Development of 2D, 3D-QSAR and Pharmacophore Modeling of Chalcones for the Inhibition of Monoamine Oxidase B

Background: Selective and reversible types of MAO-B inhibitors have emerged as promising candidates for the management of neurodegenerative diseases. Several functionalized chalcone derivatives were shown to have potential reversible MAO-B inhibitory activity, which have recently been reported from our laboratory. Methods: With the experimental results of about 70 chalcone derivatives, we further developed a pharmacophore modelling, and 2D and 3D- QSAR analyses of these reported chalcones for MAOB inhibition. Results: The 2D-QSAR model presented four variables (MATS7v, GATS 1i and 3i, and C-006) from 143 Dragon 7 molecular descriptors, with a r² value of 0.76 and a Q²cv for cross-validation equal to 0.72. An external validation also was performed using 11 chalcones, obtaining a Q²ext value of 0.74. The second 3D-QSAR model using MLR (multiple linear regression) was built starting from 128 Volsurf+ molecular descriptors, being identified as 4 variables (Molecular descriptors): D3, CW1 and LgS11, and L2LGS. Adetermination coefficient (r²) value of 0.76 and a Q²cv for cross-validation equal to 0.72 were obtained for this model. An external validation also was performed using 11 chalcones and a Q²ext value of 0.74 was found. Conclusion: This report exhibited a good correlation and satisfactory agreement between experiment and theory.