Devi Kanika, Chandra Anshuman, Chaudhuri Susmita, Kumar Goel Vijay
School of Physical Sciences, Jawaharlal Nehru University, New Delhi, 110067, India.
Centre for Biodesign, Translational Health Science and Technology Institute, Faridabad, Haryana, 121001, India.
Chem Biodivers. 2025 Jan;22(1):e202401668. doi: 10.1002/cbdv.202401668. Epub 2024 Nov 9.
Malaria, an infectious disease caused by Plasmodium falciparum, is becoming increasingly difficult to treat due to the emergence of drug-resistant strains. Recent studies have proposed purine nucleoside phosphorylase from P. falciparum (PfPNP) as a potential target for malaria treatment. In the present study, we designed a virtual library of 400 dipeptides to discover novel anti-malarial peptide inhibitors. A structure-based molecular docking method was employed to virtually screen the designed library against the wild-type structure of PfPNP (PDB: 5ZNC). The best four (Phe-Arg, Arg-His, Trp-Arg and Tyr-Arg) dipeptides, which were then investigated for their binding potential against PfPNP using Molecular Dynamics simulation studies. Parameters such as RMSD, RMSF, Rg, and SASA were analyzed to understand the structural changes, energetics, and overall behavior of PfPNP-dipeptide complexes. The PfPNP demonstrated significant stability upon binding with each of the identified dipeptides with ΔG of over -168 kcal/mol. Additionally, DFT and ADME predictions indicated that the electronic structure, energetics, and pharmacokinetic properties of Phe-Arg, Arg-His, Trp-Arg and Tyr-Arg were favourable for drug development. Our comprehensive computational investigation has identified these four dipeptides as promising candidates. These designed and selected dipeptides may further be modified using peptidomimetic and medicinal chemistry tools to develop a novel class of promising antimalarials.
疟疾是一种由恶性疟原虫引起的传染病，由于耐药菌株的出现，其治疗难度越来越大。最近的研究提出，恶性疟原虫的嘌呤核苷磷酸化酶（PfPNP）作为疟疾治疗的潜在靶点。在本研究中，我们设计了一个包含400种二肽的虚拟文库，以发现新型抗疟肽抑制剂。采用基于结构的分子对接方法，针对PfPNP的野生型结构（PDB：5ZNC）对设计的文库进行虚拟筛选。然后使用分子动力学模拟研究对最佳的四种二肽（苯丙氨酸-精氨酸、精氨酸-组氨酸、色氨酸-精氨酸和酪氨酸-精氨酸）与PfPNP的结合潜力进行研究。分析了均方根偏差（RMSD）、均方根波动（RMSF）、回旋半径（Rg）和溶剂可及表面积（SASA）等参数，以了解PfPNP-二肽复合物的结构变化、能量学和整体行为。PfPNP与每种鉴定出的二肽结合时表现出显著的稳定性，自由能变化（ΔG）超过-168 kcal/mol。此外，密度泛函理论（DFT）和药物代谢动力学（ADME）预测表明，苯丙氨酸-精氨酸、精氨酸-组氨酸、色氨酸-精氨酸和酪氨酸-精氨酸的电子结构、能量学和药代动力学性质有利于药物开发。我们全面的计算研究已将这四种二肽确定为有前景的候选物。这些设计和选择的二肽可进一步使用拟肽和药物化学工具进行修饰，以开发一类新型的有前景的抗疟药物。
