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How molecular flexibility can enhance drug discovery?

Abstract: The study of molecular flexibility can be traced to the XIX century, as in the study of carbohydrates conformations by Hermann Sachse. However, the word “conformation” appears only in 1929, in a seminal book by Haworth. Since its beginning, the use of such pioneer mathematical models gave rise to a pletora of techniques, both experimental and computational, aiming to access the dynamic nature of compounds and related properties. Since the use of RAMAN spetroscopy to determine the energy barrier for dihedrals, to NMR experiments elucidating the molecular geometry as the result of a solution ensemble to X-ray crystallography towards both single and multiple conformations, experimental techniques have been receiving the contribution of methods like docking, molecular dynamics and metadynamics, among others, to produce precise pictures of the drug-receptor recognition and, as a consequence, offering new insights to the rational design of new bioactive compounds. In our group, we have been dedicated to access the dynamic nature of molecular recognition, strengthening the structural basis for drug design, including antiviral, antimalarial, anti-inflammatory, antineoplasic and antithrombotic compounds, among others. When integrated to a careful calibration of force field parameters for both synthetic and natural compounds, those applications of molecular modeling techniques offered accurate reproduction of experimental data, culminating with a detailed description of plastic ligand-receptor recognitions, including modifications in ligands orientation, major conformational changes in ligand and/or receptor and flexible intra- and inter-molecular interactions, enhancing our knowledge about how multiple compounds act, at the molecular level, against several pathologies which, in turn, offered new avenues of investigation and design for original bioactive compounds.

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