Center of Excellence for Molecular Biology and Genomics of Shrimp, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand.
Int J Mol Sci. 2023 Jan 11;24(2):1412. doi: 10.3390/ijms24021412.
(EHP) causes slow growth syndrome in shrimp, resulting in huge economic losses for the global shrimp industry. Despite worldwide reports, there are no effective therapeutics for controlling EHP infections. In this study, five potential druggable targets of EHP, namely, aquaporin (AQP), cytidine triphosphate (CTP) synthase, thymidine kinase (TK), methionine aminopeptidase2 (MetAP2), and dihydrofolate reductase (DHFR), were identified via functional classification of the whole EHP proteome. The three-dimensional structures of the proteins were constructed using the artificial-intelligence-based program AlphaFold 2. Following the prediction of druggable sites, the ZINC15 and ChEMBL databases were screened against targets using docking-based virtual screening. Molecules with affinity scores ≥ 7.5 and numbers of interactions ≥ 9 were initially selected and subsequently enriched based on their ADMET properties and electrostatic complementarities. Five compounds were finally selected against each target based on their complex stabilities and binding energies. The compounds CHEMBL3703838, CHEMBL2132563, and CHEMBL133039 were selected against AQP; CHEMBL1091856, CHEMBL1162979, and CHEMBL525202 against CTP synthase; CHEMBL4078273, CHEMBL1683320, and CHEMBL3674540 against TK; CHEMBL340488, CHEMBL1966988, and ZINC000828645375 against DHFR; and CHEMBL3913373, ZINC000016682972, and CHEMBL3142997 against MetAP2.The compounds exhibited high stabilities and low binding free energies, indicating their abilities to suppress EHP infections; however, further validation is necessary for determining their efficacy.
（EHP）导致虾生长缓慢综合征，给全球虾产业造成巨大经济损失。尽管有全球报道，但目前尚无有效的治疗方法来控制 EHP 感染。在这项研究中，通过对整个 EHP 蛋白质组进行功能分类，鉴定了 EHP 的五个潜在可药物靶标，即水通道蛋白 (AQP)、胞苷三磷酸 (CTP) 合酶、胸苷激酶 (TK)、蛋氨酸氨基肽酶 2 (MetAP2) 和二氢叶酸还原酶 (DHFR)。使用基于人工智能的程序 AlphaFold 2 构建了蛋白质的三维结构。在预测可药物靶标后，使用基于对接的虚拟筛选对 ZINC15 和 ChEMBL 数据库针对靶点进行筛选。根据亲和力评分≥7.5 和相互作用数≥9 初步选择具有亲和力的分子，并根据其 ADMET 特性和静电互补性进行富集。最后，根据复合物稳定性和结合能，针对每个靶标选择了五个化合物。针对 AQP 选择了 CHEMBL3703838、CHEMBL2132563 和 CHEMBL133039；针对 CTP 合酶选择了 CHEMBL1091856、CHEMBL1162979 和 CHEMBL525202；针对 TK 选择了 CHEMBL4078273、CHEMBL1683320 和 CHEMBL3674540；针对 DHFR 选择了 CHEMBL340488、CHEMBL1966988 和 ZINC000828645375；针对 MetAP2 选择了 CHEMBL3913373、ZINC000016682972 和 CHEMBL3142997。这些化合物表现出高稳定性和低结合自由能，表明它们有抑制 EHP 感染的能力；然而，还需要进一步验证来确定它们的疗效。
