Design,synthesis, biological evaluation and molecular modelling studies of indole glyoxylamides as a new class of potential pancreatic lipase inhibitors |
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| Institution: | 1. College of Basic Medical Sciences, Dalian Medical University, Dalian 116000, China;2. Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116000, China;3. Translational Medicine Center, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine & Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 200000, China;4. Dalian Runsheng Kangtai Medical Laboratory Co. Ltd., Dalian 116000, China;1. Department of Microbiology and Biotechnology, R. C. Patel Arts, Commerce and Science College, Shirpur, 425405 Maharashtra, India;2. Department of Biochemistry, School of Life Sciences, North Maharashtra University, Jalgaon, Maharashtra, India;1. Department of Food Science, The Pennsylvania State University, University Park, PA, United States;2. The Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, PA, United States;3. The Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA, United States;1. Department of Biotechnology, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, China;2. Institute of Interdisciplinary Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China;3. Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China;4. Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100193, China;5. Key Laboratory of Contraceptives and Devices Research (NPFPC), Shanghai Engineer and Technology Research Center of Reproductive Health Drug and Devices, Shanghai Institute of Planned Parenthood Research, Shanghai, China;1. Department of Pharmacognosy, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt;2. Department of Agro-environmental Sciences, Graduate School of Bioresource and Bioenvironmental Science, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka, 819-0395, Japan;3. Department of Biological Resources Management, The University of Shiga Prefecture 2500, Hassaka-cho, Hikone-City, Shiga, 522-8533, Japan |
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| Abstract: | A series of eighteen indole glyoxylamide analogues were synthesized, characterized and evaluated for their pancreatic lipase inhibitory activity. Porcine pancreatic lipase (Type II) was used with 4-nitrophenyl butyrate (as substrate) for the in vitro assay. Compound 8f exhibited competitive inhibition against pancreatic lipase with IC50 value of 4.92 µM, comparable to that of the standard drug, orlistat (IC50 = 0.99 µM). Compounds 7a-i and 8a-i were subjected to molecular docking into the active site of human PL (PDB ID: 1LPB) wherein compound 8f possessed a potential MolDock score of −153.037 kcal/mol. Molecular dynamics simulation of 8f complexed with pancreatic lipase, confirmed the role of aromatic substitution in stabilizing the ligand through hydrophobic interactions (maximum observed RMSD = 3.5 Å). |
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| Keywords: | Indole glyoxylamides Inhibition kinetics Molecular dynamics Orlistat Pancreatic lipase |
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