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      Enzymatic and Inhibition Mechanism of Human Aromatase (CYP19A1) Enzyme. A Computational Perspective from QM/MM and Classical Molecular Dynamics Simulations.

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          Abstract

          The enzyme human aromatase (HA), a member of the cytochrome P450 family, catalyses in a highly specific and peculiar manner the conversion of estrogens to androgens. Thus, this enzyme is a relevant target for inhibitor design for the treatment of breast cancer and currently there are several HA inhibitors employed in clinical practice. The HA crystal structure was solved only in 2009 and, since then, several studies have been done to characterize a variety of its structural, dynamical and mechanistic properties. In the last decade, the predictive power and the accuracy of computer simulations techniques, either relying on force field or on "ab initio" description of the system, has enormously increased. This was mainly due to the development of more accurate algorithms, which allow accelerating the time-scale accessible by simulations techniques, and to the increase of computer power. Hence, computer simulations can now accurately paint an atomistic picture to the molecular mechanism of biomolecules providing also an estimate of the kinetic and thermodynamic properties of the enzyme at increasingly quantitative level. In this review, on the basis of selected examples taken from our work, we summarize current active research topics concerning HA enzyme, with a focus on computational studies. In particular, we will illustrate current results and novel hypothesis concerning the final (rate-determining) aromatization step promoted by this enzyme, on how the structural/dynamics/functional properties of HA are modulated in a membrane lipophilic environment, and finally on novel possible (allosteric) inhibition mechanisms which may modulate estrogen production in HA.

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          Author and article information

          Journal
          Mini Rev Med Chem
          Mini reviews in medicinal chemistry
          1875-5607
          1389-5575
          2016
          : 16
          : 14
          Affiliations
          [1 ] CNR-IOM-Democritos National Simulation Center c/o International School for advanced Studies (SISSA/ISAS) via Bonomea 265, Trieste, Italy. alessandra.magistrato@sissa.it.
          Article
          MRMC-EPUB-76761
          27337972
          7e3c2882-82f4-43ae-aba6-4052dd7942f2
          History

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