[BOINC] [生命科学类] SiDock@home
本帖最后由 panda7456 于 2024-2-14 14:21 编辑项目名称:SiDock@home
项目网站:https://www.sidock.si/
研究团队:纳塔利娅·尼基蒂娜博士(Dr. Natalia Nikitina)等人,项目团队主要有由俄罗斯“卡累利阿研究中心”与斯洛文尼亚马里博尔大学和卢布尔雅那大学组成。
项目介绍:
SiDock@home 是一个旨在药物发现的国际志愿者计算项目。
在我们的项目中,我们正在寻找配体(ligands)——能够成功与蛋白质靶标结合并调节对病毒生物化学至关重要的特定过程的小分子。基于分子对接,理想的配体应在形状和性质上与目标生物分子的结合位点互补。然而,小分子的互补性只是分子作为药物使用的一个先决条件。
大海捞针是寻找正确分子的最佳例证。由于可能的分子结构的数量,这是一个更加困难的问题。所有可能的分子结构的数量也被称为化学宇宙——这个抽象空间的大小可以估计为10的80次方。这个化学宇宙中有许多星系,其中一个星系是具有潜在的药理活性分子。用于此目的的方法称为虚拟筛选。原则上,我们研究的化学宇宙范围越大,找到冠状病毒潜在治疗方法的可能性就越大。
你可以帮忙处理你的电脑。在 BOINC 的帮助下,您将在计算机上下载化合物的子集,在研究目标的背景下检查化合物,并将结果发送到服务器,在那里收集它们以供以后分析。
项目成果/出版物:https://www.sidock.si/sidock/publications.php
小提示:项目目前倾向于分发长任务,计算时间较长、存盘点较少
项目当前目标(更新至2024.2):
我们的第一个任务:抗击 SARS-CoV-2,发现可能对抗 SARS-CoV-2 病毒的药物。它最初是作为 COVID.SI 项目的延伸。
项目未来拟延展到更多工作,详见下文转贴 本帖最后由 panda7456 于 2024-2-19 01:04 编辑
为下一个目标投票!|Vote for the next target!
发表于2024年1月26日
Dear all, we have obtained results for different targets of SARS-CoV-2. The computations continue, and we want to ask your opinion on the next target. You can vote for one of them until February 5th, 2024.
亲爱的大家,我们已经获得了 SARS-CoV-2 不同靶点的结果。 计算仍在继续,我们想征求您对下一个目标的意见。 您可以在 2024 年 2 月 5 日之前为其中一项投票。
SARS-CoV-2 main protease (3CLpro) further studies
This is a crucial therapeutic target against SARS-CoV-2. 3CLpro (cysteine protease; EC 3.4.22.69) in particular is crucial for the cleavage of coronavirus polyproteins to form mature non-structural proteins that are themselves essential for viral replication mechanisms. We still need much more research on this target towards new more potent inhibitors.
SARS-CoV-2主要蛋白酶(3CLpro)进一步研究
这是针对 SARS-CoV-2 的重要治疗靶点。 3CLpro(半胱氨酸蛋白酶;EC 3.4.22.69)对于切割冠状病毒多蛋白形成成熟的非结构蛋白尤其至关重要,而成熟的非结构蛋白本身对于病毒复制机制至关重要。 我们仍然需要对该靶点进行更多研究,以寻找新的更有效的抑制剂。
Ebolavirus glycoprotein (GP)
Ebola virus is a dangerous pathogen to humans and this target could be a perfect study case for PPI-type drug design scenario. The EBOV glycoprotein (GP) is the only virally expressed protein on the virion surface and is critical for attachment to host cells and catalysis of membrane fusion.
埃博拉病毒糖蛋白 (GP)
埃博拉病毒对人类来说是一种危险的病原体,这个目标可能是 PPI 型药物设计方案的完美研究案例。 EBOV 糖蛋白 (GP) 是病毒颗粒表面唯一的病毒表达蛋白,对于附着于宿主细胞和催化膜融合至关重要。
Swine acute diarrhea syndrome coronavirus (SADS-CoV PLpro)
This target would enable us to study the design on multiple related viral targets. Swine acute diarrhea syndrome coronavirus (SADS-CoV), a newly emerging enteric coronavirus, is considered to be associated with swine acute diarrhea syndrome (SADS) which has caused significantly economic losses to the porcine industry. The pathogen indicates towards host-jump potential.
猪急性腹泻综合征冠状病毒(SADS-CoV PLpro)
该目标将使我们能够研究多个相关病毒目标的设计。 猪急性腹泻综合征冠状病毒(SADS-CoV)是一种新出现的肠道冠状病毒,被认为与给养猪业造成重大经济损失的猪急性腹泻综合征(SADS)有关。 病原体表明有宿主跳跃的潜力。
由于投票已经结束,目前的投票结果如下:
1. SARS-CoV-2 main protease (3CLpro) further studies (133 votes) 37%
2. Ebolavirus glycoprotein (GP) (152 votes) 42%
3. Swine acute diarrhea syndrome coronavirus (SADS-CoV PLpro) (78 votes) 21%
似乎人们更想研究埃博拉
PS. 几位志愿者在讨论区说“I'm really impressed to see that 354 people did vote, this is great !” "Boinc is not dead ! ;)"
“看到 354 人投票,我真的很感动,这太棒了!” “BOINC没有死!;)”
PSS. 截止2024.2.19,现在的研究进度如下(与20个已完成的项目),详见https://www.sidock.si/sidock/server_status.php
Target 11: corona_Sprot_delta_v1 (%)42.617
Target 22: corona_RdRp_v2 (%)70.690
目标#23:埃博拉GP1 | Target # 23: Ebola GP1
发表于11 Jul 2024, 9:02:55 UTC
Dear participants,
亲爱的参与者,
as target # 22 is almost finished, we are glad to introduce the next target. Most of you have voted for Ebolavirus glycoprotein (GP) (174 out of 425 votes, wow!)
由于目标 # 22 即将完成,我们很高兴介绍下一个目标。你们中的大多数人都投票给了埃博拉病毒糖蛋白 (GP)(425 票中的 174 票,哇!)
The Ebola virus is a highly virulent pathogen responsible for causing Ebola hemorrhagic fever, a severe and often fatal disease. A key factor in the virus's ability to infect host cells and cause disease is its surface glycoprotein (GP), making it an attractive target for antiviral drug development. The Ebola GP is a trimeric protein composed of two subunits per monomer: GP1, responsible for receptor binding, and GP2, which mediates fusion between the viral and host cell membranes. Initially synthesized as a precursor protein, the GP is cleaved by host proteases (furin, cathepsin) into its functional subunits, a process essential for its role in mediating viral entry. The GP facilitates the virus's attachment to the host cell surface, followed by conformational changes that enable membrane fusion, allowing the virus to enter the host cell (to the host endosomal Niemann-Pick C1 (NPC1) receptor or via direct membrane binding; Vaknin et al.; ACS Infect. Dis. 2024, 10, 5, 1590–1601).
埃博拉病毒是一种高度致命的病原体,可引起埃博拉出血热,这是一种严重且往往致命的疾病。病毒能感染宿主细胞并引起疾病的一个关键因素是其表面糖蛋白 (glycoprotein, GP),使其成为抗病毒药物开发的有吸引力的目标。埃博拉 GP 是一种三聚体蛋白,每个单体由两个亚基组成:GP1,负责受体结合,GP2,介导病毒和宿主细胞膜之间的融合。GP 最初作为前体蛋白合成,被宿主蛋白酶(弗林蛋白酶、组织蛋白酶)切割成其功能性亚基,这一过程对于其介导病毒进入的作用至关重要。 GP 促进病毒附着在宿主细胞表面,随后发生构象变化,实现膜融合,从而使病毒进入宿主细胞(进入宿主内体尼曼-匹克 C1 (NPC1) 受体或通过直接膜结合;Vaknin 等人;ACS Infect. Dis. 2024, 10, 5, 1590–1601)。
Targeting the GP for drug development is advantageous due to its essential role in viral infection, its highly conserved structure among different Ebola virus strains, and the availability of specific binding cavities that can accommodate small-molecule inhibitors. Structural studies using techniques such as X-ray crystallography have identified these binding cavities and elucidated the GP's conformation in both its free and inhibited states. These insights enable the design of drugs that can specifically bind to and inhibit the GP by stabilizing it in its pre-fusion conformation or interfering with its cleavage, thereby preventing the necessary conformational changes for membrane fusion. We will employ high-resolution structures to conduct virtual screening experiments coupled to molecular dynamics simulations to ultimately identify potential GP inhibitors/modulators.
以 GP 为目标进行药物开发具有优势,因为它在病毒感染中起着重要作用,其在不同埃博拉病毒株之间的结构高度保守,并且具有可安置小分子抑制剂的特定结合腔。使用 X 射线晶体学等技术进行的结构研究已经确定了这些结合腔,并阐明了 GP 在游离状态和抑制状态下的构象。这些见解使得我们能设计出可特异性结合并抑制 GP 的药物,经由稳定 GP 的融合前构象或干扰其裂解,从而防止膜融合所需的构象变化。我们将采用高分辨率结构进行虚拟筛选实验,并结合分子动力学模拟,最终确定潜在的 GP 抑制剂/调节剂。
Promising compounds identified through these computational methods will hopefully undergo further validation using biochemical assays, pseudovirus entry assays, and structural analyses to confirm their inhibitory activity. Targeting the GP offers specificity, as it minimizes off-target effects on host cells and reduces the likelihood of resistance development. Moreover, due to the conserved nature of the GP, drugs targeting it could be effective against multiple Ebola virus strains and variants.
通过这些计算方法确定的有前景的化合物有望通过包含生化测定、假病毒进入测定和结构分析的进一步验证,以确认其抑制活性。以 GP 为靶点具有特异性,因为它可以最大限度地减少对宿主细胞的脱靶效应并降低产生抗药性的可能性。此外,由于 GP 的保守性,针对它的药物可能对多种埃博拉病毒株和变种有效。
We hope that our computations will contribute to the fight against Ebola!
我们希望我们的计算能够为抗击埃博拉病毒做出贡献!
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