Employing Hexahydroquinolines as PfCDPK4 Inhibitors to Combat Malaria Transmission: An Advanced Computational Approach.

Q2 Biochemistry, Genetics and Molecular Biology Advances and Applications in Bioinformatics and Chemistry Pub Date : 2024-09-23 eCollection Date: 2024-01-01 DOI:10.2147/AABC.S476404

Gbolahan O Oduselu, Oluwadunni F Elebiju, Temitope A Ogunnupebi, Shopnil Akash, Olayinka O Ajani, Ezekiel Adebiyi

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Abstract

Background: Existing antimalarial drugs primarily target blood-stage parasites, but there is a need for transmission-blocking drugs to combat malaria effectively. Plasmodium falciparum Calcium-dependent Protein Kinase 4 (CDPK4) is a promising target for such drugs. This study employed advanced in silico analyses of hexahydroquinolines (HHQ) derivatives to identify PfCDPK4 inhibitors capable of disrupting malaria transmission. Structure-based virtual screening (SBVS) was employed to discover HHQ derivatives with the highest binding affinities against the 3D structure of PfCDPK4 (PDB 1D: 4QOX).

Methods: Interaction analysis of protein-ligand complexes utilized Discovery Studio Client, while druglikeness and ADMET properties were assessed using SwissADME and pkCSM web servers, respectively. Quantum mechanical calculations of the top hits were conducted using density functional theory (DFT), and GROMACS was employed to perform the molecular dynamics (MD) simulations. Binding free energy was predicted using the MMPBSA.py tool from the AMBER package.

Results: SBVS identified ten best hits possessing docking scores within the range of -11.2 kcal/mol and -10.6 kcal/mol, surpassing the known inhibitor, BKI-1294 (-9.9 kcal/mol). Among these, 4-[4-(Furan-2-carbonyl)piperazin-1-yl]-1-(naphthalen-2-ylmethyl)-2-oxo-4a,5,6,7,8,8a-hexahydroquinoline-3-carbonitrile (PubChem ID: 145784778) exhibited the highest binding affinity (-11.2 kcal/mol) against PfCDPK4.

Conclusion: Comparative analysis of this compound with BKI-1294 using advanced computational approaches demonstrated competitive potential. These findings suggest the potential of 4-[4-(Furan-2-carbonyl)piperazin-1-yl]-1-(naphthalen-2-ylmethyl)-2-oxo-4a,5,6,7,8,8a-hexahydroquinoline-3-carbonitrile as a promising PfCDPK4 inhibitor for disrupting malaria transmission. However, further experimental studies are warranted to validate its efficacy and safety profile.

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利用六氢喹啉作为 PfCDPK4 抑制剂对抗疟疾传播：高级计算方法。

背景：现有的抗疟疾药物主要针对血期寄生虫，但还需要阻断传播的药物来有效防治疟疾。恶性疟原虫钙依赖蛋白激酶 4（CDPK4）是此类药物的一个有希望的靶点。本研究采用先进的六氢喹啉（HHQ）衍生物硅学分析方法来鉴定能够阻断疟疾传播的 PfCDPK4 抑制剂。通过基于结构的虚拟筛选（SBVS），发现了与 PfCDPK4 三维结构（PDB 1D: 4QOX）结合亲和力最高的 HHQ 衍生物：方法：利用 Discovery Studio Client 对蛋白质配体复合物的相互作用进行分析，同时分别利用 SwissADME 和 pkCSM 网络服务器对药物亲和性和 ADMET 特性进行评估。利用密度泛函理论（DFT）对热门化合物进行了量子力学计算，并采用 GROMACS 进行了分子动力学（MD）模拟。使用 AMBER 软件包中的 MMPBSA.py 工具预测了结合自由能：SBVS确定了10个最佳命中物，其对接得分在-11.2 kcal/mol和-10.6 kcal/mol之间，超过了已知抑制剂BKI-1294（-9.9 kcal/mol）。其中，4-[4-(呋喃-2-羰基)哌嗪-1-基]-1-(萘-2-基甲基)-2-氧代-4a,5,6,7,8,8a-六氢喹啉-3-甲腈（PubChem ID：145784778）对 PfCDPK4 的结合亲和力最高（-11.2 kcal/mol）：结论：利用先进的计算方法对该化合物与 BKI-1294 进行的比较分析表明，该化合物具有竞争潜力。这些研究结果表明，4-[4-(呋喃-2-羰基)哌嗪-1-基]-1-(萘-2-基甲基)-2-氧代-4a,5,6,7,8,8a-六氢喹啉-3-甲腈有可能成为破坏疟疾传播的 PfCDPK4 抑制剂。不过，还需要进一步的实验研究来验证其有效性和安全性。

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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来源期刊

Advances and Applications in Bioinformatics and Chemistry Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (miscellaneous)

CiteScore

6.50

自引率

0.00%

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审稿时长

16 weeks