Generation of selective TACE inhibitors: Ligand and structure based molecular modeling, virtual screening, counter pharmacophore screening to get selective molecules

This study describes the ligand based as well as structure based molecular modeling and virtual screening of selective tumor necrosis factor-a converting enzyme (TACE) inhibitors. In ligand based molecular modeling, two statistically reliable pharmacophore models HypoA1 and HypoB1 were generated using a same training set of 22 molecules. HypoA1 consists of two hydrogen bond acceptor and three hydrophobic groups whereas HypoB1 consists of one hydrogen bond donor, one ring aromatic and three hydrophobic groups. Virtual screening was performed with both models in in-house database of 1.2 million molecules. To remove non selective hits from screened molecules, a counter pharmacophore was generated using inhibitors of MMP-1, an important enzyme involved in musculoskeletal degradation. In structure based molecular modeling, docking analysis was performed to explore the important interactions between ligands and protein. On comparison, HypoA1 and HypoB1 were found to be complementing with results of docking analysis suggesting high reliability of both models for their use in virtual screening/designing of new molecules.