RESUMO
In structure-based drug design, the basic goal is to design molecules that fit complementarily to a given binding pocket. Since such computationally modeled molecules may not adopt the intended bound conformation outside the binding pocket, one challenge is to ensure that the designed ligands adopt similar low energy conformations both inside and outside of the binding pocket. Computational chemistry methods and conformational preferences of small molecules from PDB and Cambridge Structural Database (CSD) can be used to predict the bound structures of the designed molecules. Herein, we review applications of conformational control in structure-based drug design using selected examples from the recent medicinal chemistry literature. The main purpose is to highlight some intriguing conformational features that can be applied to other drug discovery programs.
Assuntos
Amidas/química , Descoberta de Drogas , Inibidores Enzimáticos/química , Amidas/síntese química , Amidas/farmacologia , Química Farmacêutica , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Humanos , Ligantes , Modelos Moleculares , Conformação Molecular , Relação Estrutura-AtividadeRESUMO
A potent, in vivo efficacious 11ß hydroxysteroid dehydrogenase type 1 (11ß HSD1) inhibitor (11j) has been identified. Compound 11j inhibited 11ß HSD1 activity in human adipocytes with an IC50 of 4.3nM and in primary human adipose tissue with an IC80 of 53nM. Oral administration of 11j to cynomolgus monkey inhibited 11ß HSD1 activity in adipose tissue. Compound 11j exhibited >1000× selectivity over other hydroxysteroid dehydrogenases, displays desirable pharmacodynamic properties and entered human clinical trials in 2011.
Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Oxazinas/química , Piridonas/química , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Tecido Adiposo/citologia , Tecido Adiposo/metabolismo , Administração Oral , Animais , Sítios de Ligação , Células Cultivadas , Sistema Enzimático do Citocromo P-450/metabolismo , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Concentração Inibidora 50 , Macaca fascicularis , Simulação de Acoplamento Molecular , Oxazinas/administração & dosagem , Oxazinas/farmacocinética , Estrutura Terciária de Proteína , Piridonas/administração & dosagem , Piridonas/farmacocinética , Ratos , Relação Estrutura-AtividadeRESUMO
Like G protein-coupled receptors (GPCRs) and protein kinases, nuclear receptors (NRs) are a rich source of pharmaceutical targets. Over 80 NR-targeting drugs have been approved for 18 NRs. The focus of drug discovery in NRs has hitherto been on identifying ligands that bind to the canonical ligand binding pockets of the C-terminal ligand binding domains (LBDs). Due to the development of drug resistance and selectivity concerns, there has been considerable interest in exploring other, non-canonical ligand binding sites. Unfortunately, the potencies of compounds binding at other sites have generally not been sufficient for clinical development. However, the situation has changed dramatically over the last 3years, as compounds with sufficient potency have been reported for several NR targets. Here we review recent developments in this area from a medicinal chemistry point of view in the hope of stimulating further interest in this area of research.
Assuntos
Receptores Citoplasmáticos e Nucleares/metabolismo , Regulação Alostérica , Sítios de Ligação , Química Farmacêutica , Desenho de Fármacos , Humanos , Ligantes , Simulação de Acoplamento Molecular , Domínios Proteicos , Receptores Citoplasmáticos e Nucleares/químicaRESUMO
Liver X receptor (LXR) agonists have been reported to lower brain amyloid beta (Aß) and thus to have potential for the treatment of Alzheimer's disease. Structure and property based design led to the discovery of a series of orally bioavailable, brain penetrant LXR agonists. Oral administration of compound 18 to rats resulted in significant upregulation of the expression of the LXR target gene ABCA1 in brain tissue, but no significant effect on Aß levels was detected.
Assuntos
Encéfalo/metabolismo , Receptores X do Fígado/efeitos dos fármacos , Transportador 1 de Cassete de Ligação de ATP/genética , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Animais , Masculino , RNA Mensageiro/genética , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Regulação para CimaRESUMO
Owing to their inherent three-dimensionality and structural novelty, spiro scaffolds have been increasingly utilized in drug discovery. In this brief review, we highlight selected examples from the primary medicinal chemistry literature during the last three years to demonstrate the versatility of spiro scaffolds. With recent progress in synthetic methods providing access to spiro building blocks, spiro scaffolds are likely to be used more frequently in drug discovery.
Assuntos
Descoberta de Drogas , Compostos Heterocíclicos/farmacologia , Compostos de Espiro/farmacologia , Animais , Química Farmacêutica , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Humanos , Estrutura Molecular , Compostos de Espiro/síntese química , Compostos de Espiro/químicaRESUMO
The HIV-1 Nef accessory factor enhances the viral life cycle in vivo, promotes immune escape of HIV-infected cells, and represents an attractive antiretroviral drug target. However, Nef lacks enzymatic activity and an active site, complicating traditional occupancy-based drug development. Here we describe the development of proteolysis targeting chimeras (PROTACs) for the targeted degradation of Nef. Nef-binding compounds, based on an existing hydroxypyrazole core, were coupled to ligands for ubiquitin E3 ligases via flexible linkers. The resulting bivalent PROTACs induced formation of a ternary complex between Nef and the cereblon E3 ubiquitin ligase thalidomide-binding domain in vitro and triggered Nef degradation in a T cell expression system. Nef-directed PROTACs efficiently rescued Nef-mediated MHC-I and CD4 downregulation in T cells and suppressed HIV-1 replication in donor PBMCs. Targeted degradation is anticipated to reverse all HIV-1 Nef functions and may help restore adaptive immune responses against HIV-1 reservoir cells in vivo.
Assuntos
HIV-1 , Linfócitos T , Regulação para Baixo , Membrana Celular , Replicação Viral , Proteólise , Ubiquitina-Proteína LigasesRESUMO
The HIV-1 Nef accessory factor is critical to the viral life cycle in vivo where it promotes immune escape of HIV-infected cells and viral persistence. While these features identify Nef as an attractive antiretroviral drug target, Nef lacks enzymatic activity and an active site, complicating development of occupancy-based drugs. Here we describe the development of proteolysis targeting chimeras (PROTACs) for the targeted degradation of Nef. Nef-binding compounds, based on a previously reported hydroxypyrazole core, were coupled to ligands for ubiquitin E3 ligases via flexible linkers. The resulting bivalent PROTACs induced formation of a ternary complex between Nef and the Cereblon E3 ubiquitin ligase, resulting in ubiquitylation of Nef and proteolytic degradation. Nef-directed PROTACs efficiently rescued Nef-mediated MHC-I and CD4 downregulation in T cells and suppressed HIV-1 replication in donor PBMCs. Targeted degradation of Nef is anticipated to reverse all HIV-1 Nef functions and may help restore adaptive immune responses against HIV-1 reservoir cells in vivo .
RESUMO
While antiretroviral drugs have transformed the lives of HIV-infected individuals, chronic treatment is required to prevent rebound from viral reservoir cells. People living with HIV also are at higher risk for cardiovascular and neurocognitive complications, as well as cancer. Finding a cure for HIV-1 infection is therefore an essential goal of current AIDS research. This review is focused on the discovery of pharmacological inhibitors of the HIV-1 Nef accessory protein. Nef is well known to enhance HIV-1 infectivity and replication, and to promote immune escape of HIV-infected cells by preventing cell surface MHC-I display of HIV-1 antigens. Recent progress shows that Nef inhibitors not only suppress HIV-1 replication, but also restore sufficient MHC-I to the surface of infected cells to trigger a cytotoxic T lymphocyte response. Combining Nef inhibitors with latency reversal agents and therapeutic vaccines may provide a path to clearance of viral reservoirs.
Assuntos
Infecções por HIV , Soropositividade para HIV , HIV-1 , Antirretrovirais/uso terapêutico , Descoberta de Drogas , Infecções por HIV/tratamento farmacológico , HIV-1/fisiologia , Humanos , Fatores de Virulência , Produtos do Gene nef do Vírus da Imunodeficiência HumanaRESUMO
Structure-based design led to the discovery of a novel class of renin inhibitors in which an unprecedented phenyl ring filling the S1 site is attached to the phenyl ring filling the S3 pocket. Optimization for several parameters including potency in the presence of human plasma, selectivity against CYP3A4 inhibition and improved rat oral bioavailability led to the identification of 8d which demonstrated antihypertensive efficacy in a transgenic rat model of human hypertension.
Assuntos
Anti-Hipertensivos/farmacologia , Inibidores Enzimáticos/farmacologia , Éteres Fenílicos/farmacologia , Renina/antagonistas & inibidores , Animais , Anti-Hipertensivos/síntese química , Anti-Hipertensivos/química , Disponibilidade Biológica , Cristalografia por Raios X , Citocromo P-450 CYP3A/sangue , Inibidores do Citocromo P-450 CYP3A , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Descoberta de Drogas , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Hipertensão/tratamento farmacológico , Modelos Moleculares , Conformação Molecular , Éteres Fenílicos/síntese química , Éteres Fenílicos/química , Ratos , Ratos Transgênicos , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/isolamento & purificação , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Synthesis of 2-adamantyl carbamate derivatives of piperidines and pyrrolidines led to the discovery of 9a with an IC(50) of 15.2 nM against human 11ß-HSD1 in adipocytes. Optimization for increased adipocyte potency, metabolic stability and selectivity afforded 11k and 11l, both of which were >25% orally bioavailable in rat.
Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Adamantano/farmacologia , Inibidores Enzimáticos/farmacologia , Adamantano/química , Animais , Descoberta de Drogas , Inibidores Enzimáticos/química , Modelos Moleculares , RatosRESUMO
Structure-guided drug design led to new alkylamine renin inhibitors with improved in vitro and in vivo potency. Lead compound 21a, has an IC(50) of 0.83nM for the inhibition of human renin in plasma (PRA). Oral administration of 21a at 10mg/kg resulted in >20h reduction of blood pressure in a double transgenic rat model of hypertension.
Assuntos
Aminas/química , Carbamatos/química , Inibidores Enzimáticos/química , Piperidinas/química , Renina/antagonistas & inibidores , Administração Oral , Aminas/síntese química , Aminas/farmacocinética , Animais , Sítios de Ligação , Pressão Sanguínea/efeitos dos fármacos , Carbamatos/síntese química , Carbamatos/farmacocinética , Cristalografia por Raios X , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Haplorrinos , Humanos , Piperidinas/síntese química , Piperidinas/farmacocinética , Ratos , Ratos Transgênicos , Renina/sangue , Renina/metabolismo , Relação Estrutura-AtividadeRESUMO
Structure-guided drug design led to the identification of a class of spirocyclic ureas which potently inhibit human 11beta-HSD1 in vitro. Lead compound 10j was shown to be orally bioavailable in three species, distributed into adipose tissue in the mouse, and its (R) isomer 10j2 was efficacious in a primate pharmacodynamic model.
Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Desenho de Fármacos , Ureia/administração & dosagem , Ureia/farmacocinética , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Administração Oral , Animais , Sítios de Ligação/fisiologia , Disponibilidade Biológica , Células CHO , Cricetinae , Cricetulus , Humanos , Macaca fascicularis , Camundongos , Ratos , Relação Estrutura-Atividade , Ureia/análogos & derivadosRESUMO
The HIV-1 Nef accessory factor is critical to the viral life cycle in vivo and promotes immune escape of infected cells via downregulation of cell-surface MHC-I. Previously, we discovered small molecules that bind directly to Nef and block many of its functions, including enhancement of viral infectivity and replication in T cell lines. These compounds also restore cell-surface MHC-I expression in HIV-infected CD4 T cells from AIDS patients, enabling recognition and killing by autologous cytotoxic T lymphocytes (CTLs). In this study, we describe the synthesis and evaluation of a diverse set of analogs based on the original hydroxypyrazole Nef inhibitor core. All analogs were screened for the interaction with recombinant HIV-1 Nef by surface plasmon resonance (SPR) and for antiretroviral activity in TZM-bl reporter cells infected with HIV-1. Active analogs were ranked on the basis of an activity score that integrates three aspects of the SPR data (affinity, residence time, and extent of binding) with antiretroviral activity. The top scoring compounds bound tightly to Nef by SPR, with KD values in the low nM to pM range, and displayed very slow dissociation from their Nef target. These analogs also suppressed HIV-1 replication in donor peripheral blood mononuclear cells (PBMCs) with IC50 values in the 1-10 nM range without cytotoxicity, inhibited Nef-mediated IL-2-inducible tyrosine kinase (Itk) and hematopoietic cell kinase (Hck) activation, and rescued MHC-I downregulation in a Nef-transfected T cell line. The development of Nef inhibitors based on the structure-activity relationships defined here has promise as a new approach to antiretroviral therapy that includes a path to eradication of HIV-infected cells via the adaptive immune response.
Assuntos
Antirretrovirais/farmacologia , Antígenos de Histocompatibilidade Classe I/genética , Pirazóis/farmacologia , Replicação Viral/efeitos dos fármacos , Produtos do Gene nef do Vírus da Imunodeficiência Humana/antagonistas & inibidores , Linhagem Celular , Regulação para Baixo , Desenvolvimento de Medicamentos , HIV-1/efeitos dos fármacos , HIV-1/fisiologia , Humanos , Concentração Inibidora 50 , Leucócitos Mononucleares/virologia , Doadores de TecidosRESUMO
Structure-based drug design led to the identification of a novel class of potent, low MW alkylamine renin inhibitors. Oral administration of lead compound 21l, with MW of 508 and IC(50) of 0.47nM, caused a sustained reduction in mean arterial blood pressure in a double transgenic rat model of hypertension.
Assuntos
Anti-Hipertensivos/química , Metilaminas/química , Renina/antagonistas & inibidores , Administração Oral , Sequência de Aminoácidos , Animais , Anti-Hipertensivos/síntese química , Anti-Hipertensivos/farmacocinética , Pressão Sanguínea , Simulação por Computador , Cristalografia por Raios X , Desenho de Fármacos , Humanos , Metilaminas/síntese química , Metilaminas/farmacocinética , Ratos , Ratos Transgênicos , Renina/metabolismo , Relação Estrutura-AtividadeRESUMO
This article describes the application of Contour to the design and discovery of a novel, potent, orally efficacious liver X receptor ß (LXRß) agonist (17). Contour technology is a structure-based drug design platform that generates molecules using a context perceptive growth algorithm guided by a contact sensitive scoring function. The growth engine uses binding site perception and programmable growth capability to create drug-like molecules by assembling fragments that naturally complement hydrophilic and hydrophobic features of the protein binding site. Starting with a crystal structure of LXRß and a docked 2-(methylsulfonyl)benzyl alcohol fragment (6), Contour was used to design agonists containing a piperazine core. Compound 17 binds to LXRß with high affinity and to LXRα to a lesser extent, and induces the expression of LXR target genes in vitro and in vivo. This molecule served as a starting point for further optimization and generation of a candidate which is currently in human clinical trials for treating atopic dermatitis.
Assuntos
Benzilaminas/química , Desenho de Fármacos , Descoberta de Drogas , Receptores Nucleares Órfãos/agonistas , Piperazinas/química , Pirimidinas/química , Pirimidinas/metabolismo , Sulfonas/química , Sulfonas/metabolismo , Sítios de Ligação , Cristalografia por Raios X , Humanos , Receptores X do Fígado , Relação Estrutura-AtividadeRESUMO
Polar surface area, total surface area and percentage surface area have been calculated from three-dimensional structures of 88 post-emergence herbicides, 93 pre-emergence herbicides and 237 insecticides. Preferred ranges of values of these parameters were identified. Since the compounds in the training sets are used on a wide variety of species and target sites with various application modes, the parameter ranges are necessarily broad. The utility of the surface-area parameter ranges in selection of compounds for agrochemical screening was compared with the use of ranges of the Lipinski Rule of 5 parameters: molecular mass, calculated log P, number of hydrogen-bond donors and number of hydrogen-bond acceptors. The more computationally intensive surface-area parameters did not offer any obvious advantage over the Lipinski Rule of 5 parameters.
Assuntos
Herbicidas/química , Inseticidas/química , Modelos Biológicos , Conformação Molecular , Estatística como Assunto , Propriedades de SuperfícieRESUMO
Biotin conjugates are of considerable value in investigating the mode of action of biologically active compounds. Two biotin conjugates related to the antifungal compound cymoxanil [1-(2-cyano-2-methoximinoacetyl)-3-ethyl urea] were prepared as the first step in an effort to employ display cloning to identify the compound's target site. In the first conjugate, prepared in five steps, the biotin moiety was attached at the position occupied by the ethyl group in cymoxanil. In the second conjugate, prepared in four steps, the biotin moiety was attached through the oxime functional group.
Assuntos
Acetamidas/síntese química , Biotina/síntese química , Fungicidas Industriais/síntese química , Biotina/análogos & derivados , Espectroscopia de Ressonância MagnéticaRESUMO
LXRs have been of interest as targets for the treatment of atherosclerosis for over a decade. In recent years, LXR modulators have also garnered interest for potential use in the treatment of inflammation, Alzheimer's disease (AD), dermatological conditions, hepatic steatosis, and oncology. To date, no LXR modulator has successfully progressed beyond phase I clinical trials. In this Perspective, we summarize published medicinal chemistry efforts in the context of the available crystallographic data, druglikeness, and isoform selectivity. In addition, we discuss the challenges that need to be overcome before an LXR modulator can reach clinical use.
Assuntos
Anticolesterolemiantes/química , Anticolesterolemiantes/uso terapêutico , Aterosclerose/tratamento farmacológico , Receptores Nucleares Órfãos/agonistas , Receptores Nucleares Órfãos/química , Anticolesterolemiantes/metabolismo , Aterosclerose/metabolismo , Benzoatos/química , Benzoatos/metabolismo , Benzoatos/uso terapêutico , Benzilaminas/química , Benzilaminas/metabolismo , Benzilaminas/uso terapêutico , Sítios de Ligação , Cristalografia por Raios X , Humanos , Hidrocarbonetos Fluorados/química , Hidrocarbonetos Fluorados/metabolismo , Hidrocarbonetos Fluorados/uso terapêutico , Receptores X do Fígado , Modelos Moleculares , Estrutura Molecular , Receptores Nucleares Órfãos/metabolismo , Isoformas de Proteínas/agonistas , Isoformas de Proteínas/química , Isoformas de Proteínas/metabolismo , Estrutura Terciária de Proteína , Sulfonamidas/química , Sulfonamidas/metabolismo , Sulfonamidas/uso terapêuticoRESUMO
Structure guided optimization of a series of nonpeptidic alkyl amine renin inhibitors allowed the rational incorporation of additional polar functionality. Replacement of the cyclohexylmethyl group occupying the S1 pocket with a (R)-(tetrahydropyran-3-yl)methyl group and utilization of a different attachment point led to the identification of clinical candidate 9. This compound demonstrated excellent selectivity over related and unrelated off-targets, >15% oral bioavailability in three species, oral efficacy in a double transgenic rat model of hypertension, and good exposure in humans.