PDF(Pubmed)
Abstract：
Monkeypox (now Mpox), a zoonotic disease caused by the monkeypox virus (MPXV) is an emerging threat to global health. In the time span of only six months, from May to October 2022, the number of MPXV cases breached 80,000 and many of the outbreaks occurred in locations that had never previously reported MPXV. Currently there are no FDA-approved MPXV-specific vaccines or treatments, therefore, finding drugs to combat MPXV is of utmost importance. The A42R profilin-like protein of the MPXV is involved in cell development and motility making it a critical drug target. A42R protein is highly conserved across orthopoxviruses, thus A42R inhibitors may work for other family members. This study sought to identify potential A42R inhibitors for MPXV treatment using computational approaches. The energy minimized 3D structure of the A42R profilin-like protein (PDB ID: 4QWO) underwent virtual screening using a library of 36,366 compounds from Traditional Chinese Medicine (TCM), AfroDb, and PubChem databases as well as known inhibitor tecovirimat via AutoDock Vina. A total of seven compounds comprising PubChem CID: 11371962, ZINC000000899909, ZINC000001632866, ZINC000015151344, ZINC000013378519, ZINC000000086470, and ZINC000095486204, predicted to have favorable binding were shortlisted. Molecular docking suggested that all seven proposed compounds have higher binding affinities to A42R (-7.2 to -8.3 kcal/mol) than tecovirimat (-6.7 kcal/mol). This was corroborated by MM/PBSA calculations, with tecovirimat demonstrating the highest binding free energy of -68.694 kJ/mol (lowest binding affinity) compared to the seven shortlisted compounds that ranged from -73.252 to -97.140 kJ/mol. Furthermore, the 7 compounds in complex with A42R demonstrated higher stability than the A42R-tecovirimat complex when subjected to 100 ns molecular dynamics simulations. The protein-ligand interaction maps generated using LigPlot+ suggested that residues Met1, Glu3, Trp4, Ile7, Arg127, Val128, Thr131, and Asn133 are important for binding. These seven compounds were adequately profiled to be potential antivirals via PASS predictions and structural similarity searches. All seven potential lead compounds were scored Pa > Pi for antiviral activity while ZINC000001632866 and ZINC000015151344 were predicted as poxvirus inhibitors with Pa values of 0.315 and 0.215, and Pi values of 0.052 and 0.136, respectively. Further experimental validations of the identified lead compounds are required to corroborate their predicted activity. These seven identified compounds represent solid footing for development of antivirals against MPXV and other orthopoxviruses.
摘要：
猴痘（现为Mpox），由猴痘病毒（MPXV）引起的人畜共患疾病是对全球健康的新威胁。在仅仅六个月的时间里，从2022年5月到10月，MPXV病例数突破了8万例，许多疫情发生在以前从未报告过MPXV的地方。目前还没有FDA批准的MPXV特异性疫苗或治疗方法，因此,寻找对抗MPXV的药物至关重要。MPXV的A42Rprofilin样蛋白参与细胞发育和运动，使其成为关键的药物靶标。A42R蛋白在正痘病毒中高度保守，因此，A42R抑制剂可能对其他家族成员有效。本研究试图使用计算方法鉴定用于MPXV治疗的潜在A42R抑制剂。A42Rprofilin样蛋白（PDBID：4QWO）的能量最小化的3D结构使用来自中药（TCM）的36,366种化合物进行了虚拟筛选，AfroDb,和PubChem数据库以及通过AutoDockVina的已知抑制剂tecovirimat。总共七个化合物包括PubChemCID:11371962、ZINC000000899909、ZINC000001632866、ZINC000015151344、ZINC000013378519、ZINC000000086470和ZINC000095486204，预计具有有利的结合入围。分子对接表明，所有七个提出的化合物对A42R的结合亲和力（-7.2至-8.3kcal/mol）均高于tecovirimat（-6.7kcal/mol）。MM/PBSA计算证实了这一点，tecovirimat显示最高的结合自由能-68.694kJ/mol（最低结合亲和力），而七个入围化合物的范围为-73.252至-97.140kJ/mol。此外，当进行100ns分子动力学模拟时，与A42R配合物的7种化合物表现出比A42R-tecovirimat配合物更高的稳定性。使用LigPlot产生的蛋白质-配体相互作用图表明残基Met1，Glu3，Trp4，Ile7，Arg127，Val128，Thr131和Asn133对于结合很重要。通过PASS预测和结构相似性搜索，这七个化合物被充分分析为潜在的抗病毒药物。所有七个潜在的先导化合物的抗病毒活性评分为Pa>Pi，而ZINC000001632866和ZINC000015151344被预测为痘病毒抑制剂，Pa值分别为0.315和0.215，Pi值分别为0.052和0.136。需要对已鉴定的先导化合物进行进一步的实验验证，以证实其预测的活性。这七个鉴定的化合物代表了开发针对MPXV和其他正痘病毒的抗病毒药物的坚实基础。
