Novel inhibitor discovery against aromatase through virtual screening and molecular dynamic simulation: a computational approach in drug design

Authors

  • Sako Mirzaie Department of Biochemistry, Sanandaj Branch, Islamic Azad University, Sanandaj, Iran
  • Latifeh Chupani Department of Biology, Faculty of Science, Science and Research Branch, Islamic Azad University, Tehran, Iran
  • Ebrahim Barzegari Asadabadi Department of Biology, Faculty of Science, Science and Research Branch, Islamic Azad University, Tehran, Iran
  • Ahmad Reza Shahverdi Department of Pharmaceutical Biotechnology, Faculty of Pharmacy and Biotechnology Research Center, Tehran University of Medical Sciences, Tehran, Iran
  • Mostafa Jamalan Department of Biology, Faculty of Science, Science and Research Branch, Islamic Azad University, Tehran, Iran

Keywords:

aromatase, androstenedione, aromatase inhibitor, structural-based virtual screening

Abstract

Inhibition of aromatase (CYTP450) as a key enzyme in the estrogen biosynthesis could result in regression of estrogen-dependent tumors and even preventing the promotion of breast cancer. Although today potent steroid and non-steroid inhibitors of aromatase are available, isoflavanone derivatives as natural compounds with least side effects have been described as the candidate for a new generation of aromatase inhibitors. 2a as an isoflavanone derivative is the most potent inhibitor of aromatase, synthesized by Bonfield et al. (2012). In our computational study, the mentioned compound was used as the template for virtual screening. Between 286 selected compounds with 70 % of structural similarity to 2a, 150 of them showed lower docking energy in comparison with 2a. Compound 2a_1 with 11.2 kcal/mol had the lowest docking energy. Interaction of 2a_1 with aromatase was further investigated and compared with 2a and androstenedione (ASD) as a natural substrate of aromatase, through 20 ns of molecular dynamic simulation. Analysis of trajectories showed, while ASD interacts with aromatase through hydrogen bonds and 2a just interacts via hydrophobic forces, 2a_1 not only accommodates in the hydrophobic active site of aromatase in a suitable manner but it also makes a stable coordination with iron atom of aromatase heme group via OB.

Published

2013-03-11

How to Cite

Mirzaie, S., Chupani, L., Asadabadi, E. B., Shahverdi, A. R., & Jamalan, M. (2013). Novel inhibitor discovery against aromatase through virtual screening and molecular dynamic simulation: a computational approach in drug design. EXCLI Journal, 12, 168–183. Retrieved from https://www.excli.de/index.php/excli/article/view/1140

Issue

Section

Original articles

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