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2.
Orv Hetil ; 161(14): 523-531, 2020 Apr.
Artigo em Húngaro | MEDLINE | ID: mdl-32223419

RESUMO

The one disease - one target - one drug paradigm was an almost dominant principle in drug discovery from the 1960s to the 2000s. The stagnation and even decline in the productivity of drug innovation around the turn of the millennium and beyond, the realization of limitations of the one-target approach, especially in the treatment of multifactorial diseases, have drawn attention considerably to the one disease - multiple target - one drug multi-targeting drug concept. In this review, we outline old and new molecular design strategies and their practical implementation with own and other examples that also demonstrate unique therapeutic and diagnostic values and benefits of the multi-targeting approach. Finally, we point out that the full potential of the multi-targeting concept can emerge through data analytics and association methods (such as artificial intelligence) and system-based approach, preferably by linking it to quantitative systems pharmacology. This new systems pharmacology drug approach may also lead to novel breakthrough drugs, drug combinations and drug repositioning. Orv Hetil. 2020; 161(14): 523-531.


Assuntos
Desenho de Fármacos , Descoberta de Drogas/tendências , Previsões , Humanos
3.
Biochem Soc Trans ; 48(1): 271-280, 2020 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-31985743

RESUMO

Fragment-based drug discovery (FBDD) has become a mainstream technology for the identification of chemical hit matter in drug discovery programs. To date, the food and drug administration has approved four drugs, and over forty compounds are in clinical studies that can trace their origins to a fragment-based screen. The challenges associated with implementing an FBDD approach are many and diverse, ranging from the library design to developing methods for identifying weak affinity compounds. In this article, we give an overview of current progress in fragment library design, fragment to lead optimisation and on the advancement in techniques used for screening. Finally, we will comment on the future opportunities and challenges in this field.


Assuntos
Desenho de Fármacos , Descoberta de Drogas/métodos , Descoberta de Drogas/tendências , Bibliotecas de Moléculas Pequenas/química , Cristalografia por Raios X , Aprovação de Drogas , Avaliação Pré-Clínica de Medicamentos/métodos , Ensaios de Triagem em Larga Escala/tendências , Humanos , Espectroscopia de Ressonância Magnética , Ligação Proteica
5.
Biochim Biophys Acta Rev Cancer ; 1873(1): 188319, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31678141

RESUMO

The treatment of cancer is still a major challenge. But tremendous progress in anticancer drug discovery and development has occurred in the last few decades. However, this progress has resulted in few effective oncology products due to challenges associated with anticancer drug delivery. Oral administration is the most preferred route for anticancer drug delivery, but the majority of anticancer drugs currently in product pipelines and the majority of those that have been commercially approved have inherently poor water solubility, and this cannot be mitigated without compromising their potency and stability. The poor water solubility of anticancer drugs, in conjunction with other factors, leads to suboptimal pharmacokinetic performance. Thus, these drugs have limited efficacy and safety when administered orally. The amorphous solid dispersion (ASD) is a promising formulation technology that primarily enhances the aqueous solubility of poorly water-soluble drugs. In this review, we discuss the challenges associated with the oral administration of anticancer drugs and the use of ASD technology in alleviating these challenges. We emphasize the ability of ASDs to improve not only the pharmacokinetics of poorly water-soluble anticancer drugs, but also their efficacy and safety. The goal of this paper is to rationalize the application of ASD technology in the formulation of anticancer drugs, thereby creating superior oncology products that lead to improved therapeutic outcomes.


Assuntos
Antineoplásicos/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Monitoramento de Medicamentos/métodos , Tecnologia Farmacêutica/métodos , Administração Oral , Antineoplásicos/química , Antineoplásicos/farmacocinética , Química Farmacêutica , Sistemas de Liberação de Medicamentos/tendências , Descoberta de Drogas/métodos , Descoberta de Drogas/tendências , Monitoramento de Medicamentos/tendências , Humanos , Solubilidade , Tecnologia Farmacêutica/tendências , Água/química
6.
Ann N Y Acad Sci ; 1459(1): 69-85, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31762048

RESUMO

The rising threat of multidrug-resistant Gram-negative bacteria is exacerbated by the scarcity of new antibiotics in the development pipeline. Permeability through the outer membrane remains one of the leading hurdles in discovery efforts. However, the essentiality of a robust outer membrane makes itself an intriguing antimicrobial target. Herein, we review drug discovery efforts targeting the outer membrane and the prospective antimicrobial leads identified.


Assuntos
Antibacterianos/metabolismo , Sistemas de Liberação de Medicamentos/tendências , Descoberta de Drogas/tendências , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Negativas/metabolismo , Animais , Antibacterianos/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Descoberta de Drogas/métodos , Farmacorresistência Bacteriana Múltipla/fisiologia , Humanos
8.
Nat Rev Microbiol ; 18(5): 275-285, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31745331

RESUMO

Antibacterial resistance is a great concern and requires global action. A critical question is whether enough new antibacterial drugs are being discovered and developed. A review of the clinical antibacterial drug pipeline was recently published, but comprehensive information about the global preclinical pipeline is unavailable. This Review focuses on discovery and preclinical development projects and has found, as of 1 May 2019, 407 antibacterial projects from 314 institutions. The focus is on Gram-negative pathogens, particularly bacteria on the WHO priority bacteria list. The preclinical pipeline is characterized by high levels of diversity and interesting scientific concepts, with 135 projects on direct-acting small molecules that represent new classes, new targets or new mechanisms of action. There is also a strong trend towards non-traditional approaches, including diverse antivirulence approaches, microbiome-modifying strategies, and engineered phages and probiotics. The high number of pathogen-specific and adjunctive approaches is unprecedented in antibiotic history. Translational hurdles are not adequately addressed yet, especially development pathways to show clinical impact of non-traditional approaches. The innovative potential of the preclinical pipeline compared with the clinical pipeline is encouraging but fragile. Much more work, focus and funding are needed for the novel approaches to result in effective antibacterial therapies to sustainably combat antibacterial resistance.


Assuntos
Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , Terapia Biológica/tendências , Descoberta de Drogas/tendências , Avaliação Pré-Clínica de Medicamentos/tendências , Antibacterianos/uso terapêutico , Infecções Bacterianas/tratamento farmacológico , Farmacorresistência Bacteriana , Resultado do Tratamento
9.
Adv Exp Med Biol ; 1188: 61-75, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31820383

RESUMO

Reverse phase protein arrays (RPPA) are miniature dot blots constructed using robotic arrayers to deposit protein containing samples onto nitrocellulose-coated glass slides. Reverse phase protein arrays address the challenge of quantifying low-abundance proteins and posttranslationally modified proteins in cellular lysates and body fluids. RPPA technology is ideally suited to biomarker discovery, signal pathway profiling, functional phenotype analysis, and mechanism of action studies for drug discovery. Each array is fabricated with specimens, controls, and calibrators, thus providing a complete assay on each slide. Constructing a reverse phase protein array initially consists of selecting an arrayer, pin type, print head configuration, and nitrocellulose slide that is optimized for the particular specimen type and protein detection method. Herein we present the nuances of RPPA fabrication and study design using a solid pin arrayer and nitrocellulose-coated slides.


Assuntos
Análise Serial de Proteínas , Proteínas , Colódio , Descoberta de Drogas/instrumentação , Descoberta de Drogas/tendências , Impressão Tridimensional , Análise Serial de Proteínas/instrumentação , Proteínas/química
10.
Adv Exp Med Biol ; 1188: 203-226, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31820390

RESUMO

Since its inception as a scalable and cost-effective method for precise quantification of the abundance of multiple protein analytes and post-translational epitopes across large sample sets, reverse phase protein array (RPPA) has been utilized as a drug discovery tool. Key RPPA drug discovery applications include primary screening of abundance or activation state of nominated protein targets, secondary screening for toxicity and selectivity, mechanism-of-action profiling, biomarker discovery, and drug combination discovery. In recent decades, drug discovery strategies have evolved dramatically in response to continual advances in technology platforms supporting high-throughput screening, structure-based drug design, new therapeutic modalities, and increasingly more complex and disease-relevant cell-based and in vivo preclinical models of disease. Advances in biological laboratory capabilities in drug discovery are complemented by significant developments in bioinformatics and computational approaches for integrating large complex datasets. Bioinformatic and computational analysis of integrated molecular, pathway network and phenotypic datasets enhance multiple stages of the drug discovery process and support more informative drug target hypothesis generation and testing. In this chapter we discuss and present examples demonstrating how the latest advances in RPPA complement and integrate with other emerging drug screening platforms to support a new era of more informative and evidence-led drug discovery strategies.


Assuntos
Análise Serial de Proteínas , Proteômica , Animais , Descoberta de Drogas/métodos , Descoberta de Drogas/tendências , Avaliação Pré-Clínica de Medicamentos , Humanos , Análise Serial de Proteínas/normas , Proteínas/química
13.
Expert Rev Gastroenterol Hepatol ; 13(12): 1145-1152, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31692390

RESUMO

Introduction: Liver cirrhosis is the most deleterious consequence of chronic liver diseases of different etiologies. Progression of liver diseases to cirrhosis, irrespective of etiology, involves chronic parenchymal injury, persistent activation of inflammatory response, sustained activation of fibrogenesis and wound-healing response. Despite intensive research on antifibrotic drugs, novel therapeutics specifically for liver have not been yet licensed. This review will examine compounds currently under development and key challenges in specific settings as for example that of NAFLD associated fibrosis.Areas covered: Results of the main phase II and III trial, including those with negative results, are presented and discussed. The endpoints selected and their limitations highlighted in order to suggest potential options to move forward.Expert opinion: Strategies based on single-molecule targets, associated so far with some disappointing results, may be unlikely to succeed in the context of such complex pathogenesis. Blocking at the same time different pathways that drive fibrosis progression may be required to provide significant benefit.


Assuntos
Desenvolvimento de Medicamentos/tendências , Descoberta de Drogas/tendências , Cirrose Hepática/tratamento farmacológico , Fígado/efeitos dos fármacos , Terapia de Alvo Molecular/tendências , Animais , Difusão de Inovações , Humanos , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Transdução de Sinais
14.
Adv Exp Med Biol ; 1163: 65-87, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31707700

RESUMO

An allosteric mechanism refers to the biological regulation process wherein macromolecules propagate the effect of ligand binding at one site to a spatially distant orthosteric locus, thus affecting activity. The theory has remained a trending topic in biology research for over 50 years, since the understanding of allostery is fundamental for gleaning numerous biological processes and developing new drug therapies. In the past two decades, the allosteric paradigm has evolved into more descriptive models, with ever-expanding amounts of experimental data pertaining to newly identified allosteric molecules. The AlloSteric Database (ASD, accessible at http://mdl.shsmu.edu.cn/ASD ), which is a comprehensive knowledge repository, has provided the public with integrated information encompassing allosteric proteins, modulators, sites, pathways, and networks to investigate allostery since 2009. In this chapter, we introduce the history and usage of the ASD and give attention to specific applications that have benefited from the ASD.


Assuntos
Sítio Alostérico , Descoberta de Drogas , Proteínas , Regulação Alostérica , Bases de Dados de Proteínas , Descoberta de Drogas/tendências , Proteínas/química
15.
Adv Exp Med Biol ; 1163: 141-169, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31707703

RESUMO

With the increasing difficulty to develop new drugs and the emergence of resistance to traditional orthosteric-site inhibitors, the search for alternatives is finally approaching the focus on allosteric sites. Allosteric sites offer opportunities to regulate many pharmacologically targeted pathways by inhibition or activation. In addition, allosteric sites tend to be less conserved than the functional site, which may facilitate the design of specific effectors in the protein families for which specific orthosteric inhibitors have proved difficult to design. Furthermore, recent evidence suggests that all proteins might be susceptible of allosteric regulation, increasing the space of druggable targets. Computational identification of allosteric sites has therefore become an active field of research. The problem can be approached from two sides: (1) the identification of allosteric-communication pathways between the functional site and potential allosteric sites and (2) the functional-site-independent identification of allosteric sites. While the first approach tends to be more laborious and thus restricted to a single protein, the second tends to be more amenable to larger-scale analysis, thus providing tools for the two drug discovery scenarios: the analysis of known targets and the screening for new potential targets. Here, I show some basic concepts and methods useful to the identification of allosteric sites and pathways, in line with these two approaches. I describe them in some detail to build a clear framework, at the risk of losing the interest of experts. Examples of recent studies involving these methods are also illustrated, focusing on the techniques rather than on their findings on allosterism.


Assuntos
Sítio Alostérico , Descoberta de Drogas , Proteínas , Regulação Alostérica , Descoberta de Drogas/tendências , Proteínas/química
16.
Adv Exp Med Biol ; 1163: 171-186, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31707704

RESUMO

NMR allows assessment of protein structure in solution. Unlike conventional X-ray crystallography that provides snapshots of protein conformations, all conformational states are simultaneously accessible to analysis by NMR. This is a significant advantage for discovery and characterization of allosteric effects. These effects are observed when binding at one site of the protein affects another distinct site through conformational transitions. Allosteric regulation of proteins has been observed in multiple physiological processes in health and disease, providing an opportunity for the development of allosteric inhibitors. These compounds do not directly interact with the orthosteric site of the protein but influence its structure and function. In this book chapter, we provide an overview on how NMR methods are utilized to identify allosteric sites and to discover novel inhibitors, highlighting examples from the field. We also describe how NMR has contributed to understanding of allosteric mechanisms and propose that it is likely to play an important role in clarification and further development of key concepts of allostery.


Assuntos
Sítio Alostérico , Descoberta de Drogas , Ligantes , Espectroscopia de Ressonância Magnética , Regulação Alostérica , Sítios de Ligação , Descoberta de Drogas/métodos , Descoberta de Drogas/tendências , Conformação Proteica
18.
Malar J ; 18(1): 337, 2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31581943

RESUMO

BACKGROUND: The recent emergence in Southeast Asia of artemisinin resistance poses major threats to malaria control and elimination globally. Green nanotechnologies can constitute interesting tools for discovering anti-malarial medicines. This systematic review focused on the green synthesis of metal nanoparticles as potential source of new antiplasmodial drugs. METHODS: Seven electronic database were used following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: A total of 17 papers were included in the systematic review. 82.4% of the studies used plant leaves to produce nanoparticles (NPs) while three studies used microorganisms, including bacteria and fungi. Silver was the main metal precursor for the synthesis of NPs. The majority of studies obtained nanoparticles spherical in shape, with sizes ranging between 4 and 65 nm, and reported no or little cytotoxic effect of the NPs. Results based on 50% inhibitory concentration (IC50) varied between studies but, in general, could be divided into three NP categories; (i) those more effective than positive controls, (ii) those more effective than corresponding plant extracts and, (iii) those less effective than the positive controls or plant extracts. CONCLUSIONS: This study highlights the high antiplasmodial potential of green-synthesized metal nanoparticles thereby underscoring the possibility to find and develop new anti-malarial drugs based on green synthesis approaches. However, the review also highlights the need for extensive in vitro and in vivo studies to confirm their safety in humans and the elucidation of the mechanism of action.


Assuntos
Antimaláricos/síntese química , Descoberta de Drogas/tendências , Nanopartículas Metálicas/química , Folhas de Planta/metabolismo , Plasmodium falciparum/efeitos dos fármacos , Artemisininas/farmacologia , Malária/tratamento farmacológico , Extratos Vegetais/química , Prata
20.
Microb Pathog ; 136: 103678, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31437579

RESUMO

Japanese encephalitis (JE) has emerged as one of the most important form of viral encephalitis, which accounts for an estimated 70,000 cases each year with approximately 10,000 fatalities. The clinical presentations and outcome of the infection is dependent upon both virulence of viral determinants and host immune responses. The causative pathogen of JE is a virus known as Japanese encephalitis virus (JEV), which penetrates into the CNS from blood and triggers rapid humoral and cell-mediated immune response. Humoral response is crucial for the control of dissemination of JEV infection and the cytokines produced by cell-mediated immunity during JEV infections serve as potent immune mediators. Till date, JE is only vaccine preventable and no complete antiviral treatment is available so far. Further, vaccine-mediated prevention also has certain limitations. Therefore, an understanding of the pathogenesis of JEV infection can enable the researchers to presume the depth of treatment regime. This review highlights the importance of understanding of the immune mechanisms that are operated in the host during JEV infection and would be helpful in improving future vaccination strategy against JEV.


Assuntos
Vírus da Encefalite Japonesa (Espécie)/imunologia , Encefalite Japonesa/prevenção & controle , Encefalite Japonesa/fisiopatologia , Vacinas contra Encefalite Japonesa/imunologia , Vacinas contra Encefalite Japonesa/isolamento & purificação , Descoberta de Drogas/métodos , Descoberta de Drogas/tendências , Humanos , Imunidade Celular , Imunidade Humoral
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