背景:本研究旨在研究Mpro的非共价和非肽抑制剂,一个关键的蛋白质靶标,通过采用整合分子对接的综合方法,分子动力学模拟,和热门活动预测。重点是阐明与Mpro的潜在抑制剂的非共价和非肽结合模式。
方法:我们采用了半柔性分子对接方法,结合评分和ADME筛选,基于结构,从CMNPD和HERB中筛选化合物。这些方法允许我们根据它们的结合值和与主要蛋白酶的结合位点的相互作用找到潜在的候选物。为了进一步评估这些相互作用的稳定性,我们进行了分子动力学模拟和计算结合能。最终,我们采用了一种顶级活性预测方法,根据预测的抑制潜力对化合物进行优先排序.
结果:通过结合结合能计算和活性预测,我们确定了六种潜在的抑制剂分子,它们对Mpro具有有希望的活性。这些化合物表现出良好的结合相互作用和稳定性,使他们成为有吸引力的候选人进一步的实验验证和药物开发工作针对Mpro。
BACKGROUND: This study aims to investigate non-covalent and non-peptide inhibitors of Mpro, a crucial protein target, by employing a comprehensive approach that integrates molecular docking, molecular dynamics simulations, and top-hits activity predictions. The focus is on elucidating the non-covalent and non-peptide binding modes of potential inhibitors with Mpro.
METHODS: We employed a semi-flexible molecular docking methodology, binding score and ADME screening, which are based on structure, to screen compounds from CMNPD and HERB in silico. These methodologies allowed us to find potential candidates depending on their binding values and interactions with the binding site of main protease. To further evaluate the stability of these interactions, we conducted molecular dynamics simulations and calculated binding energies. Ultimately, a top-hits activity prediction method was employed to prioritize compounds based on their predicted inhibitory potential.
RESULTS: Through a combination of binding energy calculations and activity predictions, we identified six potential inhibitor molecules exhibiting promising activity against Mpro. These compounds demonstrated favorable binding interactions and stability profiles, making them attractive candidates for further experimental validation and drug development efforts targeting Mpro.