Structure- and ligand-based drug design approaches for neglected tropical diseases

Abstract

Drug discovery has moved toward more rational strategies based on our increasing understanding of the fundamental principles of protein-ligand interactions. Structure-(SBDD) and ligand-based drug design (LBDD) approaches bring together the most powerful concepts in modern chemistry and biology, linking medicinal chemistry with structural biology. The definition and assessment of both chemical and biological space have revitalized the importance of exploring the intrinsic complementary nature of experimental and computational methods in drug design. Major challenges in this field include the identification of promising hits and the development of high-quality leads for further development into clinical candidates. It becomes particularly important in the case of neglected tropical diseases (NTDs) that affect disproportionately poor people living in rural and remote regions worldwide, and for which there is an insufficient number of new chemical entities being evaluated owing to the lack of innovation and R&D investment by the pharmaceutical industry. This perspective paper outlines the utility and applications of SBDD and LBDD approaches for the identification and design of new small-molecule agents for NTDs.

Doenças tropicais negligenciadas: uma nova era de desafios e oportunidades

“…Os compostos bioativos com melhores propriedades são eleitos como compostos líderes (do termo em inglês lead compounds) para etapas posteriores de otimização molecular. 10 Com o auxílio de métodos de química medicinal é possível explorar o imenso espaço químico delineando o trabalho investigativo na identificação, seleção e otimização de moléculas capazes de interagir com alta afinidade e seletividade com o alvo molecular selecionado (e.g., enzima, receptor), o qual representa o espaço biológico do binômio químico-biológico em questão. Várias estratégias em química medicinal podem ser empregadas para a investigação do espaço químico-biológico, como a organização de bases padrões de dados, a aplicação de filtros moleculares, o emprego de ensaios biológicos automatizados em larga escala (HTS, da sigla inglesa para high-throughput screening), a triagem virtual (VS, da sigla inglesa para virtual screening), as técnicas de planejamento baseado na estrutura do receptor (SBDD, da sigla inglesa para structure--based drug design) e de planejamento baseado na estrutura do ligante (LBDD, da sigla inglesa para ligand-based drug design), além dos estudos das relações quantitativas entre a estrutura e atividade (QSAR, da sigla inglesa para quantitative structure-activity relationships).…”

Synthesis and trypanocidal activity of novel benzimidazole derivatives

“…Ligand-based drug design is one of the most important molecular modification tools based on the knowledge of other molecules that bind to the biological target of interest. 16 In this context, our research group has synthesized a large number of benzimidazole derivatives with antiparasitic activities. 17,18 Some of these compounds present activity as TcTIM inhibitors, such as derivatives (I) and (II) shown in Based on the above study, a set of molecules designed by the isosteric replacement of the thiazole group by pyrazine, pyrimidine, substituted pyridines and substituted anilines (Table 1) are proposed in this work.…”

“…In turn, 2-chloroacetamides(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29) were previously synthetized by condensing 2-chloroacetyl chloride (30) with the appropriate aromatic amines (31-44). Chloroform and triethylamine were used under a N 2 atmosphere.On the other hand, the synthesis of the common precursor 15 was carried out following the reactions outlined in Scheme 2.…”

Triagem virtual de inibidores da enzima di-hidrofolato redutase de <i>Schistosoma mansoni</i> (SmDHFR)

“…A Modelagem Molecular se constitui de um conjunto de ferramentas de química computacional utilizadas para construir, manipular, visualizar e analisar das estruturas moleculares que são obtidas através de química computacional (BARREIRO et al, 1997;ITAI et al, 1996;SILVA, 2003 OLIVA; ANDRICOPULO, 2012;ITAI et al, 1996;SILVA, 2003).…”