RESUMEN
Type 2 diabetes mellitus and diabetic foot ulcers remain serious worldwide health problems. Caffeic acid is one of the natural products that has been experimentally proven to have diverse pharmacological properties. This study aimed to assess the inhibitory activity of caffeic acid and ethanolic extract of spent coffee grounds targeting DPP-4 and MMP-9 enzymes and evaluate the molecular interactions through 50-ns molecular dynamics simulations. This study also introduced our new version of PyPLIF HIPPOS, PyPLIF HIPPOS 0.2.0, which allowed us to identify protein-ligand interaction fingerprints and interaction hotspots resulting from molecular dynamics simulations. Our findings revealed that caffeic acid inhibited the DPP-4 and MMP-9 activity with an IC50 of 158.19 ± 11.30 µM and 88.99 ± 3.35 µM while ethanolic extract of spent coffee grounds exhibited an IC50 of 227.87 ± 23.80 µg/100 µL and 81.24 ± 6.46 µg/100 µL, respectively. Molecular dynamics simulations showed that caffeic acid interacted in the plausible allosteric sites of DPP-4 and in the active site of MMP-9. PyPLIF HIPPOS 0.2.0 identified amino acid residues interacting more than 10% throughout the simulation, which were Lys463 and Trp62 in the plausible allosteric site of DPP-4 and His226 in the active site of MMP-9.
Asunto(s)
Café , Diabetes Mellitus Tipo 2 , Humanos , Café/química , Metaloproteinasa 9 de la Matriz , Etanol , Extractos Vegetales/farmacologíaRESUMEN
BACKGROUND: Chalcones, originated from natural product, have been broadly studied their biological activity against various proteins which at the molecular level, are responsible for the progress of the diseases in cancer (e.g. kinases), inflammation (oxidoreductases), atherosclerosis (cathepsins receptor), and diabetes (e.g. α-glucosidase). OBJECTIVE: Here we synthesize 10 chalcone derivatives to be evaluated their in vitro enzymatic inhibition activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). METHODS: The synthesis was carried out using Claissen-Schimdt condensation and the in vitro assay was conducted using Ellman Method. RESULTS: Compounds 2b and 4b demonstrated as the best IC50 of 9.3 µM and 68.7 µM respectively, towards AChE and BChE inhibition. Molecular docking studies predicted that this activity might be due to the interaction of the chalcones with important amino acid residues in the binding site of AChE such as SER200 and in that of BChE, such as TRP82, SER198, TRP430, TYR440, LEU286 and VAL288. CONCLUSION: Chalcone can be used as the scaffold for cholinesterase inhibitor, in particularly either fluorine or nitro group to be augmented at the para-position of Ring B, whereas the hydrophobic chain is necessary at the meta-position of Ring B.