Departamento de Biofísica e Farmacologia, Universidade Federal do Rio Grande do Norte, 59072-970, Natal, RN, Brazil.
Phys Chem Chem Phys. 2020 Jul 21;22(27):15683-15695. doi: 10.1039/d0cp02254c. Epub 2020 Jul 3.
The emergent Zika virus (ZIKV) infection has become a threat to global health due to its association with severe neurological abnormalities, namely Guillain-Barré Syndrome (GBS) in adults and Congenital Zika virus Syndrome (CZS) in neonates. Many studies are nowadays being conducted to find an effective antiviral drug against ZIKV. In particular, NS2B-NS3 protease is an attractive drug target due to its essential function in viral replication, although a drug is not yet commercially available. In this context, we present here a comparative structural study, based on quantum chemistry calculations, to analyze the intermolecular binding energies between the crystallographic structure of NS2B-NS3 protease and dipeptide boronic acid (cn-716) and aldehyde (acyl-KR-aldehyde) peptidomimetic inhibitors, by using the molecular fractionation with conjugate caps (MFCC) scheme within the density functional theory (DFT) formalism. Most intermolecular interactions in cn-716/NS2B-NS3 (acyl-KR-aldehyde/NS2B-NS3) are due to the amino acid residues Asp83*, His51, Asp129, Ser81*, Gly133, Ala132, Tyr161, Asn152 and Asp75 (Asp83*, Asp129, His51, Asn152, Tyr161, Tyr130, Gly153, Gly151, Asp75, Pro131, and Gly82). Additionally, we have considered missense mutation analysis of these residues to evaluate the destabilization and the increase of the flexibility of the protease, showing that mutation of the residues Tyr161 and Tyr130 causes more impact. Our simulations are a valuable tool for a better understanding of the binding mechanism of recognized inhibitors of NS2B-NS3 protease, and can lead to the rational design and development of novel anti-Zika drugs with improved efficiency.
新兴的 Zika 病毒（ZIKV）感染因其与严重神经异常有关，包括成人中的格林-巴利综合征（GBS）和新生儿中的先天性 Zika 病毒综合征（CZS），已成为全球健康的威胁。目前正在进行许多研究以寻找针对 ZIKV 的有效抗病毒药物。特别是，NS2B-NS3 蛋白酶由于其在病毒复制中的重要功能，是一种有吸引力的药物靶标，尽管尚未有商业化的药物。在这种情况下，我们在此基于量子化学计算提出了一项比较结构研究，以分析结晶 NS2B-NS3 蛋白酶结构与二肽硼酸（cn-716）和醛（酰基-KR-醛）肽模拟抑制剂之间的分子间结合能，使用分子分段与共轭帽（MFCC）方案在密度泛函理论（DFT）形式下。cn-716/NS2B-NS3（酰基-KR-醛/NS2B-NS3）中的大多数分子间相互作用归因于氨基酸残基 Asp83*、His51、Asp129、Ser81*、Gly133、Ala132、Tyr161、Asn152 和 Asp75（Asp83*、Asp129、His51、Asn152、Tyr161、Tyr130、Gly153、Gly151、Asp75、Pro131 和 Gly82）。此外，我们考虑了这些残基的错义突变分析，以评估蛋白酶的不稳定性和柔韧性增加，表明 Tyr161 和 Tyr130 残基的突变造成更大的影响。我们的模拟为更好地理解 NS2B-NS3 蛋白酶的识别抑制剂的结合机制提供了有价值的工具，并可以导致设计和开发具有更高效率的新型抗 Zika 药物。
