Molecular Bio-Computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban, 4001, South Africa.
Department of Veterinary Parasitology and Entomology, Faculty of Veterinary Medicine, University of Ibadan, Nigeria.
Comput Biol Chem. 2021 Feb;90:107412. doi: 10.1016/j.compbiolchem.2020.107412. Epub 2020 Nov 7.
Most notable Kinetoplastids are of the genus Trypanosoma and Leishmania, affecting several millions of humans in Africa and Latin America. Current therapeutic options are limited by several drawbacks, hence the need to develop more efficacious inhibitors. An investigation to decipher the mechanism behind greater inhibitory potency of a chroman-4-one derivative (compound 1) in Trypanosoma brucei pteridine reductase 1 (TbPTR1) and Leishmania major pteridine reductase 1 (LmPTR1) was performed. Estimation of ΔG revealed that compound 1 had a greater binding affinity in TbPTR1 with a ΔG value of -49.0507 Kcal/mol than -29.2292 Kcal/mol in LmPTR1. The ΔGbind in TbPTR1 were predominantly contributed by "strong" electrostatic energy compared to the "weak" van der Waals in LmPTR1. In addition to this, the NADPH cofactor contributed significantly to the total energy of TbPTR1. A characteristic weak aromatic π interaction common in PTR1 was more prominent in TbPTR1 than LmPTR1. The consistent occurrence of high-affinity conventional hydrogen bond interactions as well as a steady interaction of crucial active site residues like Arg14/Arg17, Ser95/Ser111, Phe97/Phe113 in TbPTR1/LmPTR1 with chroman-4-one moiety equally revealed the important role the moiety played in the activity of compound 1. Overall, the structural and conformational analysis of the active site residues in TbPTR1 revealed them to be more rigid than LmPTR1. This could be the mechanism of interaction TbPTR1 employs in exerting a greater potency than LmPTR1. These findings will further give insight that will be assistive in modifying compound 1 for better potency and the design of novel inhibitors of PTR1.
最著名的锥虫是锥体虫属和利什曼原虫属，影响着非洲和拉丁美洲的数百万人。目前的治疗选择受到多种缺陷的限制，因此需要开发更有效的抑制剂。为了解释色满-4-酮衍生物（化合物 1）在布氏锥虫喋啶还原酶 1（TbPTR1）和利什曼原虫喋啶还原酶 1（LmPTR1）中抑制活性更强的机制，进行了一项研究。ΔG 的估计表明，化合物 1 在 TbPTR1 中的结合亲和力更大，ΔG 值为-49.0507 Kcal/mol，而在 LmPTR1 中为-29.2292 Kcal/mol。与 LmPTR1 中的“弱”范德华力相比，TbPTR1 中的ΔGbind 主要由“强”静电能贡献。此外，NADPH 辅因子对 TbPTR1 的总能量有显著贡献。在 PTR1 中常见的特征性弱芳香π相互作用在 TbPTR1 中比在 LmPTR1 中更为突出。高亲和力常规氢键相互作用的一致发生以及关键活性位点残基如 Arg14/Arg17、Ser95/Ser111、Phe97/Phe113 与色满-4-酮部分的稳定相互作用同样表明该部分在化合物 1 的活性中起着重要作用。总的来说，TbPTR1 中活性位点残基的结构和构象分析表明，它们比 LmPTR1 更具刚性。这可能是 TbPTR1 发挥比 LmPTR1 更强活性的相互作用机制。这些发现将进一步提供深入了解，有助于修饰化合物 1 以提高其效力，并设计 PTR1 的新型抑制剂。
