Confirmation by molecular docking of the pharmacophore defined as 4D-QSAR using the MCET method for the 2-hydroxydiarylamide derivatives

Abstract

For the 2-hydroxydiarylamide derivative series that inhibits serine proteases by mediating various events related to the basic processes of tumor invasion and metastasis in cancer, the pharmacophore responsible for the activity was estimated by the Molecular Conformer Electron Topological (MCET) method. The atoms in the common core structure of the molecules and template are aligned so that the remaining oriented atoms superimposition with the maximum number. In the 4D-Quantitative Structure Activity Relationship analysis, it is selected and used to represent the molecule that can interact best by the receptor among all conformers. Despite the unknown structure of the receptor, arranging molecules on the 3D coordinate system ensures that the ligand-receptor interaction is in the same direction and in the same manner. Pha, which is a subset, was estimated by accepting / rejection step by applying Genetic Algorithm steps to the clusters formed by the atomic clusters in the 3D coordinate system. The model proposed in the training set was verified in the external test set and the electronic identifying values of the Pha atoms in both sets were considered. The model was developed by splitting the molecules into training and external test sets according to similarities of both activities and descriptors. With Leave One Out-Cross Validation the model proposed according to 33 molecules in the training set (q2 = 0.998) was validated by using 8 molecules (r2 = 0.993) in the external test set. As a result of the MCET method, the proposed pharmacophore structure was confirmed using molecular docking.

Keywords

• 2-hydroxydiarylamide derivatives
• Molecular docking
• 4D-QSAR
• MCET
• Klopman index

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