A computational strategy for systematic virtual screening of plasmodium falciparum heme detoxification protein inhibitors from the Drugbank database

Antimalarial drug resistance poses one of the greatest threats to malaria treatment, resulting in increased morbidity and mortality. Heme Detoxification Protein (HDP) is among the essential hemoglobinases of P. falciparum (Pf), a vital molecular target for the treatment of malaria. In this study, we utilized the virtual screening workflow tool of the Schrodinger suite to find the best hits for the PfHDP from the DrugBank library. A total of 14,942 compounds were identified against the PfHDP. The top compounds with the highest docking scores and least energy scores were subjected to molecular simulations for 500 nanosecond to check the stability of the protein-drug complexes. The top three DrugBank compounds were found to be stable over 500 ns, namely DB09298 (silibinin), DB07426 (1-Hydroxy-2-(1,1':3',1''-Terphenyl-3-Yloxy) Ethane-1,1-Diyl] Bis (Phosphonic Acid), and DB07410 [(2-(3-Dibenzofuran-4-yl-Phenyl)-1-Hydroxy-1-Phosphono-Ethyl]-Phosphonic Acid). Overall analysis suggests that the top three compounds, DB09298, DB07426, and DB07410, have good stability for 500 ns. Their scaffolds can be used to design and develop new analogs of the target HDP protein. Silibinin, the anti-cancer drug, was found to be highly stable for the entire simulation period as compared to the other compounds. DB07426 shows its therapeutic effect on bones, especially in the treatment of osteoporosis, and DB07410 has anti-tumor, antibacterial, anti-oxidative, and anti-viral activities. All three compounds can be considered for repurposing as antimalarial drugs to evaluate the binding capacity or inhibition potential of these compounds. Further in-vivo and in-vitro analysis against the PfHDP protein should be conducted.

抗疟药耐药性是疟疾治疗领域面临的最严峻威胁之一，可导致疟疾的发病率与死亡率显著升高。血红素解毒蛋白（Heme Detoxification Protein，HDP）是恶性疟原虫（P. falciparum，Pf）必需的血红蛋白酶之一，亦是疟疾治疗的关键分子靶点。本研究依托施罗德（Schrödinger）软件套件的虚拟筛选流程工具，从DrugBank数据库中筛选靶向PfHDP的最优命中化合物，共鉴定出14942种可结合PfHDP的化合物。选取对接得分最高、能量得分最低的优质化合物开展500纳秒分子动力学模拟，以验证蛋白-药物复合物的结构稳定性。结果显示，排名前三的DrugBank化合物在500纳秒模拟周期内均表现出良好的稳定性，分别为DB09298（水飞蓟宾，silibinin）、DB07426（1-羟基-2-(1,1':3',1''-三联苯-3-氧基)乙烷-1,1-二基双(膦酸)）与DB07410（(2-(3-二苯并呋喃-4-基苯基)-1-羟基-1-膦酰基乙基)膦酸）。综合分析表明，上述三种化合物DB09298、DB07426与DB07410在500纳秒模拟周期内稳定性优异，其母核结构可用于设计开发靶向HDP蛋白的新型衍生物。其中，作为抗癌药物的水飞蓟宾在整个模拟周期内的稳定性优于其余两种化合物；DB07426对骨骼具有治疗作用，尤其可用于骨质疏松症的治疗；而DB07410则具备抗肿瘤、抗菌、抗氧化与抗病毒活性。上述三种化合物均可考虑作为抗疟药物进行老药新用，以评估其与PfHDP的结合能力或抑制潜能，后续需开展针对PfHDP蛋白的体内与体外实验验证。