Identification of megacerotonic acid and a quinazoline derivative from Universal Natural Product Database as potential inhibitors of Trypanosoma brucei brucei alternative oxidase: molecular docking, molecular dynamic simulation and MM/PBSA analysis.
Identification of megacerotonic acid and a quinazoline derivative from Universal Natural Product Database as potential inhibitors of Trypanosoma brucei brucei alternative oxidase: molecular docking, molecular dynamic simulation and MM/PBSA analysis.
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从通用天然产物数据库中鉴定大丙酮酸和喹唑啉衍生物作为布氏锥虫替代氧化酶的潜在抑制剂：分子对接、分子动力学模拟和 MM/PBSA 分析。
DOI：
10.1080/07391102.2021.2003862
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发表时间：
2023
影响因子：
4.4
通讯作者：
Balogun,EmmanuelOluwadare
中科院分区：
文献类型：
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作者：
Adamu,RahmaMuhammad;Ibrahim,Bashiru;Ibrahim,MohammedAuwal;Balogun,EmmanuelOluwadare
非洲锥虫病是由布氏锥虫亚种引起的，现有的抗非洲锥虫病药物由于药代动力学特性差而不能令人满意。锥虫替代氧化酶（TAO）是一个有吸引力的目标，抗锥虫合理的药物发现，因为它是必不可少的寄生虫特异性ATP的产生和缺乏在哺乳动物宿主。在这项研究中，从通用天然产物数据库中筛选出360个配体，并将其对接到T上。布鲁氏菌TAO（PDB-ID 3VVA）。从虚拟筛选中，选择结合能为-10.6至-9.0 kcal/mol的10个配体作为命中物，并进一步进行药代动力学和毒性分析，其中所有配体均通过Lipinski的五分法则。此外，化合物是非致突变性的，非致瘤性的，并且可以穿过血脑屏障。两个最高的命中（UNPD 29179;巨角鲨酸和UNPD 41551;喹唑啉衍生物）与酶催化位点上接近二铁（2种铁元素）的4种谷氨酸（Glu 123、Glu 162、Glu 213和Glu 266）相互作用。随后，使用GROMACS进行两个最顶部命中的100 ns MD模拟，其中观察到0.75 nm（TA 0-UNPD 29179）和0.52 nm（TA 0-UNPD 41551）的高RMSD值、低残基波动和一致的回转半径值。此外，两种复合物的溶剂可溶解表面积显示出160 nm 2的一致值，而TAO-UNPD 29179具有比TAO-UNPD 41551更高的氢键数。同样，MM/PBSA计算表明UNPD 29179与TAO的自由结合能高于UNPD 41551。这些数据表明，巨松酸和喹唑啉衍生物可能是TAO的潜在抑制剂，具有改善的药代动力学特性。Sarma
African trypanosomiasis is caused byTrypanosoma bruceisubspecies and available drugs against it, are unsatisfactory due to poor pharmacokinetic properties. Trypanosomal Alternative Oxidase (TAO) is an attractive target for anti-trypanosome rational drug discovery because it is essential for parasite-specific ATP generation and absent in the mammalian host. In this study, 360 filtered ligands from the Universal Natural Product Database were virtually screened and docked onT. brucei bruceiTAO (PDB-ID 3VVA). From the virtual screening, 10 ligands with binding energy from −10.6 to −9.0 kcal/mol were selected as hits and further subjected pharmacokinetic and toxicity analyses where all of them passed Lipinski’s rule of five. Also, the compounds were non-mutagenic, non-tumorigenic and could cross the blood brain barrier. The two topmost hits (UNPD29179; megacerotonic acid and UNPD41551; a quinazoline derivative) interacted with `four glutamates (Glu123, Glu162, Glu213 and Glu266) close to di-iron (2 iron elements) at the catalytic site of the enzyme. Subsequently, 100 ns MD simulations of the two topmost hits were performed using GROMACS where high RMSD values of 0.75 nm (TAO-UNPD29179) and 0.52 nm (TAO- UNPD41551), low residues fluctuations and consistent values of radius of gyration were observed. Moreover, Solvent Accessible Surface Area showed a consistent value of 160 nm2for both complexes while TAO-UNPD29179 had higher number of hydrogen bonds than the TAO-UNPD41551. Similarly, MM/PBSA calculations indicated that UNPD29179 had higher free binding energy with TAO than UNPD41551. The data suggest that megacerotonic acid and a quinazoline derivative could be potential inhibitors of TAO with improved pharmacokinetic properties.Communicated by Ramaswamy H. Sarma