Oduselu Gbolahan O, Elebiju Oluwadunni F, Ogunnupebi Temitope A, Akash Shopnil, Ajani Olayinka O, Adebiyi Ezekiel
Covenant University Bioinformatics Research (CUBRe), Covenant University, Ota, OG, Nigeria.
Department of Chemistry, Covenant University, Ota, OG, Nigeria.
Adv Appl Bioinform Chem. 2024 Sep 23;17:83-105. doi: 10.2147/AABC.S476404. eCollection 2024.
Existing antimalarial drugs primarily target blood-stage parasites, but there is a need for transmission-blocking drugs to combat malaria effectively. 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 CDPK4 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 CDPK4 (PDB 1D: 4QOX).
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.
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 CDPK4.
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 CDPK4 inhibitor for disrupting malaria transmission. However, further experimental studies are warranted to validate its efficacy and safety profile.
现有的抗疟药物主要针对血液阶段的寄生虫，但需要传播阻断药物来有效对抗疟疾。钙依赖性蛋白激酶4（CDPK4）是这类药物的一个有前景的靶点。本研究采用先进的六氢喹啉（HHQ）衍生物计算机模拟分析，以鉴定能够破坏疟疾传播的CDPK4抑制剂。基于结构的虚拟筛选（SBVS）用于发现对CDPK4的3D结构（PDB ID：4QOX）具有最高结合亲和力的HHQ衍生物。
利用Discovery Studio Client对蛋白质-配体复合物进行相互作用分析，同时分别使用SwissADME和pkCSM网络服务器评估类药性质和ADMET性质。使用密度泛函理论（DFT）对顶级命中物进行量子力学计算，并使用GROMACS进行分子动力学（MD）模拟。使用AMBER软件包中的MMPBSA.py工具预测结合自由能。
SBVS鉴定出十个最佳命中物，其对接分数在-11.2 kcal/mol至-10.6 kcal/mol范围内，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-腈（PubChem ID：145784778）对CDPK4表现出最高的结合亲和力（-11.2 kcal/mol）。
使用先进的计算方法将该化合物与BKI-1294进行比较分析，显示出其竞争潜力。这些发现表明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-腈作为一种有前景的CDPK4抑制剂，具有破坏疟疾传播的潜力。然而，需要进一步的实验研究来验证其疗效和安全性。
