Structure prediction of gBP21 protein of <i>L. donovani</i> and its molecular interaction
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Visceral leishmaniasis (Kala-azar) is a fatal disease caused by the obligate intracellular parasite <i>Leishmania donovani</i> and the available drugs for the treatment are few, and are frequently associated with side effects and toxicity. RNA editing is one of the essential metabolic processes in the kinetoplastids, where the pre-mRNAs are edited post-transcriptionally by the guide RNAs with the addition or deletion of uridine residues. The aim is to block the gBP21 protein involved in RNA editing process thereby other direct and indirect protein activity is reduced and ultimately the editing process in <i>L. donovani</i> is disturbed and it will inhibit the growth. RNA editing factors are RNA-linked proteins essential for <i>in vivo</i> editing i.e. mitochondrial RNA binding protein1 (MRP 1) originally called as gBP21. The model of <i>L. donovani</i> gBP21 (gBP21Ldv) showed that this protein bears an anti-parallel ß sheet (segregated α and ß regions) with ß-ß-ß-ß-α-ß-ß-ß-ß-α-type topology (“whirly” transcription-factor fold). Each of the four ß strands within a given ß-ß-ß-ß-α repeats and form a curved anti-parallel ß-sheet that packs perpendicularly against the sheet from the other repeat. Among all of the computationally screened compounds by the GLIDE program (Schrödinger) and GOLD program hyperoside1a, posaconazole, quercetin, and pentanediol, 427 exhibited higher binding affinities with the modeled gBP21 protein of <i>L. donovani</i>. Ligandfit program <i>(</i>DSv2.5) revealed that DNA, RNA polymerase inhibitors acyclovir, mitomycin C, and daunorubicin have better binding affinity towards gBP21Ldv. These compounds may be given in combination with miltefosine (first line therapy) against patients with VL and other associated disorders like anemia.
内脏利什曼病（黑热病，Kala-azar）是由专性细胞内寄生虫杜氏利什曼原虫（Leishmania donovani）引发的致死性疾病，当前可用治疗药物稀缺，且常伴随不良反应与毒性反应。RNA编辑是动基体目（Kinetoplastids）生物的核心代谢过程之一，该过程通过向导RNA（guide RNAs）在转录后对前体mRNA进行尿苷残基的添加或删除操作。本研究旨在阻断参与RNA编辑过程的gBP21蛋白，以降低其他直接与间接相关蛋白的活性，最终干扰杜氏利什曼原虫体内（in vivo）的RNA编辑进程，从而抑制其生长。RNA编辑因子是与RNA结合的、体内编辑所必需的蛋白，其中线粒体RNA结合蛋白1（mitochondrial RNA binding protein 1, MRP1）最初被命名为gBP21蛋白。对杜氏利什曼原虫gBP21蛋白（gBP21Ldv）的结构建模显示，该蛋白含有反向平行β折叠片层（由分离的α螺旋区与β折叠区组成），其拓扑结构为β-β-β-β-α-β-β-β-β-α型，即"whirly"转录因子折叠模体。单个β-β-β-β-α重复单元内的4条β链各自卷曲，形成弯曲的反向平行β折叠片层，该片层会与其他重复单元的片层垂直堆叠。通过Schrödinger公司的GLIDE程序与GOLD程序完成计算筛选的427种化合物中，金丝桃苷1a（hyperoside1a）、泊沙康唑（posaconazole）、槲皮素（quercetin）与戊二醇（pentanediol）与杜氏利什曼原虫建模的gBP21蛋白表现出更高的结合亲和力。使用DSv2.5的LigandFit程序分析发现，RNA聚合酶抑制剂类化合物阿昔洛韦（acyclovir）、丝裂霉素C（mitomycin C）与柔红霉素（daunorubicin）对gBP21Ldv具有更优的结合亲和力。上述化合物可与米替福新（miltefosine，一线治疗方案）联合使用，用于治疗内脏利什曼病患者及伴随贫血等相关病症的患者。
