Discovery of Novel 5-Lipoxygenase-Activating Protein (FLAP) Inhibitors by Exploiting a Multistep Virtual Screening Protocol

OLĞAÇ A., Carotti A., Kretzer C., Zergiebel S., Seeling A., Garscha U., ...Daha Fazla

JOURNAL OF CHEMICAL INFORMATION AND MODELING, cilt.60, sa.3, ss.1737-1748, 2020 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 60 Sayı: 3
  • Basım Tarihi: 2020
  • Doi Numarası: 10.1021/acs.jcim.9b00941
  • Dergi Adı: JOURNAL OF CHEMICAL INFORMATION AND MODELING
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Applied Science & Technology Source, Chemical Abstracts Core, Compendex, Computer & Applied Sciences, EMBASE, MEDLINE
  • Sayfa Sayıları: ss.1737-1748
  • Gazi Üniversitesi Adresli: Evet

Özet

Leukotrienes (LTs) are proinflammatory mediators derived from arachidonic acid (AA), which play significant roles in inflammatory diseases. The 5-lipoxygenase-activating protein (FLAP) is an integral membrane protein, which is essential for the initial step in LT biosynthesis. The aim of this study was to discover novel and chemically diverse FLAP inhibitors for treatment of inflammatory diseases requiring anti-LT therapy. Both ligand- and structure-based approaches were applied to explain the activities of known FLAP inhibitors in relation to their predicted binding modes. We gained valuable insights into the binding modes of the inhibitors by molecular modeling and generated a multistep virtual screening (VS) workflow in which 6.2 million compounds were virtually screened, and the molecular hypotheses were validated by testing VS-hit compounds biologically. The most potent hit compounds showed significant inhibition of FLAP-dependent cellular LT biosynthesis with IC50 values in the range from 0.13 to 0.87 mu M. Collectively, this study provided novel bioactive chemotypes with potential for further development as effective antiinflammatory drugs.