replication enzymes and supporting factors to transcribe and replicate their genomes. The proteins performing these essential processes are prime antiviral drug targets, but drug discovery is hindered by our incomplete understanding of coronavirus RNA synthesis and processing. In infected cells, the RNA-dependent RNA polymerase must coordinate with other viral and host factors to produce both viral mRNAs and new genomes. Recent research aiming to decipher and contextualize the structures, functions and interplay of the subunits of the SARS-CoV-2 replication and transcription complex proteins has burgeoned. In this Review, we discuss recent advancements in our understanding of the molecular basis and complexity of the coronavirus RNA-synthesizing machinery. Specifically, we outline the mechanisms and regulation of RNA translation, replication and transcription. We also discuss the composition of the replication and transcription complexes and their suitability as targets for antiviral therapy.


Asunto(s)
Antivirales/farmacología , Diseño de Fármacos , SARS-CoV-2/genética , SARS-CoV-2/fisiología , Transcripción Genética , Replicación Viral/fisiología , Animales , Humanos , ARN Viral/metabolismo , Transcripción Genética/efectos de los fármacos , Replicación Viral/efectos de los fármacos
10.
Cell ; 176(3): 459-467.e13, 2019 01 24.
Artículo en Inglés | MEDLINE | ID: mdl-30639103

RESUMEN

The cannabinoid receptor CB2 is predominately expressed in the immune system, and selective modulation of CB2 without the psychoactivity of CB1 has therapeutic potential in inflammatory, fibrotic, and neurodegenerative diseases. Here, we report the crystal structure of human CB2 in complex with a rationally designed antagonist, AM10257, at 2.8 Å resolution. The CB2-AM10257 structure reveals a distinctly different binding pose compared with CB1. However, the extracellular portion of the antagonist-bound CB2 shares a high degree of conformational similarity with the agonist-bound CB1, which led to the discovery of AM10257's unexpected opposing functional profile of CB2 antagonism versus CB1 agonism. Further structural analysis using mutagenesis studies and molecular docking revealed the molecular basis of their function and selectivity for CB2 and CB1. Additional analyses of our designed antagonist and agonist pairs provide important insight into the activation mechanism of CB2. The present findings should facilitate rational drug design toward precise modulation of the endocannabinoid system.


Asunto(s)
Receptor Cannabinoide CB2/metabolismo , Receptor Cannabinoide CB2/ultraestructura , Animales , Antagonistas de Receptores de Cannabinoides/farmacología , Cannabinoides/farmacología , Diseño de Fármacos , Endocannabinoides , Humanos , Ligandos , Simulación del Acoplamiento Molecular , Unión Proteica , Receptor Cannabinoide CB1/antagonistas & inhibidores , Receptor Cannabinoide CB2/química , Receptores de Cannabinoides/química , Receptores de Cannabinoides/metabolismo , Receptores de Cannabinoides/ultraestructura , Receptores Acoplados a Proteínas G/metabolismo , Células Sf9 , Relación Estructura-Actividad
11.
Cell ; 176(3): 636-648.e13, 2019 01 24.
Artículo en Inglés | MEDLINE | ID: mdl-30682372

RESUMEN

Despite intensive efforts to discover highly effective treatments to eradicate tuberculosis (TB), it remains as a major threat to global human health. For this reason, new TB drugs directed toward new targets are highly coveted. MmpLs (Mycobacterial membrane proteins Large), which play crucial roles in transporting lipids, polymers and immunomodulators and which also extrude therapeutic drugs, are among the most important therapeutic drug targets to emerge in recent times. Here, crystal structures of mycobacterial MmpL3 alone and in complex with four TB drug candidates, including SQ109 (in Phase 2b-3 clinical trials), are reported. MmpL3 consists of a periplasmic pore domain and a twelve-helix transmembrane domain. Two Asp-Tyr pairs centrally located in this domain appear to be key facilitators of proton-translocation. SQ109, AU1235, ICA38, and rimonabant bind inside the transmembrane region and disrupt these Asp-Tyr pairs. This structural data will greatly advance the development of MmpL3 inhibitors as new TB drugs.


Asunto(s)
Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/ultraestructura , Proteínas de Transporte de Membrana/metabolismo , Proteínas de Transporte de Membrana/ultraestructura , Adamantano/análogos & derivados , Adamantano/metabolismo , Antituberculosos/química , Transporte Biológico , Sistemas de Liberación de Medicamentos , Diseño de Fármacos , Etilenodiaminas/metabolismo , Humanos , Proteínas de la Membrana/metabolismo , Pruebas de Sensibilidad Microbiana , Mycobacterium tuberculosis/metabolismo , Mycobacterium tuberculosis/ultraestructura , Compuestos de Fenilurea/metabolismo , Rimonabant/metabolismo , Tuberculosis/microbiología
12.
Annu Rev Biochem ; 87: 105-129, 2018 06 20.
Artículo en Inglés | MEDLINE | ID: mdl-29401000

RESUMEN

Proteins are increasingly used in basic and applied biomedical research. Many proteins, however, are only marginally stable and can be expressed in limited amounts, thus hampering research and applications. Research has revealed the thermodynamic, cellular, and evolutionary principles and mechanisms that underlie marginal stability. With this growing understanding, computational stability design methods have advanced over the past two decades starting from methods that selectively addressed only some aspects of marginal stability. Current methods are more general and, by combining phylogenetic analysis with atomistic design, have shown drastic improvements in solubility, thermal stability, and aggregation resistance while maintaining the protein's primary molecular activity. Stability design is opening the way to rational engineering of improved enzymes, therapeutics, and vaccines and to the application of protein design methodology to large proteins and molecular activities that have proven challenging in the past.


Asunto(s)
Proteínas/química , Proteínas/metabolismo , Animales , Evolución Molecular Dirigida/métodos , Diseño de Fármacos , Humanos , Modelos Moleculares , Filogenia , Agregado de Proteínas , Ingeniería de Proteínas/métodos , Pliegue de Proteína , Estabilidad Proteica , Proteínas/genética , Termodinámica
13.
Annu Rev Biochem ; 87: 159-185, 2018 06 20.
Artículo en Inglés | MEDLINE | ID: mdl-29589959

RESUMEN

Flavin-dependent halogenases (FDHs) catalyze the halogenation of organic substrates by coordinating reactions of reduced flavin, molecular oxygen, and chloride. Targeted and random mutagenesis of these enzymes have been used to both understand and alter their reactivity. These studies have led to insights into residues essential for catalysis and FDH variants with improved stability, expanded substrate scope, and altered site selectivity. Mutations throughout FDH structures have contributed to all of these advances. More recent studies have sought to rationalize the impact of these mutations on FDH function and to identify new FDHs to deepen our understanding of this enzyme class and to expand their utility for biocatalytic applications.


Asunto(s)
Flavinas/metabolismo , Halogenación/genética , Halogenación/fisiología , Oxidorreductasas/genética , Oxidorreductasas/metabolismo , Biocatálisis , Dominio Catalítico/genética , Evolución Molecular Dirigida , Diseño de Fármacos , Estabilidad de Enzimas/genética , Hidrocarburos Halogenados/química , Hidrocarburos Halogenados/metabolismo , Redes y Vías Metabólicas , Modelos Moleculares , Mutagénesis , Oxidorreductasas/química , Especificidad por Sustrato
14.
Annu Rev Biochem ; 87: 131-157, 2018 06 20.
Artículo en Inglés | MEDLINE | ID: mdl-29494241

RESUMEN

Directed evolution is a powerful technique for generating tailor-made enzymes for a wide range of biocatalytic applications. Following the principles of natural evolution, iterative cycles of mutagenesis and screening or selection are applied to modify protein properties, enhance catalytic activities, or develop completely new protein catalysts for non-natural chemical transformations. This review briefly surveys the experimental methods used to generate genetic diversity and screen or select for improved enzyme variants. Emphasis is placed on a key challenge, namely how to generate novel catalytic activities that expand the scope of natural reactions. Two particularly effective strategies, exploiting catalytic promiscuity and rational design, are illustrated by representative examples of successfully evolved enzymes. Opportunities for extending these approaches to more complex biocatalytic systems are also considered.


Asunto(s)
Evolución Molecular Dirigida/métodos , Enzimas/genética , Enzimas/metabolismo , Animales , Biocatálisis , Diseño de Fármacos , Enzimas/química , Variación Genética , Ensayos Analíticos de Alto Rendimiento , Humanos , Redes y Vías Metabólicas/genética , Modelos Moleculares , Ingeniería de Proteínas/métodos , Proteínas/química , Proteínas/genética , Proteínas/metabolismo , Selección Genética , Estereoisomerismo , Especificidad por Sustrato
15.
Annu Rev Biochem ; 87: 451-478, 2018 06 20.
Artículo en Inglés | MEDLINE | ID: mdl-29570352

RESUMEN

Genetic information is translated into proteins by the ribosome. Structural studies of the ribosome and of its complexes with factors and inhibitors have provided invaluable information on the mechanism of protein synthesis. Ribosome inhibitors are among the most successful antimicrobial drugs and constitute more than half of all medicines used to treat infections. However, bacterial infections are becoming increasingly difficult to treat because the microbes have developed resistance to the most effective antibiotics, creating a major public health care threat. This has spurred a renewed interest in structure-function studies of protein synthesis inhibitors, and in few cases, compounds have been developed into potent therapeutic agents against drug-resistant pathogens. In this review, we describe the modes of action of many ribosome-targeting antibiotics, highlight the major resistance mechanisms developed by pathogenic bacteria, and discuss recent advances in structure-assisted design of new molecules.


Asunto(s)
Antibacterianos/farmacología , Ribosomas/efectos de los fármacos , Animales , Antibacterianos/química , Péptidos Catiónicos Antimicrobianos/química , Péptidos Catiónicos Antimicrobianos/farmacología , Sitios de Unión , Diseño de Fármacos , Farmacorresistencia Microbiana , Humanos , Modelos Biológicos , Modelos Moleculares , Biosíntesis de Proteínas/efectos de los fármacos , Inhibidores de la Síntesis de la Proteína/química , Inhibidores de la Síntesis de la Proteína/farmacología , Ribosomas/química , Ribosomas/metabolismo , Relación Estructura-Actividad
16.
Cell ; 172(6): 1319-1334, 2018 03 08.
Artículo en Inglés | MEDLINE | ID: mdl-29522750

RESUMEN

Enveloped viruses enter cells by inducing fusion of viral and cellular membranes, a process catalyzed by a specialized membrane-fusion protein expressed on their surface. This review focuses on recent structural studies of viral fusion proteins with an emphasis on their metastable prefusion form and on interactions with neutralizing antibodies. The fusion glycoproteins have been difficult to study because they are present in a labile, metastable form at the surface of infectious virions. Such metastability is a functional requirement, allowing these proteins to refold into a lower energy conformation while transferring the difference in energy to catalyze the membrane fusion reaction. Structural studies have shown that stable immunogens presenting the same antigenic sites as the labile wild-type proteins efficiently elicit potently neutralizing antibodies, providing a framework with which to engineer the antigens for stability, as well as identifying key vulnerability sites that can be used in next-generation subunit vaccine design.


Asunto(s)
Vacunas Sintéticas/inmunología , Vacunas Virales/inmunología , Virosis/inmunología , Virus/inmunología , Animales , Diseño de Fármacos , Interacciones Huésped-Patógeno/inmunología , Humanos , Proteínas del Envoltorio Viral/inmunología , Proteínas Virales de Fusión/inmunología , Proteínas Virales de Fusión/metabolismo , Virosis/virología , Virus/metabolismo
17.
Annu Rev Biochem ; 86: 567-583, 2017 06 20.
Artículo en Inglés | MEDLINE | ID: mdl-28654325

RESUMEN

Multidrug resistance is a global threat as the clinically available potent antibiotic drugs are becoming exceedingly scarce. For example, increasing drug resistance among gram-positive bacteria is responsible for approximately one-third of nosocomial infections. As ribosomes are a major target for these drugs, they may serve as suitable objects for novel development of next-generation antibiotics. Three-dimensional structures of ribosomal particles from Staphylococcus aureus obtained by X-ray crystallography have shed light on fine details of drug binding sites and have revealed unique structural motifs specific for this pathogenic strain, which may be used for the design of novel degradable pathogen-specific, and hence, environmentally friendly drugs.


Asunto(s)
Antibacterianos/síntesis química , Proteínas Bacterianas/química , Diseño de Fármacos , Ribosomas/efectos de los fármacos , Staphylococcus aureus/efectos de los fármacos , Antibacterianos/metabolismo , Antibacterianos/farmacología , Proteínas Bacterianas/antagonistas & inhibidores , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Sitios de Unión , Infección Hospitalaria/tratamiento farmacológico , Infección Hospitalaria/microbiología , Cristalografía por Rayos X , Deinococcus/efectos de los fármacos , Deinococcus/genética , Deinococcus/metabolismo , Farmacorresistencia Bacteriana Múltiple , Escherichia coli/efectos de los fármacos , Escherichia coli/genética , Escherichia coli/metabolismo , Expresión Génica , Humanos , Modelos Moleculares , Ribosomas/metabolismo , Ribosomas/ultraestructura , Infecciones Estafilocócicas/tratamiento farmacológico , Infecciones Estafilocócicas/microbiología , Staphylococcus aureus/genética , Staphylococcus aureus/metabolismo , Thermus thermophilus/efectos de los fármacos , Thermus thermophilus/genética , Thermus thermophilus/metabolismo
18.
Annu Rev Immunol ; 28: 413-44, 2010.
Artículo en Inglés | MEDLINE | ID: mdl-20192810

RESUMEN

Licensed vaccines against viral diseases generate antibodies that neutralize the infecting virus and protect against infection or disease. Similarly, an effective vaccine against HIV-1 will likely need to induce antibodies that prevent initial infection of host cells or that limit early events of viral dissemination. Such antibodies must target the surface envelope glycoproteins of HIV-1, which are highly variable in sequence and structure. The first subunit vaccines to enter clinical trails were safe and immunogenic but unable to elicit antibodies that neutralized most circulating strains of HIV-1. However, potent virus neutralizing antibodies (NAbs) can develop during the course of HIV-1 infection, and this is the type of antibody response that researchers seek to generate with a vaccine. Thus, current vaccine design efforts have focused on a more detailed understanding of these broadly neutralizing antibodies and their epitopes to inform the design of improved vaccines.


Asunto(s)
Vacunas contra el SIDA/inmunología , Anticuerpos Anti-VIH/inmunología , Animales , Anticuerpos Neutralizantes/inmunología , Diseño de Fármacos , Epítopos/inmunología , Humanos
19.
Cell ; 168(5): 867-877.e13, 2017 02 23.
Artículo en Inglés | MEDLINE | ID: mdl-28235198

RESUMEN

The adenosine A1 receptor (A1-AR) is a G-protein-coupled receptor that plays a vital role in cardiac, renal, and neuronal processes but remains poorly targeted by current drugs. We determined a 3.2 Å crystal structure of the A1-AR bound to the selective covalent antagonist, DU172, and identified striking differences to the previously solved adenosine A2A receptor (A2A-AR) structure. Mutational and computational analysis of A1-AR revealed a distinct conformation of the second extracellular loop and a wider extracellular cavity with a secondary binding pocket that can accommodate orthosteric and allosteric ligands. We propose that conformational differences in these regions, rather than amino-acid divergence, underlie drug selectivity between these adenosine receptor subtypes. Our findings provide a molecular basis for AR subtype selectivity with implications for understanding the mechanisms governing allosteric modulation of these receptors, allowing the design of more selective agents for the treatment of ischemia-reperfusion injury, renal pathologies, and neuropathic pain.


Asunto(s)
Receptor de Adenosina A1/química , Agonistas del Receptor de Adenosina A1/química , Antagonistas del Receptor de Adenosina A1/química , Sitio Alostérico , Cristalografía por Rayos X , Diseño de Fármacos , Humanos , Receptor de Adenosina A1/genética , Receptor de Adenosina A2A/química
20.
Cell ; 170(2): 249-259.e25, 2017 Jul 13.
Artículo en Inglés | MEDLINE | ID: mdl-28669536

RESUMEN

Widespread resistance to first-line TB drugs is a major problem that will likely only be resolved through the development of new drugs with novel mechanisms of action. We have used structure-guided methods to develop a lead molecule that targets the thioesterase activity of polyketide synthase Pks13, an essential enzyme that forms mycolic acids, required for the cell wall of Mycobacterium tuberculosis. Our lead, TAM16, is a benzofuran class inhibitor of Pks13 with highly potent in vitro bactericidal activity against drug-susceptible and drug-resistant clinical isolates of M. tuberculosis. In multiple mouse models of TB infection, TAM16 showed in vivo efficacy equal to the first-line TB drug isoniazid, both as a monotherapy and in combination therapy with rifampicin. TAM16 has excellent pharmacological and safety profiles, and the frequency of resistance for TAM16 is ∼100-fold lower than INH, suggesting that it can be developed as a new antitubercular aimed at the acute infection. PAPERCLIP.


Asunto(s)
Antituberculosos/farmacología , Benzofuranos/farmacología , Diseño de Fármacos , Farmacorresistencia Bacteriana , Mycobacterium tuberculosis/efectos de los fármacos , Piperidinas/farmacología , Tuberculosis/microbiología , Animales , Antituberculosos/química , Benzofuranos/química , Benzofuranos/farmacocinética , Línea Celular , Femenino , Ratones , Ratones Endogámicos BALB C , Modelos Moleculares , Piperidinas/química , Piperidinas/farmacocinética , Organismos Libres de Patógenos Específicos
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