DESIGN, IN-SILICO DOCKING AND PREDICTIVE ADME PROPERTIES OF NOVEL PYRAZOLINE DERIVATIVES WITH SELECTIVE HUMAN MAO INHIBITORY ACTIVITY
Keywords:Pyrazoline, hMAO inhibitors, Molecular docking simulation, Autodock420, Pharmacokinetic parameters, Schrodinger LLC, Structure-activity relationship
Objectives: Curcumin, a known hMAO-A (human Monoamine oxidase-A) inhibitor from Curcuma longa has never been recognized for this property due to its poor permeability and extensive metabolism. Thus, the main objective of this study is to incorporate structural features of Curcumin in the pyrazoline scaffold as an attempt to get potent, selective hMAO-isoform inhibitors with improved permeability.
Methods: A series of twelve novel 4, 4'-(4, 5-dihydro-1H-pyrazole-3,5-diyl)bis(2-methoxyphenol) derivatives (1-12) were designed based on the structure of Curcumin. All the designed compounds were evaluated for their hMAO inhibitory activity by in-silico docking studies (Autodock4.20). The both isomers (R-and S-isomer) are considered for simulation approach to understand the effect of chirality and other structural features that determine the potency and selectivity. In order to judge the pharmacokinetic behavior, all the derivatives were evaluated for their in-silico ADME properties by using Qik Prop v 3.0.
Results: The results of the present study showed that all the designed compounds were found to be potent and selective hMAO-isoform inhibitors, and exhibited lead like properties from the calculated ADME parameters. Curcumin was taken as a standard for comparison to judge any improvement in permeability.
Conclusion: The design strategy adopted has predicted improved potency, selective towards hMAO-isoform and permeability characteristics in comparison with Curcumin.
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