In-silico analysis of potent Mosquirix vaccine adjuvant leads.

IF 3.6 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY
Okello Harrison Onyango, Cynthia Mugo Mwenda, Grace Gitau, John Muoma, Patrick Okoth
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Abstract

Background: World Health Organization recommend the use of malaria vaccine, Mosquirix, as a malaria prevention strategy. However, Mosquirix has failed to reduce the global burden of malaria because of its inefficacy. The Mosquirix vaccine's modest effectiveness against malaria, 36% among kids aged 5 to 17 months who need at least four doses, fails to aid malaria eradication. Therefore, highly effective and efficacious malaria vaccines are required. The well-characterized P. falciparum circumsporozoite surface protein can be used to discover adjuvants that can increase the efficacy of Mosquirix. Therefore, the study sought to undertake an in-silico discovery of Plasmodium falciparum circumsporozoite surface protein inhibitors with pharmacological properties on Mosquirix using hierarchical virtual screening and molecular dynamics simulation.

Results: Monoclonal antibody L9, an anti-Plasmodium falciparum circumsporozoite surface protein molecule, was used to identify Plasmodium falciparum circumsporozoite surface protein inhibitors with pharmacological properties on Mosquirix during a virtual screening process in ZINCPHARMER that yielded 23 hits. After drug-likeness and absorption, distribution, metabolism, excretion, and toxicity property analysis in the SwissADME web server, only 9 of the 23 hits satisfied the requirements. The 9 compounds were docked with Plasmodium falciparum circumsporozoite surface protein using the PyRx software to understand their interactions. ZINC25374360 (-8.1 kcal/mol), ZINC40144754 (-8.3 kcal/mol), and ZINC71996727 (-8.9 kcal/mol) bound strongly to Plasmodium falciparum circumsporozoite surface protein with binding affinities of less than -8.0 kcal/mol. The stability of these molecularly docked Plasmodium falciparum circumsporozoite surface protein-inhibitor complexes were assessed through molecular dynamics simulation using GROMACS 2022. ZINC25374360 and ZINC71996727 formed stable complexes with Plasmodium falciparum circumsporozoite surface protein. They were subjected to in vitro validation for their inhibitory potential. The IC50 values ranging between 250 and 350 ng/ml suggest inhibition of parasite development.

Conclusion: Therefore, the two Plasmodium falciparum circumsporozoite surface protein inhibitors can be used as vaccine adjuvants to increase the efficacy of the existing Mosquirix vaccine. Nevertheless, additional in vivo tests, structural optimization studies, and homogenization analysis are essential to determine the anti-plasmodial action of these adjuvants in humans.

强效蚊子疫苗佐剂导联的计算机分析。
背景:世界卫生组织建议使用疟疾疫苗moquirix作为一项疟疾预防战略。然而,由于其无效性,moquirix未能减轻全球疟疾负担。moquirix疫苗对疟疾的有效性不高,在需要至少四剂疫苗的5至17个月大的儿童中只有36%的人有效,但未能帮助根除疟疾。因此,需要高效和有效的疟疾疫苗。表征良好的恶性疟原虫环孢子子表面蛋白可用于发现可提高蚊子功效的佐剂。因此,本研究试图通过分层虚拟筛选和分子动力学模拟,在计算机上发现对蚊子具有药理作用的恶性疟原虫环孢子子表面蛋白抑制剂。结果:利用抗恶性疟原虫环孢子子表面蛋白分子L9单克隆抗体,在ZINCPHARMER虚拟筛选过程中鉴定出对蚊子具有药理作用的恶性疟原虫环孢子子表面蛋白抑制剂,命中23个。在SwissADME网站服务器上进行药物相似、吸收、分布、代谢、排泄和毒性分析后,23个结果中只有9个符合要求。利用PyRx软件将这9种化合物与恶性疟原虫环孢子子表面蛋白对接,了解它们之间的相互作用。ZINC25374360 (-8.1 kcal/mol)、ZINC40144754 (-8.3 kcal/mol)和ZINC71996727 (-8.9 kcal/mol)与恶性疟原虫环孢子子表面蛋白结合较强,结合亲和力小于-8.0 kcal/mol。利用GROMACS 2022进行分子动力学模拟,评估这些分子对接的恶性疟原虫环孢子子表面蛋白抑制剂复合物的稳定性。ZINC25374360和ZINC71996727与恶性疟原虫环孢子子表面蛋白形成稳定的配合物。对其抑菌潜能进行了体外验证。IC50值在250 ~ 350 ng/ml之间,表明对寄生虫发育有抑制作用。结论:因此,两种恶性疟原虫环孢子子表面蛋白抑制剂可作为疫苗佐剂,提高现有蚊疫苗的效力。然而,额外的体内试验、结构优化研究和均质分析对于确定这些佐剂在人体内的抗疟原虫作用至关重要。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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