Introduction:
Acetyl-CoA Carboxylases (ACC) have been an important target for
the therapy of metabolic syndrome, such as obesity, hepatic steatosis, insulin resistance,
dyslipidemia, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis
(NASH), type 2 diabetes (T2DM), and some other diseases.
Methods:
In this study, virtual screening strategy combined with Bayesian categorization
modeling, molecular docking and binding site analysis with protein ligand interaction fingerprint
(PLIF) was adopted to validate some potent ACC inhibitors. First, the best Bayesian
model with an excellent value of Area Under Curve (AUC) value (training set AUC: 0.972,
test set AUC: 0.955) was used to screen compounds of validation library. Then the compounds
screened by best Bayesian model were further screened by molecule docking again.
Results:
Finally, the hit compounds evaluated with four percentages (1%, 2%, 5%, 10%)
were verified to reveal enrichment rates for the compounds. The combination of the ligandbased
Bayesian model and structure-based virtual screening resulted in the identification of
top four compounds which exhibited excellent IC 50 values against ACC in top 1% of the
validation library.
Conclusion:
In summary, the whole strategy is of high efficiency, and would be helpful for
the discovery of ACC inhibitors and some other target inhibitors.</P>
Discover Novel Covalent Inhibitors Targeting FLT3 through Hybrid Virtual Screening Strategy
