Effectiveness of cyclohexyl functionality in ugonins from Helminthostachys zeylanica to PTP1B and alpha-glucosidase inhibitions

Abstract

Ugonins are unique flavonoids with cyclohexyl motif from Helminthostachys zeylanica. Ugonins (1-6) from the target plant displayed significant inhibitions against both PTP1B (IC(50)s = 0.6-7.3 mu M) and alpha-glucosidase (IC(50)s = 3.9-32.9 mu M), which are crucial enzymes associated with diabetes. A cyclohexyl motif was proved to be the key functionality for PTP1B and alpha-glucosidase. For example, 1 was 26-fold effective to PTP1B and 15-fold to alpha-glucosidase than its mother compound, luteolin. This tendency was well elucidated with distinctive differences of binding affinities (K-SV) between ugonins and mother compounds to PTP1B enzyme. Inhibitory mechanisms to PTP1B and alpha-glucosidase were fully characterized to be competitive, non-competitive and mixed type I according to the position of cyclohexyl functionality. In particular, the ugonin J (1) has a cyclohexyl on the B ring was estimated as a reversible, competitive and a slow binding inhibitor with parameters: K-i(app)=0.1234 mu M, k(3)=0.5713 mu M-1 min(-1), and k(4) = 0.0705 min(-1). In-depth molecular docking experiments disclosed the specific binding sites and residues of competitive inhibitor (1) and non-competitive inhibitor (4) to PTP1B enzymes. As well, all six ugonins (1-6) also inhibited alpha-glucosidase effectively, in which cyclohexyl motif was also the key functionality of inhibitions. (c) 2020 Published by Elsevier B.V.