Structure-guided Design and Optimization of small Molecules as Pancreatic Lipase Inhibitors using Pharmacophore, 3D-QSAR, Molecular Docking, and Molecular Dynamics Simulation Studies

药效团 分子动力学 数量结构-活动关系 对接(动物) 计算生物学 化学 广告 计算化学 立体化学 奥利斯特 脂肪酶 小分子 生物化学 生物 医学 肥胖 内科学 护理部 体外 减肥
作者
Shristi Modanwal,Viswajit Mulpuru,Nidhi Mishra
出处
期刊:Current Computer - Aided Drug Design [Bentham Science Publishers]
卷期号:19 (4): 258-277 被引量:5
标识
DOI:10.2174/1573409919666230103144045
摘要

Obesity has now become a global issue due to the increase in the population of obese people. It also substantially impacts the individual's social, financial, and psychological well-being, which may contribute to depression. Being overweight induces many metabolic and chronic disorders, urging many researchers to focus on developing the drug for obesity treatment. Pancreatic lipase inhibitors and natural product/compound-derived pancreatic lipase inhibitors have recently received much attention because of their structural variety and low toxicity.This study aimed to build pharmacophores and QSAR for analyzing the necessary structure of pancreatic lipase inhibitors and designing new molecules with the best activity.Ligand-based pharmacophore modeling and Atom-Based 3D-QSAR were carried out using the PHASE module of Schrodinger to determine the critical structural properties necessary for pancreatic lipase (PL) inhibitory activity. A total of 157 phytoconstituents and a standard drug, orlistat, were selected for the present study. Considering the important features for pancreatic lipase inhibition, 15 new molecules were designed and subjected to molecular docking studies and molecular dynamics simulations. The activity of designed molecules was predicted using the Atom- Based QSAR tool of the PHASE module.The top docked score molecule is structure-7 with a docking score of -6.094 Kcal/mol, whereas the docking score of orlistat and tristin is -3.80Kcal/mol and -5.63Kcal/mol, respectively.The designed molecules have a high docking score and good stability, are in the desirable ADME range and are derived from natural products, so they might be used as lead molecules for anti-obesity drug development.
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