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Viruses ; 12(6)2020 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-32486283


Single-stranded positive RNA ((+) ssRNA) viruses include several important human pathogens. Some members are responsible for large outbreaks, such as Zika virus, West Nile virus, SARS-CoV, and SARS-CoV-2, while others are endemic, causing an enormous global health burden. Since vaccines or specific treatments are not available for most viral infections, the discovery of direct-acting antivirals (DAA) is an urgent need. Still, the low-throughput nature of and biosafety concerns related to traditional antiviral assays hinders the discovery of new inhibitors. With the advances of reverse genetics, reporter replicon systems have become an alternative tool for the screening of DAAs. Herein, we review decades of the use of (+) ssRNA viruses replicon systems for the discovery of antiviral agents. We summarize different strategies used to develop those systems, as well as highlight some of the most promising inhibitors identified by the method. Despite the genetic alterations introduced, reporter replicons have been shown to be reliable systems for screening and identification of viral replication inhibitors and, therefore, an important tool for the discovery of new DAAs.

Antivirais/farmacologia , Descoberta de Drogas/métodos , Genes Reporter/fisiologia , Vírus de RNA/efeitos dos fármacos , Replicon/fisiologia , Animais , Antivirais/química , Linhagem Celular , Chlorocebus aethiops , Cricetinae , Humanos , Vírus de RNA/genética , Transfecção , Células Vero
Drug Dev Res ; 2020 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-32045013


Malaria is an infectious disease caused by protozoan parasites of the genus Plasmodium and transmitted by Anopheles spp. mosquitos. Due to the emerging resistance to currently available drugs, great efforts must be invested in discovering new molecular targets and drugs. N-myristoyltransferase (NMT) is an essential enzyme to parasites and has been validated as a chemically tractable target for the discovery of new drug candidates against malaria. In this work, 2D and 3D quantitative structure-activity relationship (QSAR) studies were conducted on a series of benzothiophene derivatives as P. falciparum NMT (PfNMT) and human NMT (HsNMT) inhibitors to shed light on the molecular requirements for inhibitor affinity and selectivity. A combination of Quantitative Structure-activity Relationship (QSAR) methods, including the hologram quantitative structure-activity relationship (HQSAR), comparative molecular field analysis (CoMFA), and comparative molecular similarity index analysis (CoMSIA) models, were used, and the impacts of the molecular alignment strategies (maximum common substructure and flexible ligand alignment) and atomic partial charge methods (Gasteiger-Hückel, MMFF94, AM1-BCC, CHELPG, and Mulliken) on the quality and reliability of the models were assessed. The best models exhibited internal consistency and could reasonably predict the inhibitory activity against both PfNMT (HQSAR: q2 /r2 /r2 pred = 0.83/0.98/0.81; CoMFA: q2 /r2 /r2 pred = 0.78/0.97/0.86; CoMSIA: q2 /r2 /r2 pred = 0.74/0.95/0.82) and HsNMT (HQSAR: q2 /r2 /r2 pred = 0.79/0.93/0.74; CoMFA: q2 /r2 /r2 pred = 0.82/0.98/0.60; CoMSIA: q2 /r2 /r2 pred = 0.62/0.95/0.56). The results enabled the identification of the polar interactions (electrostatic and hydrogen-bonding properties) as the major molecular features that affected the inhibitory activity and selectivity. These findings should be useful for the design of PfNMT inhibitors with high affinities and selectivities as antimalarial lead candidates.

Br J Pharmacol ; 173(2): 396-410, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26562357


BACKGROUND AND PURPOSE: Cathepsin K (CatK) is a major drug target for the treatment of osteoporosis. Potent active site-directed inhibitors have been developed and showed variable success in clinical trials. These inhibitors block the entire activity of CatK and thus may interfere with other pathways. The present study investigates the antiresorptive effect of an exosite inhibitor that selectively inhibits only the therapeutically relevant collagenase activity of CatK. EXPERIMENTAL APPROACH: Human osteoclasts and fibroblasts were used to analyse the effect of the exosite inhibitor, ortho-dihydrotanshinone (DHT1), and the active site inhibitor, odanacatib (ODN), on bone resorption and TGF-ß1 degradation. Cell cultures, Western blot, light and scanning electron microscopy as well as energy dispersive X-ray spectroscopy, molecular modelling and enzymatic assays were used to evaluate the inhibitors. KEY RESULTS: DHT1 selectively inhibited the collagenase activity of CatK, without affecting the viability of osteoclasts. Both inhibitors abolished the formation of resorption trenches, with DHT1 having a slightly higher IC50 value than ODN. Maximal reductions of other resorption parameters by DHT1 and ODN were comparable, respectively 41% and 33% for total resorption surface, 46% and 48% for resorption depths, and 83% and 61% for C-terminal telopetide fragment (CTX) release. DHT1 did not affect the turnover of fibrosis-associated TGF-ß1 in fibroblasts, whereas 500 nM ODN was inhibitory. CONCLUSIONS AND IMPLICATIONS: Our study shows that an exosite inhibitor of CatK can specifically block bone resorption without interfering with other pathways.

Abietanos/metabolismo , Compostos de Bifenilo/metabolismo , Reabsorção Óssea/metabolismo , Catepsina K/antagonistas & inibidores , Catepsina K/metabolismo , Abietanos/farmacologia , Abietanos/uso terapêutico , Animais , Compostos de Bifenilo/farmacologia , Compostos de Bifenilo/uso terapêutico , Reabsorção Óssea/tratamento farmacológico , Catepsina K/química , Bovinos , Relação Dose-Resposta a Droga , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Estrutura Terciária de Proteína
Curr Pharm Des ; 20(27): 4474-85, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24245758


Worldwide, tuberculosis (TB) is the leading cause of death among curable infectious diseases. The emergence of multidrug resistant (MDR) and extensively drug resistant (XDR) TB is a growing global health concern and there is an urgent need for new anti-TB drugs. Enzymes involved in DNA and ATP biosynthesis are potential targets for tuberculostatic drug design, since these enzymes are essential for Mycobacterium tuberculosis growth. This review presents the current progress and applications of structure-activity relationship analysis for the discovery of innovative tuberculostatic agents as inhibitors of ribonucleotide reductase, DNA gyrase, ATP synthase, and thymidylate kinase enzymes, highlighting present challenges and new opportunities in TB drug design.

Antituberculosos/química , Desenho de Fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Ácidos Nucleicos/biossíntese , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Antituberculosos/farmacologia , Antituberculosos/uso terapêutico , Tuberculose Extensivamente Resistente a Medicamentos/tratamento farmacológico , Tuberculose Extensivamente Resistente a Medicamentos/microbiologia , Humanos , Estrutura Molecular , Mycobacterium tuberculosis/enzimologia , Mycobacterium tuberculosis/metabolismo , Relação Quantitativa Estrutura-Atividade , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia
Bioorg Med Chem Lett ; 23(8): 2436-41, 2013 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-23499236


We here report the discovery of novel Plasmodium falciparum enoyl-ACP reductase (PfENR) inhibitors as new antimalarial hits through ligand- and structure-based drug design approaches. We performed 2D and 3D QSAR studies on a set of rhodanine analogues using hologram QSAR (HQSAR), comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques. Statistical and satisfactory results were obtained for the best HQSAR (r(2) of 0.968 and qLOO(2) of 0.751), CoMFA (r(2) of 0.955 and qLOO(2) of 0.806) and CoMSIA (r(2) of 0.965 and qLOO(2) of 0.659) models. The information gathered from the QSAR models guided us to design new PfENR inhibitors. Three new hits were predicted with potency in the submicromolar range and presented drug-like properties.

Antimaláricos/química , Antimaláricos/farmacologia , Enoil-(Proteína de Transporte de Acila) Redutase (NADH)/antagonistas & inibidores , Enoil-(Proteína de Transporte de Acila) Redutase (NADH)/química , Plasmodium falciparum/enzimologia , Rodanina/análogos & derivados , Rodanina/farmacologia , Sítios de Ligação , Desenho de Fármacos , Descoberta de Drogas , Enoil-(Proteína de Transporte de Acila) Redutase (NADH)/metabolismo , Humanos , Ligantes , Modelos Moleculares , Plasmodium falciparum/efeitos dos fármacos , Ligação Proteica , Relação Quantitativa Estrutura-Atividade , Rodanina/química
J Mol Model ; 19(1): 179-92, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22846924


Tuberculosis (TB) still remains one of the most deadly infectious diseases. Mycobacterium tuberculosis thymidine monophosphate kinase (TMPKmt) has emerged as an attractive molecular target for the design of a novel class of anti-TB agents since blocking it will affect the pathways involved in DNA replication. Aiming at shedding some light on structural and chemical features that are important for the affinity of thymidine derivatives to TMPKmt, we have employed a special fragment-based method to develop robust quantitative structure-activity relationship models for a large and chemically diverse series of thymidine-based analogues. Significant statistical parameters (r2= 0.94, q2= 0.76, r2pred= 0.89) were obtained, indicating the reliability of the hologram QSAR model in predicting the biological activity of untested compounds. The 2D model was then used to predict the potency of an external test set, and the predicted values obtained from the HQSAR model were in good agreement with the experimental results. We have accordingly designed novel TMPKmt inhibitors by utilizing the fragments proposed by HQSAR analysis and predicted with good activity in the developed models. The new designed compounds also presented drug-like characteristics based on Lipinski's rule of 5. The generated molecular recognition patterns gathered from the HQSAR analysis combined with quantum mechanics/molecular mechanics (QM/MM) docking studies, provided important insights into the chemical and structural basis involved in the molecular recognition process of this series of thymidine analogues and should be useful for the design of new potent anti-TB agents.

Simulação de Dinâmica Molecular , Núcleosídeo-Fosfato Quinase/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Relação Quantitativa Estrutura-Atividade , Teoria Quântica , Antituberculosos/química , Antituberculosos/farmacologia , Sítios de Ligação , Holografia , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/enzimologia