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Identification of selective Lyn inhibitors from the chemical databases through integrated molecular modelling approaches
SAR and QSAR in Environmental Research ( IF 3 ) Pub Date : 2020-11-09 , DOI: 10.1080/1062936x.2020.1799433
V.V. Shetve 1 , S. Bhowmick 2 , S.A. Alissa 3 , Z.A. Alothman 4 , S.M. Wabaidur 4 , F.A. Alasmary 4 , H.M Alhajri 4 , M.A. Islam 5, 6, 7
Affiliation  

ABSTRACT

In the current study, the Asinex and ChEBI databases were virtually screened for the identification of potential Lyn protein inhibitors. Therefore, a multi-steps molecular docking study was carried out using the VSW utility tool embedded in Maestro user interface of the Schrödinger suite. On initial screening, molecules having a higher XP-docking score and binding free energy compared to Staurosporin were considered for further assessment. Based on in silico pharmacokinetic analysis and a common-feature pharmacophore mapping model developed from the Staurosporin, four molecules were proposed as promising Lyn inhibitors. The binding interactions of all proposed Lyn inhibitors revealed strong ligand efficiency in terms of energy score obtained in molecular modelling analyses. Furthermore, the dynamic behaviour of each molecule in association with the Lyn protein-bound state was assessed through an all-atoms molecular dynamics (MD) simulation study. MD simulation analyses were confirmed with notable intermolecular interactions and consistent stability for the Lyn protein-ligand complexes throughout the simulation. High negative binding free energy of identified four compounds calculated through MM-PBSA approach demonstrated a strong binding affinity towards the Lyn protein. Hence, the proposed compounds might be taken forward as potential next-generation Lyn kinase inhibitors for managing numerous Lyn associated diseases or health complications after experimental validation.



中文翻译:

通过集成分子建模方法从化学数据库中鉴定选择性Lyn抑制剂

摘要

在当前的研究中,对Asinex和ChEBI数据库进行了虚拟筛选,以鉴定潜在的Lyn蛋白抑制剂。因此,使用嵌入在Schrödinger套件的Maestro用户界面中的VSW实用工具进行了多步分子对接研究。初步筛选时,与Staurosporin相比具有更高XP靠谱得分和结合自由能的分子被认为需要进一步评估。基于计算机药物动力学分析和由Staurosporin开发的通用功能药效团作图模型,提出了四个分子作为有前途的Lyn抑制剂。所有提出的Lyn抑制剂的结合相互作用都显示出很强的配体效率,这是通过分子建模分析获得的能量得分得出的。此外,通过全原子分子动力学(MD)模拟研究评估了与Lyn蛋白结合状态相关的每个分子的动力学行为。在整个模拟过程中,MD模拟分析均以明显的分子间相互作用和稳定的Lyn蛋白-配体复合物稳定性得到确认。通过MM-PBSA方法计算出的四种化合物的高负结合自由能显示出对Lyn蛋白的强结合亲和力。因此,在实验验证后,建议的化合物可作为潜在的下一代Lyn激酶抑制剂,用于管理众多Lyn相关疾病或健康并发症。在整个模拟过程中,MD模拟分析均通过明显的分子间相互作用和稳定的Lyn蛋白-配体复合物稳定性得到确认。通过MM-PBSA方法计算出的四种化合物的高负结合自由能显示出对Lyn蛋白的强结合亲和力。因此,在实验验证后,建议的化合物可作为潜在的下一代Lyn激酶抑制剂,用于管理众多Lyn相关疾病或健康并发症。在整个模拟过程中,MD模拟分析均以明显的分子间相互作用和稳定的Lyn蛋白-配体复合物稳定性得到确认。通过MM-PBSA方法计算出的四种化合物的高负结合自由能显示出对Lyn蛋白的强结合亲和力。因此,在实验验证后,建议的化合物可作为潜在的下一代Lyn激酶抑制剂,用于管理众多Lyn相关疾病或健康并发症。

更新日期:2020-11-09
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