Hossain Md Shahadat, Shovon Md Tanjil Islam, Hasan Md Rafid, Hakim Fuad Taufiqul, Hasan Mohammad Mehedi, Esha Sadia Afrose, Tasnim Sabiha, Nazir Md Shahoriar, Akhter Fahmida, Ali Md Ackas, Halim Mohammad A
Division of Infectious Diseases and Division of Computer-Aided Drug Design, The Red-Green Research Center, BICCB, Tejgaon 1215, Dhaka, Bangladesh.
Department of Chemistry and Biochemistry, Kennesaw State University, Kennesaw, Georgia 30144, United States.
ACS Omega. 2023 Sep 13;8(38):35207-35218. doi: 10.1021/acsomega.3c04903. eCollection 2023 Sep 26.
The NS2B/NS3 protease is highly conserved among various proteases of the Zika virus, making it an important therapeutic target for developing broad-spectrum antiviral drugs. The NS2B/NS3 protease is a crucial enzyme in the replication cycle of Zika virus and plays a significant role in viral maturation and assembly. Inhibiting the activity of this protease can potentially prevent viral replication, making it an attractive target for developing therapies against Zika virus infection. This work screens 429 antiviral peptides in comparison with substrate peptide against the NS2B/NS3 of Zika virus using molecular docking and molecular dynamics (MD) simulation. Based on the docking screening, MD simulation conducted for the best four peptides including AVP0239, AVP0642, AVP0660, and AVP2044, could be effective against NS2B/NS3. These results were compared with the control substrate peptide. Further analysis indicates that AVP0642 and AVP2044 are the most promising candidates. The interaction analysis showed that the catalytic site residues including His51, Asp75, Ser135 and other non-catalytic residues such as Asp129, Asp83, and Asp79 contribute substantial interactions. Hydrogen bonds (41%) and hydrophobic interactions (33%) are observed as the prominent non-covalent interaction prompting the peptide-protein complex formation. Furthermore, the structure-activity relationship (SAR) illustrates that positively charged (Lys, Arg) residues in the peptides dominate the interactions. This study provides the basis for developing novel peptide-based protease inhibitors for Zika virus.
NS2B/NS3蛋白酶在寨卡病毒的各种蛋白酶中高度保守，使其成为开发广谱抗病毒药物的重要治疗靶点。NS2B/NS3蛋白酶是寨卡病毒复制周期中的关键酶，在病毒成熟和组装中起重要作用。抑制这种蛋白酶的活性可能会阻止病毒复制，使其成为开发抗寨卡病毒感染疗法的有吸引力的靶点。这项工作使用分子对接和分子动力学（MD）模拟，与针对寨卡病毒NS2B/NS3的底物肽相比，筛选了429种抗病毒肽。基于对接筛选，对包括AVP0239、AVP0642、AVP0660和AVP2044在内的最佳四种肽进行MD模拟，可能对NS2B/NS3有效。这些结果与对照底物肽进行了比较。进一步分析表明，AVP0642和AVP2044是最有希望的候选者。相互作用分析表明，包括His51、Asp75、Ser135在内的催化位点残基以及其他非催化残基如Asp129、Asp83和Asp79贡献了大量相互作用。氢键（41%）和疏水相互作用（33%）被观察为促使肽-蛋白质复合物形成的突出非共价相互作用。此外，构效关系（SAR）表明，肽中的带正电荷（Lys、Arg）残基主导相互作用。本研究为开发新型基于肽的寨卡病毒蛋白酶抑制剂提供了依据。
