The data set used to generate the 3D predictive QSAR models consisted of 70 adenosine derivatives Figure 5a , which were designed based on significant structural differences between the active sites of Leishmania mexicana enzymes and its human homologue.
The molecular properties were quantitatively related to inhibitory potency, using methods of comparative molecular field analysis CoMFA Cramer et al. These methods consider that the biological activity of a data set is directly related to intermolecular interactions prevailing in the molecular recognition and binding affinity process, i. Because of their 3D character, molecular interaction fields MIF are used as descriptors.
Another striking feature is the study of bioactive conformations and the 3D structural alignment orientation in Cartesian space of molecules from the dataset. For that purpose, this study used molecular docking methods to obtain the molecular alignment of inhibitors in the binding site of enzyme Lm GAPDH Figure 5B. CoMFA and CoMSIA models with high internal correlation and external prediction consistency were generated, indicating their usefulness in the design of new more potent and selective inhibitors Figure 5C.
An additional feature of the 3D QSAR methods is to enable visualization of regions in the space that can be directly related to biological property Figure 5D. The detailed analysis of contour maps enabled elucidating the structural bases involved in the molecular recognition process, as well as in the potency and selectivity of the inhibitors investigated, evidencing, therefore, the complementary nature of and synergy between the QSAR and SBDD methods.
Another interesting example of the integration of experimental and computational methods, particularly of enzyme kinetics and molecular modeling can be seen in the study of a series of chalcones with activity against Mycobacterium tuberculosis tyrosine phosphatase A M t PtpA Figure 6A , a biomolecule that plays a central role in the processes of cell signaling and invasion in mycobacteria Mascarello et al.
Briefly, enzyme kinetic studies have indicated a reversible mechanism of the competitive type for chalcones, with K i values in the low micromolar range Figure 6B. Based on this information, molecular modeling studies have been conducted to evaluate the mode of interaction of inhibitors against the target enzyme and identify the structural basis responsible for the molecular recognition process.
The models indicated the critical role of hydrogen bonding and n-electron interactions between chemical functionalities of the ligands substituents of the phenyl group and naphthyl aromatic system and amino acid residues from the active site of MtPtpA Thr12, Arg17, His49 and Trp48, Figure 6C. Subsequently, in vitro and in vivo studies demonstrated both the low toxicity of synthetic chalcones and their ability to prevent intracellular survival and proliferation of mycobacteria, suggesting the potential of this class for the development of new drug candidates for the treatment of tuberculosis.
This trend should increase sharply through investments in infrastructure, personnel qualification and research, thus encouraging a more balanced regional development and the strengthening of partnerships between university, government and industry. Looking to the future requires a strategic perspective of continuity. Creativity and boldness are essential to understand and anticipate new opportunities. The common commitment is to integrate actions, participate and contribute in the best way possible to the advancement of scientific knowledge and technological expertise. It is essential to combine organized efforts, coordinate strategies for attracting financial, human and material resources, consolidate ideas and find new solutions that will ensure, in the coming decades, Brazil's evolution from an emerging nation to a world power in the area of drugs and medicines.
Structure-based drug design strategies in medicinal chemistry. BIND: the biomolecular interaction network database. Nucleic Acids Res. Neglected diseases, civil conflicts, and the right to health. Lancet , v. Translation of new technologies: from basic research to drug discovery and development. Drug Discov.
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Medicinal Chemistry: A Biochemical Approach
Virtual screening and its integration with modern drug design technologies. Structural basis for selective inhibition of trypanosomatid glyceraldehydephosphate dehydrogenase: molecular docking and 3D QSAR studies. Molecular similarity indices in a comparative analysis CoMSIA of drug molecules to correlate and predict their biological activity. Inhibition of Mycobacterium tuberculosis tyrosine phosphatase PtpA by synthetic chalcones: kinetics, molecular modeling, toxicity and effect on growth. Representativity of target families in the Protein Data Bank: impact for family-directed structure-based drug discovery.
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Natural products as sources of new drugs over the last 25 years. J Nat Prod. Natural products as sources of new drugs over the period The Essential Medicinal Chemistry of Curcumin. Fabricant D, Farnsworth N.
The value of plants used in traditional medicine for drug discovery. Environ Health Perspect. Discovery of anticancer agents of diverse natural origin. Pure Appl Chem. Demain A, Sanchez S. Microbial drug discovery: 80 years of progress. J Antibiot Tokyo. Discovery and development of the anticancer agent salinosporamide A NPI Bioorg Med Chem. Challis G. Genome mining for novel natural product discovery. Molinski T.