Abstract
Background: Curcumin reduces the proliferation of cancer cells through inhibition of the DYRK2 enzyme, which is a positive regulator of the 26S proteasome. Methods: In the present work, curcumin analogues have been screened from the MolPort database using a pharmacophore model that comprised a ligand-based approach. The result of the screening was then evaluated by molecular docking and molecular dynamics based on binding the free energy of the interaction between each compound with the binding pocket of DYRK2. The hit compounds were then confirmed by absorption, distribution, metabolism, and excretion (ADME) prediction. Results: Screening of 7.4 million molecules from the MolPort database afforded six selected hit compounds. By considering the ADME prediction, three prospective curcumin analogues have been selected. These are: 2‐[2‐(1‐methylpyrazol‐4‐yl)ethyl]‐1H,5H,6H,7H,8H‐imidazo[4,5‐c]azepin‐4‐one (Molport-035-369-361), methyl 4‐(3‐hydroxy‐1,2‐oxazol‐5‐yl)piperidine‐1‐carboxylate (Molport-000-004-273) and (1S)‐1‐[5‐(furan‐3‐carbonyl)‐4H,6H,7H‐pyrazolo[1,5‐a]pyrazin‐2‐yl]ethanol (MolPort-035-585-822). Conclusion: Pharmacophore modelling, combined with molecular docking and molecular dynamics simulation, as well as ADME prediction were successfully applied to screen curcumin analogues from the MolPort database as DYRK2 inhibitors. All selected compounds that have better predicted pharmacokinetic properties than that of curcumin are considered for further study.
Highlights
Curcumin is a compound derived from turmeric (Curcuma longa), which is responsible for the yellow rhizome extract coloration
Protein preparation 5ZTN was the Protein Data Bank accession number of the dual-specificity tyrosine-regulated kinase 2 (DYRK2) protein used in this study,[17] and curcumin acted as the native ligand
Ligand-based pharmacophore modeling The hypothetic pharmacophore was grouped based on the number of features, comprising 3 to 7, and each has 10 models, totaling to 50
Summary
Curcumin is a compound derived from turmeric (Curcuma longa), which is responsible for the yellow rhizome extract coloration. A large number of people in India, China, Indonesia and other Asian countries have applied turmeric powder in therapeutic herbs and as a food additive.[1,2,3,4,5] The curcumin (diferuloylmethane) constituent is a tautomeric compound known to exist as an enolic form in organic solvents, and in keto form in water.[6] The wide range of biological activities are currently being tested in vivo and in vitro to develop the numerous potentials in treating various diseases. All selected compounds that have better predicted pharmacokinetic properties than that of curcumin are considered for further study
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