Virtual screening approach of sirtuin inhibitors results in two new scaffolds.
Sirtuins (SIRT1-SIRT7) are NAD dependent deacetylases and intriguing drug targets in for example neurodegenerative diseases and cancer. Virtual screening has been shown to be a fast and efficient method of discovering new sirtuin inhibitors. In this study, a new putative binding site on the zinc binding domain of sirtuins was utilized to screen the ZINC database virtually in order to discover new sirtuin inhibiting scaffolds. Altogether 26 compounds were tested in vitro and initially 15 inhibitors displayed >30% SIRT3 inhibition. However, the evaluation of raw data from in vitro assay revealed that many of the compounds had intrinsic property to interfere with the fluorescence signal at the assay wavelengths resulting in false positives. All compounds with over 30% SIRT3 inhibition were studied more closely for their behavior in the assay and eventually, three compounds were identified as novel sirtuin inhibitors. They displayed 32-40% SIRT3 and 21-60% SIRT2 inhibition. The inhibitors display two new scaffolds, the smaller of which can be considered as a promising fragment, which offers a base for structural optimization.
School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland.
Piia
P
Kokkonen
School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland.
Tarja
T
Kokkola
School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland.
Tiina
T
Suuronen
School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland.
Antti
A
Poso
School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland. Electronic address: Elina.Jarho@uef.fi.
Elina
E
Jarho
School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland. Electronic address: Maija.Lahtela-Kakkonen@uef.fi.
Maija
M
Lahtela-Kakkonen
D000494:Allosteric Regulation; D016477:Artifacts; D001665:Binding Sites; D020134:Catalytic Domain; D017076:Computer-Aided Design; D015195:Drug Design; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D011485:Protein Binding; D011487:Protein Conformation; D056565:Sirtuin 2 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D056566:Sirtuin 3 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013050:Spectrometry, Fluorescence; D013329:Structure-Activity Relationship
D056572:Histone Deacetylase Inhibitors; D056565:Sirtuin 2; D056566:Sirtuin 3
Inhibitor; Sirtuin; Virtual screening