Discovery and evaluation of inhibitory activity and mechanism of arylcoumarin derivatives on Theileria annulata enolase
- PDF / 2,404,253 Bytes
- 16 Pages / 595.276 x 790.866 pts Page_size
- 64 Downloads / 154 Views
ORIGINAL ARTICLE
Discovery and evaluation of inhibitory activity and mechanism of arylcoumarin derivatives on Theileria annulata enolase by in vitro and molecular docking studies Sinem Yakarsonmez1,2 · Ozkan Danis3 · Ozal Mutlu4 · Murat Topuzogullari1 · Emrah Sariyer5 · Basak Yuce‑Dursun3 · Dilek Turgut‑Balik1 Received: 7 August 2019 / Accepted: 15 November 2019 © Springer Nature Switzerland AG 2019
Abstract In this study, the inhibition potential of 3- and 4-arylcoumarin derivatives on Theileria annulata enolase (TaENO) was assessed for the first time in the literature. Firstly, protein stabilization analyses of TaENO were performed and it was found that the enzyme remains stable with the addition of 6 M ethylene glycol at + 4 °C. Inhibitor screening analyses were carried out using 25 coumarin derivatives on highly purified TaENO (> 95%), and four coumarin derivatives [4-(3,4-dimethoxyphenyl)-6,7-dihydroxy-2H-chromen-2-one (C8); 4-(3,4-dihydroxyphenyl)-7,8 dihydroxy-2H-chromen-2one (C9); 4-(3,4-dihydroxyphenyl)-6,7-dihydroxy-2H-chromen-2 one (C21); and 3-(3,4-dihydroxyphenyl)-7,8-dihydroxy-2Hchromen-2-one (C23)] showed the highest inhibitory effects with the I C50 values of 10.450, 13.170, 8.871 and 10.863 µM, respectively. The kinetic results indicated that these compounds inhibited the enzyme by uncompetitive inhibition. In addition, the successful binding of the most potent inhibitor (C21) into TaENO was confirmed by using MALDI-TOF mass spectrophotometry. Molecular docking analyses have predicted that C8 and C21 coumarin derivatives which showed high inhibitory effects on TaENO were interacted with high affinity to the potential regions out of the active site. Taken together, these coumarin derivatives (C8, C9, C21 and C23) are first known potent, nonsubstrate, uncompetitive inhibitors of TaENO and these results will facilitate further in vitro and in vivo analysis toward structure-based drug design studies. Graphic abstract
Keywords Structure-based drug design · Theileriosis · Drug resistance · Coumarin · Enolase · Enzyme inhibition * Dilek Turgut‑Balik [email protected] Extended author information available on the last page of the article
13
Vol.:(0123456789)
Introduction Structure-based drug design is a growing pharmaceutical area that provides an approach to understand the interaction between target macromolecules and small-molecule ligands. This method involves identifying a target structure and screening various compounds on the target to evaluate novel drug candidate compounds [1, 2]. When sufficient knowledge of the target protein is obtained by cloning, purification, in silico analyses and crystallography methods, drug design strategies steps would be routinely carried out [1, 3]. In this study, Theileria annulata enolase (TaENO) was chosen as a target to investigate its druggable potential by using structure-based drug design strategies. Theileria annulata is a protozoan parasite transmitted by tick vectors from Hyalomma species and causes tropical theileriosis in cattle [4, 5]. Recent
Data Loading...
