Abstract
Objective: Malonyl CoA decarboxylase (MCD) enzyme plays important role in fatty acid and glucose oxidation. Inhibition of MCD might turn to a novel approach to treat ischemia. The main objective of this research article was to develop a novel pharmacophore for enhanced activity.Methods: Three-dimensional quantitative structure-activity relationships (3D-QSAR) was performed for pyrazoline derivatives as MCD inhibitors using VLife MDS 4.6 software. The QSAR model was developed using the stepwise 3D-QSAR kNN-MFA method.Results: The statistical results generated from kNN-MFA method indicated the significance and requirements for better MCD inhibitory activity. The information rendered by 3D-QSAR model may render to better understanding and designing of novel MCD inhibitors.Conclusion: 3D-QSAR is an important tool in understanding the structural requirements for the design of novel and potent MCD inhibitors. It can be employed to design new drug discovery.
Highlights
Cardiovascular disease, being one of the leading causes of death in the world, is continuing to act as a major problem of health in both developing and developed countries
Inhibition of malonyl CoA decarboxylase (MCD) increases the levels of malonyl-CoA, which further reduces fatty acid oxidation and increases glucose oxidation in the mitochondria of heart cells
3D-QSAR by a kNN-MFA model coupled with a stepwise variable selection method was developed for 18 novel 3, 5diaryl-(pyrazol-1-yl)-1, 3-thiazole-4(5H)-one derivatives (1-10) and 3, 5-diaryl-(pyrazol-1-yl)-ethanone derivatives (11-18) based on steric, electrostatic and hydrophobic fields
Summary
Cardiovascular disease, being one of the leading causes of death in the world, is continuing to act as a major problem of health in both developing and developed countries. After the development of ischemia, increased fatty acid level in circulation causes increased fatty acid oxidation and decreased glucose oxidation by heart cells. This leads to uncoupling of glucose oxidation and glycolysis, causing heart cells’ acidosis [4,5]. Increase in glucose oxidation has two benefits, (i) reduction in acidosis of heart cells and, (ii) increased ATP production, causing more energy supply to heart cells [9,10,11,12] These observations affirm the further scope and need for the development of newer MCD inhibitors for ischemia treatment
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