Molecular docking, simulation and binding free energy analysis of small molecules as PfHT1 inhibitors.
Molecular docking, simulation and binding free energy analysis of small molecules as PfHT1 inhibitors.
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DOI：
10.1371/journal.pone.0268269
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发表时间：
2022
期刊：
影响因子：
3.7
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中科院分区：
文献类型：
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抗疟疾药物的耐药性给消灭疟疾的工作带来了麻烦。需要新的药物来辅助支持现有的疟疾控制工作。恶性疟原虫的生存和增殖需要宿主的葡萄糖。在此基础上，参与己糖渗透的恶性疟原虫己糖转运蛋白1（PfHT1）被认为是潜在的药物靶点。在这项研究中，我们使用计算技术测试了一些化合物对PfHT1的抗疟活性。我们对21，352种针对PfHT1的小分子化合物进行了高通量虚拟筛选。通过分子动力学（MD）模拟100纳秒来评价先导化合物络合物的稳定性。我们还根据Lipinksi规则研究了化合物的药效学，药代动力学和生理学特征，以结合和抑制PfHT 1。使用具有广义玻恩和表面积（MMGBSA）溶剂化的分子力学进行分子对接和自由结合能分析，以确定命中化合物对PfHT 1相对于人葡萄糖转运蛋白（hGLUT 1）直向同源物的选择性。鉴定了五种重要的PfHT 1抑制剂：金丝桃苷（CID 5281643）; avicularin（CID 5490064）; sylibin（CID 5213）;哈巴俄苷（CID 5481542）和槲皮苷（CID 5281680）。这些化合物通过保守的氨基酸残基（Val314、Gly183、Thr49、Asn52、Gly183、Ser315、Ser317和Asn48）与PfHT1靶标的结合口袋形成分子间相互作用。MMGBSA分析的复合物产生高的自由结合能。发现四种（CID5281643、CID5490064、CID5213和CID5481542）鉴定的化合物在整个100纳秒模拟运行时间内在PfHT1结合口袋内稳定。这四种化合物对PfHT1的亲和力高于人主要葡萄糖转运蛋白（hGLUT1）。本研究证明了sylibin，金丝桃苷，哈巴俄苷，和avicularin对PfHT 1受体的抑制潜力。需要稳健的临床前研究来验证所鉴定的化合物的化疗性质。
Antimalarial drug resistance has thrown a spanner in the works of malaria elimination. New drugs are required for ancillary support of existing malaria control efforts. Plasmodium falciparum requires host glucose for survival and proliferation. On this basis, P. falciparum hexose transporter 1 (PfHT1) protein involved in hexose permeation is considered a potential drug target. In this study, we tested the antimalarial activity of some compounds against PfHT1 using computational techniques. We performed high throughput virtual screening of 21,352 small-molecule compounds against PfHT1. The stability of the lead compound complexes was evaluated via molecular dynamics (MD) simulation for 100 nanoseconds. We also investigated the pharmacodynamic, pharmacokinetic and physiological characteristics of the compounds in accordance with Lipinksi rules for drug-likeness to bind and inhibit PfHT1. Molecular docking and free binding energy analyses were carried out using Molecular Mechanics with Generalized Born and Surface Area (MMGBSA) solvation to determine the selectivity of the hit compounds for PfHT1 over the human glucose transporter (hGLUT1) orthologue. Five important PfHT1 inhibitors were identified: Hyperoside (CID5281643); avicularin (CID5490064); sylibin (CID5213); harpagoside (CID5481542) and quercetagetin (CID5281680). The compounds formed intermolecular interaction with the binding pocket of the PfHT1 target via conserved amino acid residues (Val314, Gly183, Thr49, Asn52, Gly183, Ser315, Ser317, and Asn48). The MMGBSA analysis of the complexes yielded high free binding energies. Four (CID5281643, CID5490064, CID5213, and CID5481542) of the identified compounds were found to be stable within the PfHT1 binding pocket throughout the 100 nanoseconds simulation run time. The four compounds demonstrated higher affinity for PfHT1 than the human major glucose transporter (hGLUT1). This investigation demonstrates the inhibition potential of sylibin, hyperoside, harpagoside, and avicularin against PfHT1 receptor. Robust preclinical investigations are required to validate the chemotherapeutic properties of the identified compounds.