title: Structure-based design of pseudopeptidic inhibitors for SIRT1 and SIRT2.
abstract: The lack of substrate-bound crystal structures of SIRT1 and SIRT2 complicates the drug design for these targets. In this work, we aim to study whether SIRT3 could serve as a target structure in the design of substrate based pseudopeptidic inhibitors of SIRT1 and SIRT2. We created a binding hypothesis for pseudopeptidic inhibitors, synthesized a series of inhibitors, and studied how well the fulfillment of the binding criteria proposed by the hypothesis correlated with the in vitro inhibitory activities. The chosen approach was further validated by studying docking results between 12 different SIRT3, Sir2Tm, SIRT1 and SIRT2 X-ray structures and homology models in different conformational forms. It was concluded that the created binding hypothesis can be used in the design of the substrate based inhibitors of SIRT1 and SIRT2 although there are some reservations, and it is better to use the substrate-bound structure of SIRT3 instead of the available apo-SIRT2 as the target structure.
authors: School of Pharmacy, Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland.
authors: Tero
authors: T
authors: Huhtiniemi
authors: Heikki S
authors: HS
authors: Salo
authors: Tiina
authors: T
authors: Suuronen
authors: Antti
authors: A
authors: Poso
authors: Antero
authors: A
authors: Salminen
authors: Jukka
authors: J
authors: Leppänen
authors: Elina
authors: E
authors: Jarho
authors: Maija
authors: M
authors: Lahtela-Kakkonen
mesh_terms: D000107:Acetylation; D001059:Apoproteins / Q000037:antagonists & inhibitors; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D018716:Molecular Mimicry; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors*; D056565:Sirtuin 2 / Q000037:antagonists & inhibitors*; D060327:Solid-Phase Synthesis Techniques; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D001059:Apoproteins; D010455:Peptides; D016159:Tumor Suppressor Protein p53; C447939:SIRT1 protein, human; C474199:SIRT2 protein, human; D056564:Sirtuin 1; D056565:Sirtuin 2