Pharmaceutical Sciences Postgraduate Programme, Universidade Federal do Paraná, Curitiba, Brazil.
Department of Pharmacy, Fametro University Centre (UNIFAMETRO), Fortaleza-Ceará, Brazil.
J Biomol Struct Dyn. 2024 Jul;42(11):5881-5894. doi: 10.1080/07391102.2023.2229446. Epub 2023 Jul 2.
This study aimed to identify natural bioactive compounds (NBCs) as potential inhibitors of the spike (S1) receptor binding domain (RBD) of the COVID-19 Omicron variant using computer simulations (. NBCs with previously proven biological activity were obtained from the ZINC database and analyzed through virtual screening, molecular docking, molecular dynamics (MD), molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA), and molecular mechanics/generalized Born surface area (MM/GBSA). Remdesivir was used as a reference drug in docking and MD calculations. A total of 170,906 compounds were analyzed. Molecular docking screening revealed the top four NBCs with a high affinity with the spike (affinity energy <-7 kcal/mol) to be ZINC000045789238, ZINC000004098448, ZINC000008662732, and ZINC000003995616. In the MD analysis, the four ligands formed a complex with the highest dynamic equilibrium S1 (mean RMSD <0.3 nm), lowest fluctuation of the complex amino acid residues (RMSF <1.3), and solvent accessibility stability. However, the ZINC000045789238-spike complex (naringenin-4'-O glucuronide) was the only one that simultaneously had minus signal (-) MM/PBSA and MM/GBSA binding free energy values (-3.74 kcal/mol and -15.65 kcal/mol, respectively), indicating favorable binding. This ligand (naringenin-4'-O glucuronide) was also the one that produced the highest number of hydrogen bonds in the entire dynamic period (average = 4601 bonds per nanosecond). Six mutant amino acid residues formed these hydrogen bonds from the RBD region of S1 in the Omicron variant: Asn417, Ser494, Ser496, Arg403, Arg408, and His505. Naringenin-4'-O-glucuronide showed promising results as a potential drug candidate against COVID-19. and preclinical studies are needed to confirm these findings.Communicated by Ramaswamy H. Sarma.
本研究旨在利用计算机模拟鉴定新型冠状病毒奥密克戎变异株刺突（S1）受体结合域（RBD）的天然生物活性化合物（NBCs）作为潜在抑制剂。从 ZINC 数据库中获得了具有先前证明的生物学活性的 NBCs，并通过虚拟筛选、分子对接、分子动力学（MD）、分子力学/泊松-玻尔兹曼表面面积（MM/PBSA）和分子力学/广义 Born 表面面积（MM/GBSA）进行分析。瑞德西韦被用作对接和 MD 计算中的参考药物。共分析了 170906 种化合物。分子对接筛选显示，与刺突（亲和力能量 <-7kcal/mol）具有高亲和力的前 4 种 NBCs 分别为 ZINC000045789238、ZINC000004098448、ZINC000008662732 和 ZINC000003995616。在 MD 分析中，这四种配体与 S1 形成复合物，具有最高的动态平衡 S1（平均 RMSD<0.3nm）、复合物氨基酸残基最低波动（RMSF<1.3）和溶剂可及性稳定性。然而，ZINC000045789238-刺突复合物（柚皮素-4'-O 葡萄糖醛酸苷）是唯一同时具有负信号（-）MM/PBSA 和 MM/GBSA 结合自由能值（-3.74kcal/mol 和-15.65kcal/mol）的复合物，表明结合有利。这种配体（柚皮素-4'-O 葡萄糖醛酸苷）也是整个动态过程中产生氢键数量最多的一种（平均每个纳秒 4601 个氢键）。在奥密克戎变异株的 S1 的 RBD 区域，有六个突变氨基酸残基形成这些氢键：Asn417、Ser494、Ser496、Arg403、Arg408 和 His505。柚皮素-4'-O-葡萄糖醛酸苷作为一种潜在的抗新型冠状病毒药物候选物显示出良好的效果，但需要进行临床前研究来证实这些发现。通讯作者为拉马萨马·H·萨马。
