PART I. In-silico Investigation of Isoform Selectivity for CYP1 Enzymes

Abstract

PART I. In-silico Investigation of Isoform Selectivity for CYP1 Enzymes

Although several families of compounds have been identified as scaffolds for inhibitors of the CYP1 family, the isoform selectivity determining structural features have not been fully clarified at the molecular interaction level. We studied the CYP1 isoform selectivity for stilbenoid inhibitors using integrated induced fit docking and molecular dynamics simulations. The hydrophobic interactions with the specific phenylalanine residues in the F helix are correlated with inhibitory potency in the CYP1 family. Through this study, we found that the adaptable, small and semirigid ligand is a promising starting point for the development of isoform-selective inhibitors and investigation of selectivity-determining features.

PART II. Exploration of Piper Amide Derivatives as Melanogenesis Inhibitors Using Molecular Modeling

Piper-amides exhibit diverse biological activities, including antimelanogenic effects. In our previous studies, we identified a potent piper-amide derivative that inhibited melanogenesis via the TRPM1 calcium channel. Despite its potential as a therapeutic target, the three-dimensional structure of TRPM1 is still not available. Thus, structure-guided compound design and the discovery of novel inhibitors of melanogenesis have been limited. In the present study, a series of computational methods, including homology modeling, docking, molecular dynamics simulation and field-based pharmacophore modeling, were integrated to explore the structural features of natural piper-amide-like compounds related to the TRPM1 target. These studies suggested the binding mode and provided a 3D pharmacophore model of the ligands, which can be helpful in understanding the TRPM1-ligand interactions at the molecular level and in designing potent antagonist of TRPM1.