Department of Chemical Engineering, Istanbul Technical University, Istanbul, Turkey.
Computational Science and Engineering Division, Informatics Institute, Istanbul Technical University, Istanbul, Turkey.
J Biomol Struct Dyn. 2023 May;41(8):3496-3510. doi: 10.1080/07391102.2022.2051743. Epub 2022 Mar 18.
Experimental evidence indicated that bacterial pyruvate kinase of glycolysis can be evaluated as an alternative target to eliminate infections, while antibiotic resistance poses a global threat. Here, we use a computational workflow to reveal and investigate the potential allosteric sites of methicillin-resistant PK, which can help in designing species-specific drugs to inhibit activity of this organism. Residue interaction networks point to a known allosteric site at the small C-C interface, a potential allosteric site near the small interface (site #1), and a second potential allosteric site at the large interface (site #2). 2 µs-long molecular dynamics (MD) simulations with AMBER16 generate different conformations of one narrow target site. Known and potential allosteric sites on the selected conformers are investigated using ensemble docking with AutoDock Vina and a library of 2447 FDA-approved drugs. We determine 18 hits, comprising ergot-alkaloids, anti-cancer-agents, antivirals, analgesics, cardiac glycosides, all with a high docking -score for three sites. 5 selected compounds with high, average and low -scores are subjected to 50 ns-long MD simulations for MM-GBSA calculations. ΔG values up to -49.3 kcal/mol at the C-C interface, up to -32.7 kcal/mol at site #1, and up to -53.3 kcal/mol at site #2 support the docking calculations. We investigate mitapivat and TT-232 as reference compounds under clinical trial, targeting human PK isomers. We suggest 18 FDA-approved hits from the docking calculations and TT-232 as potential inhibitors with multiple target sites on PK. This study also proposes pharmacophores models for drug design.Communicated by Ramaswamy H. Sarma.
实验证据表明，糖酵解中的细菌丙酮酸激酶可以作为消除感染的替代靶标进行评估，而抗生素耐药性则构成了全球性威胁。在这里，我们使用计算工作流程来揭示和研究耐甲氧西林 PK 的潜在变构位点，这有助于设计针对该物种的特异性药物来抑制该生物的活性。残基相互作用网络指向小 C-C 界面上的一个已知变构位点、小界面附近的一个潜在变构位点（位点#1）和大界面上的第二个潜在变构位点（位点#2）。使用 AMBER16 进行 2 µs 长的分子动力学（MD）模拟会产生一个狭窄靶标位点的不同构象。使用 AutoDock Vina 进行整体对接并结合 2447 种 FDA 批准药物库，研究选定构象体上的已知和潜在变构位点。我们确定了 18 个命中物，包括麦角生物碱、抗癌剂、抗病毒药、镇痛药、强心苷，它们在三个位点的对接得分都很高。选择具有高、中、低对接得分的 5 种化合物进行 50 ns 长的 MD 模拟，用于 MM-GBSA 计算。在 C-C 界面处的 ΔG 值高达-49.3 kcal/mol，在位点#1 处高达-32.7 kcal/mol，在位点#2 处高达-53.3 kcal/mol，支持对接计算。我们研究了米他培南和 TT-232 作为临床试验中的参考化合物，针对人类 PK 同工酶。我们建议将对接计算中的 18 种 FDA 批准的命中物和 TT-232 作为具有多个靶标位点的潜在抑制剂，用于 PK。该研究还提出了药物设计的药效团模型。由 Ramaswamy H. Sarma 传达。
