Structural Analysis of 2-Piperidin-4-yl-Actamide Derivatives for hERG Blocking and MCH R1 Antagonistic Activities

N.      S. Hari Narayana Moorthy; Maria      J. Ramos; Pedro      A. Fernandes

Abstract

In the present investigation, a computational based structural analysis was performed on a series of 2-piperidin- 4-yl-acetamide derivatives to investigate the physicochemical features of the molecules responsible for the hERG blocking and melanin concentrating hormone receptor-1 (MCH R1) antagonistic activities. The QSAR models derived from MLR analysis were validated by various validation methods and they provided significant statistical results such as Q2, F, ttest, R, predicated residual error values, etc. These significant models were constructed with different type of physicochemical descriptors which showed that the hydrophobic properties on the vdW surface of the molecules are favorable for both the activities (MCH R1 antagonistic and hERG blocking activities) and the presence of polar/electronegative groups in the molecules is detrimental for those activities. The presence of flexible aromatic rings in the molecules has favorable hERG blocking activity. The MCH R1 antagonistic activity also depends upon the vdW volume, shape and flexibility of the molecules. In addition, the presented results will guide for the optimized design of novel bioactive molecules with less/free of hERG blocking activities to avoid unwanted potential cardiotoxic side effects related with the use of these possible antiarrhythmic and anti-obesity agents in humans.

Keywords: anti-obesity drugs, hERG, hydrophobicity, MCH R1, multiple linear regressions, pharmacophore, QSAR, Piperidin, MLR analysis, mellitus