Investigation of 3D pharmacophore of N-benzyl benzamide molecules of melanogenesis inhibitors using a new descriptor Klopman index: uncertainties in model.

ABSTRACT

We used a new descriptor called the Klopman index in our software of the "molecular comparative electron topology" (MCET) method to reduce the uncertainty resulting from the descriptors used in QSAR studies. The 3D pharmacophore model (3D-PhaM), which can demonstrate three-dimensional interaction between the ligand -receptor (L-R), is only possible with local reactive descriptors (LRD). The Klopman index, containing both Coulombic and frontier orbital and interactions of atoms of the ligand, is a good LRD. Molecular conformers having the best matching atoms with the template conformer can be selected as one of the most suitable spatial structures for interaction with the receptor, and the LRD values of the atoms in this conformer serve to determine 3D-PhaM. The 3D-PhaM of the N-benzyl benzamide derivatives, such as the melanogenesis inhibitor, was determined by ligand-based MCET and confirmed by the structure-based FlexX docking method. For compounds of the training set (42) and the external cross validation test set (6), the Q2 (0.862) and R2 (0.913) of the statistical parameters were calculated, respectively, and were checked by rm2 (0.85) of the stringent validation.