Department of Physiology, Biochemistry and Pharmacology, Faculty of Veterinary Medicine, King Faisal University, Hofuf, Alahsa, Saudi Arabia.
Department of Pharmacology, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafrelsheikh, Kafrelsheikh, Egypt.
PLoS One. 2019 Feb 7;14(2):e0212065. doi: 10.1371/journal.pone.0212065. eCollection 2019.
Plasmodium falciparum thymidylate kinase (PfTMK) showed structural and catalytic distinctions from the host enzyme rendering it a hopeful antiprotozoal drug target. Despite the comprehensive enzymologic, structural, inhibitory and chemical synthesis approaches targeting this enzyme, the elucidation of the exact mechanism underlying the recognition of the atypical purine substrates remains to be determined. In this study, molecular dynamics (MD) simulation of a broad range of substrates and inhibitors as well as the inhibitory properties of deoxyguanosine (dG) derivatives were used to assess the PfTMK substructure molecular rearrangements. The estimated changes during the favourable binding of high affinity substrate (TMP) include lower interaction with P-loop, free residue fluctuations of the lid domain and the average RMSD value. The RMSD of TMP complex was higher and more rapidly stabilized than the dGMP complex. The lid domain flexibility is severely affected by dGMP and β-thymidine derivatives, while being partially fluctuating with other thymidine derivatives. The TMK-purine (dGMP) complex was slowly and gradually stabilized with lower over all structure flexibility and residue fluctuations especially at the lid domain, which closes the active site during its catalytic state. Thymidine derivatives allow structure flexibility of the lid domain being highly fluctuating in α- and β-thymidine derivatives and TMP. dG derivatives remains less efficient than thymidine derivatives in inhibiting TMK. The variations in the structural dynamics of the P-loop and lid domain in response to TMP or dGMP might favour thymidine-based compounds. The provided MD simulation strategy can be used for predicating structural changes in PfTMK during lead optimization.
疟原虫胸苷酸激酶（PfTMK）在结构和催化方面与宿主酶存在差异，使其成为有希望的抗原生动物药物靶点。尽管针对该酶进行了全面的酶学、结构、抑制和化学合成研究，但仍需确定识别非典型嘌呤底物的确切机制。在这项研究中，使用广泛的底物和抑制剂的分子动力学（MD）模拟以及脱氧鸟苷（dG）衍生物的抑制特性来评估 PfTMK 亚结构分子重排。估计在高亲和力底物（TMP）的有利结合过程中发生的变化包括与 P 环的相互作用降低、盖子结构域的自由残基波动以及平均 RMSD 值。TMP 复合物的 RMSD 比 dGMP 复合物更高且更快地稳定。盖子结构域的灵活性受到 dGMP 和β-胸苷衍生物的严重影响，而与其他胸苷衍生物部分波动。TMK-嘌呤（dGMP）复合物的稳定性逐渐提高，整体结构灵活性和残基波动降低，特别是在活性部位的盖子结构域，在其催化状态下关闭。胸苷衍生物允许盖子结构域的结构灵活性高度波动，在α-和β-胸苷衍生物和 TMP 中。dG 衍生物在抑制 TMK 方面的效率不如胸苷衍生物。P 环和盖子结构域的结构动力学对 TMP 或 dGMP 的响应变化可能有利于基于胸苷的化合物。所提供的 MD 模拟策略可用于预测 PfTMK 在先导优化过程中的结构变化。
