QSAR Studies and Scaffold Optimization of Predicted Novel ACC 2 Inhibitors to Treat Metabolic Syndrome

Abstract

Background: Metabolic syndrome is one of the major non-communicable global health hazards of the modern world owing to its amplifying prevalence. Acetyl coenzyme-A carboxylase 2 (ACC 2) is one of the most crucial enzymes involved in the manifestation of this disease because of its regulatory role in fatty acid metabolism.

Objective: To find novel potent ACC 2 inhibitors as therapeutic potential leads for combating metabolic syndrome.

Methods: In the present study, a two-dimensional quantitative structure-activity relationship (2D QSAR) approach was executed on biologically relevant thiazolyl phenyl ether derivatives as ACC 2 inhibitors for structural optimization. The physiochemical descriptors were calculated and thus a correlation was derived between the observed and predicted activity by the regression equation. The significant descriptors i.e. log P (Whole Molecule) and Number of H-bond Donors (Substituent 1) obtained under study were considered for the design of new compounds and their predicted biological activity was calculated from the regression equation of the developed model. The compounds were further validated by docking studies with the prepared ACC 2 receptor.

Results: The most promising predicted leads with the absence of an H-bond donor group at the substituted phenyl ether moiety yet increased overall lipophilicity exhibited excellent amino acid binding affinity with the receptor and showed predicted inhibitory activity of 0.0025 μM and 0.0027 μM. The newly designed compounds were checked for their novelty. Lipinski's rule of five was applied to check their druggability and no violation of this rule was observed.

Conclusion: The compounds designed in the present study have tremendous potential to yield orally active ACC 2 inhibitors to treat metabolic syndrome.

Keywords: ACC 2; QSAR; descriptor; log P; metabolic syndrome; molecular docking.; regression.