Application of temperature-dependent and steered molecular dynamics simulation to screen anti-dengue compounds against Marburg virus

Marburg virus infections are extremely fatal with a fatality range of 23% to 90%, therefore there is an urgent requirement to design and develop efficient therapeutic molecules. Here, a comprehensive temperature-dependent molecular dynamics (MD) simulation method was implemented to identify the potential molecule from the anti-dengue compound library that can inhibit the function of the VP24 protein of Marburg. Virtual high throughput screening identified five effective binders of VP24 after screening 484 anti-dengue compounds. These compounds were treated in MD simulation at four different temperatures: 300, 340, 380, and 420 K. Higher temperatures showed dissociation of hit compounds from the protein. Further, triplicates of 100 ns MD simulation were conducted which showed that compounds ID = <b>118717693</b>, and ID = <b>5361</b> showed strong stability with the protein molecule. These compounds were further validated using ΔG binding free energies and they showed: −30.38 kcal/mol, and −67.83 kcal/mol binding free energies, respectively. Later, these two compounds were used in steered MD simulation to detect its dissociation. Compound ID = <b>5361</b> showed the maximum pulling force of 199.02 kcal/mol/nm to dissociate the protein-ligand complex while ID = <b>118717693</b> had a pulling force of 101.11 kcal/mol/nm, respectively. This ligand highest number of hydrogen bonds with varying occupancies at 89.93%, 69.80%, 57.93%, 52.33%, and 50.63%. This study showed that ID = <b>5361</b> can bind with the VP24 strongly and has the potential to inhibit its function which can be validated in the in-vitro experiment.

马尔堡病毒感染致死性极强，病死率介于23%至90%之间，因此亟需设计并开发高效的治疗性分子。本研究采用全面的温度依赖性分子动力学（Molecular Dynamics, MD）模拟方法，从抗登革病毒化合物库中筛选可抑制马尔堡病毒VP24蛋白功能的潜在分子。通过虚拟高通量筛选，在484种抗登革病毒化合物中鉴定出5种有效的VP24结合剂。随后在300 K、340 K、380 K及420 K四种不同温度下对这些化合物开展MD模拟，结果显示高温条件下命中化合物会从蛋白表面解离。进一步开展三次重复的100 ns MD模拟，结果表明化合物ID=118717693与ID=5361可与VP24蛋白保持极强的结合稳定性。通过结合自由能ΔG对这两种化合物进行验证，二者的结合自由能分别为-30.38 kcal/mol与-67.83 kcal/mol。随后对这两种化合物实施拉伸分子动力学（Steered MD）模拟以检测其解离行为：化合物ID=5361解离蛋白-配体复合物所需的最大拉力为199.02 kcal/mol/nm，而化合物ID=118717693的解离拉力为101.11 kcal/mol/nm。其中，化合物ID=5361可形成最多数量的氢键，其氢键占有率分别为89.93%、69.80%、57.93%、52.33%与50.63%。本研究证实，化合物ID=5361可与VP24蛋白紧密结合，具备抑制其功能的潜力，可通过体外实验进一步验证。