Pencarian Inhibitor DYRK2 dari Database Bahan Alam Zinc15: Analisis Farmakofor, Simulasi Docking dan Dinamika Molekule

Abstract

DYRK2 is a protein kinase that has many roles in various biological processes, including division, proliferation, differentiation, and apoptosis of cell. DYRK2 is involved in cell cycle regulation by regulating the activity of the 26S proteasome so that inhibition of DYRK2 activity can inhibit the function of the 26S proteasome and reduce the proliferation of cancer cells. In vitro test, Curcumin reduces the proliferation of cancer cells through inhibition of the DYRK2 enzyme. In the present work, curcumin analogues have been screened from the Zinc15 natural product database using a ligand-based pharmacophore model approach. The result was then evaluated by molecular docking and dynamics based on interaction energy, the average of binding free energy and interaction stability between ligand and active site of DYRK2. Screening of 270.547 molecules from Zinc15 database yielded 110 selected hit compounds. Molecular docking and dynamics consider three prospective curcumin analogues i.e. ZINC000085597244, ZINC000217945958, and ZINC000217643970. These molecules have better criteria than curcumin in some criteria, such as interaction energy, free binding energy, and interaction stability with the target. In conclusion, ZINC000085597244, ZINC000217945958, and ZINC000217643970 compounds are predicted to be potential candidates for anticancer drugs with a specific mechanism of action against DYRK2