Quantitative structure–activity relationships for a series of inhibitors of cruzain from Trypanosoma cruzi: Molecular modeling, CoMFA and CoMSIA studies

Trossini, Gustavo Henrique Goulart; Güido, Rafael Victório Carvalho; Oliva, Glaucius; Ferreira, Elizabeth Igne; Andricopulo, Adriano D.

doi:10.1016/j.jmgm.2009.03.001

Cited by 48 publications

(35 citation statements)

References 44 publications

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“…The integration of these approaches has been successfully employed in a number of investigations of structural, chemical and biological data [10,11].…”

Section: Introductionmentioning

confidence: 99%

Molecular Docking and Structure-Based Drug Design Strategies

et al. 2015

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Pharmaceutical research has successfully incorporated a wealth of molecular modeling methods, within a variety of drug discovery programs, to study complex biological and chemical systems. The integration of computational and experimental strategies has been of great value in the identification and development of novel promising compounds. Broadly used in modern drug design, molecular docking methods explore the ligand conformations adopted within the binding sites of macromolecular targets. This approach also estimates the ligand-receptor binding free energy by evaluating critical phenomena involved in the intermolecular recognition process. Today, as a variety of docking algorithms are available, an understanding of the advantages and limitations of each method is of fundamental importance in the development of effective strategies and the generation of relevant results. The purpose of this review is to examine current molecular docking strategies used in drug discovery and medicinal chemistry, exploring the advances in the field and the role played by the integration of structure-and ligand-based methods.

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“…The integration of these approaches has been successfully employed in a number of investigations of structural, chemical and biological data [10,11].…”

Section: Introductionmentioning

confidence: 99%

Molecular Docking and Structure-Based Drug Design Strategies

et al. 2015

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“…In addition, the CoMFA and CoMSIA contour maps, representing the effects of the steric, electrostatic, hydrophobic, and hydrogen-bond donor and acceptor molecular fields, allowed the identification of key chemical and structural features responsible for selectivity and biological potency [47]. Similarly, molecular modeling studies were carried out in order to identify the preferred binding mode of a series of thiosemicarbazone derivatives as covalent reversible inhibitors of cruzain [48]. Docking investigations led to the identification of the essential structural requirements for the molecular alignment, and robust CoMFA and CoMSIA models were developed on the basis of the predicted bioactive conformations.…”

Section: R V C Guido Et Almentioning

confidence: 99%

“…Additionally, detailed analysis of the CoMFA electrostatic maps provided structural insights into the reversible covalent mechanism of inhibition of this class of compounds. According to the model, key hydrogen bond interactions may play an important role in the backward reaction [48].…”

Section: R V C Guido Et Almentioning

confidence: 99%

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

Güido

Oliva

Andricopulo

2012

Pure and Applied Chemistry

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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.

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“…This technology plays a vital role in drug design and has been employed, and continue to be developed and employed, both to correlate information in data sets and as a tool to facilitate, for example, the discovery of enzyme inhibitors, agonist or antagonists of important drug targets (Fig. 10) [24,71,[106][107][108][109][110][111][112][113].…”

Section: Structure-based Lead Optimizationmentioning

confidence: 99%

“…For this reason, SBDD approaches (e.g., docking, pharmacophore models) are commonly used in CoMFA studies to generate 3D structural alignments of distinct data sets, incorporating important structural elements for the development and interpretation of the 3D QSAR models in terms of their chemical and biological significance (e.g., molecular mechanisms underlying the biological effects). In fact, several studies have shown the successful use of 3D QSAR and SBDD methods in a complementary way [71,[106][107][108][109][110][111][112][113]. The integration of these technologies represents an efficient approach for drug discovery and lead optimization.…”

Section: Structure-based Lead Optimizationmentioning

confidence: 99%

Structure-Based Drug Design Strategies in Medicinal Chemistry

Andricopulo¹,

Salum²,

Abraham

2009

CTMC

139

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A broad variety of medicinal chemistry approaches can be used for the identification of hits, generation of leads, as well as to accelerate the development of high quality drug candidates. Structure-based drug design (SBDD) methods are becoming increasingly powerful, versatile and more widely used. This review summarizes current developments in structure-based virtual screening and receptor-based pharmacophores, highlighting achievements as well as challenges, along with the value of structure-based lead optimization, with emphasis on recent examples of successful applications for the identification of novel active compounds.Keywords: Structure-based drug design, medicinal chemistry, virtual screening, QSAR, pharmacophores. STRUCTURE-BASED DRUG DESIGNThe performance of biochemical processes and cell mechanisms are dependent upon complex and multiple noncovalent intermolecular interactions between proteins and small-molecule modulators. The understanding of the structural and chemical binding properties of important drug targets in biologically relevant pathways allows the design of small molecules capable of regulating or modulating specific target functions in the body that are closely linked to human diseases and disorders, through multiple intermolecular interactions within a well-defined binding pocket [1][2][3][4]. In general, the identification of promising hits for further optimization is a major challenge faced by the both pharmaceutical and academic laboratories. Although the trial-anderror nature is inherent in drug research, rational concepts and modern computational methods have become widely employed for lead selection and optimization.The use of three-dimensional (3D) protein structure information in the development of new biologically active molecules, which is termed Structure-Based Drug Design (SBDD), is a well-established, successful and highly attarctive strategy used by academic and pharmaceutical research laboratories worldwide [3][4][5][6][7][8]. As a creative and knowledgedriven approach, an essential requirement for structure-based studies is a substantial understanding of the spatial and energetic aspects that affect the binding affinities of proteinligand complexes. Considering that the shape and chemical nature of the binding site of a specific target protein are known, and the possible intermolecular interactions between ligands and the protein within its active site have been identified, this qualified information can be directly employed for the identification of new ligands and the optimization of lead compounds. This opens new possibilities to boost the search for lead molecules and to limit the number of compounds that need to be evaluated experimentally.Hits can be identified through the docking of smallmolecule ligands (selected from databases of chemical structures) into protein active sites or by using receptorbased pharmacophore models. Furthermore, drug candidates can be designed de novo by improving the complementary binding properties of lead compounds and the r...

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Quantitative structure–activity relationships for a series of inhibitors of cruzain from Trypanosoma cruzi: Molecular modeling, CoMFA and CoMSIA studies

Cited by 48 publications

References 44 publications

Molecular Docking and Structure-Based Drug Design Strategies

Molecular Docking and Structure-Based Drug Design Strategies

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

Structure-Based Drug Design Strategies in Medicinal Chemistry

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