Molecular Bio-Computation & Drug Design Lab, School of Health Sciences, University of KwaZulu-Natal, Westville, Durban, 4000, South Africa.
Chem Biodivers. 2019 Dec;16(12):e1900365. doi: 10.1002/cbdv.201900365. Epub 2019 Nov 11.
The quest for reliable dihydroorotate dehydrogenase (DHODH) inhibitors has engendered the discovery of potential therapeutic compounds at different stages of clinical trials. Although promising, high attrition rates and unfavorable bioactivities have limited their drug developmental progress. A recent structural modification of DSM265, a triazolopyrimidine-based inhibitor, yielded DSM421, derived by the substitution of the SF -aniline group on DSM265 with a CF -pyridinyl moiety. Consequently, DSM421 exhibited improved pharmacological and pharmacokinetics attributes relative to DSM265. The improved bioactivity mediated by the CF -pyridinyl group leaves us with a curiosity to investigate underlying ligand-binding mechanisms and dynamics using computational methods. Presented in this study are insights that clearly explain the effects of structural SF -aniline→CF -pyridinyl modifications on pfDHODH inhibition. Findings showed that the CF -pyridinyl group induced an optimal and stabilized positioning of DSM421 within the binding pocket, allowing for steady and strong intermolecular interactions which favored its stronger binding affinity as estimated and correlated with bioactivity data. These interactions consequently induced a pronounced stabilization of the structural conformation of pfDHODH by restricting residue motions, which possibly underpinned its enhanced inhibitory activity relative to DSM265. Active site interactions of the CF -pyrinidyl group with residues Ser236, Ile237, and Phe188 characterized by strong π-π stacking and halogen interactions also stabilized its positioning which altogether accounted for its enhanced inhibitory prowess towards pfDHODH. On the contrary, fewer and weaker interactions characterized DSM265 binding which could explain its relatively lower binding affinity. Findings will facilitate the design of novel pfDHODH inhibitors with enhanced properties.
寻找可靠的二氢乳清酸脱氢酶 (DHODH) 抑制剂，已经在临床试验的不同阶段发现了有潜力的治疗化合物。尽管前景广阔，但高淘汰率和不良的生物活性限制了它们的药物研发进展。最近对 DSM265 的结构修饰，一种基于三唑嘧啶的抑制剂，产生了 DSM421，它是通过用 CF-吡啶基取代 DSM265 上的 SF-苯胺基得到的。因此，DSM421 相对于 DSM265 表现出改善的药理学和药代动力学特性。CF-吡啶基介导的改善的生物活性引起了我们的好奇心，我们使用计算方法研究潜在的配体结合机制和动力学。本研究提供了明确的见解，解释了 SF-苯胺→CF-吡啶基结构修饰对 pfDHODH 抑制的影响。研究结果表明，CF-吡啶基基团诱导 DSM421 在结合口袋内的最佳和稳定定位，允许稳定和强烈的分子间相互作用，有利于其较强的结合亲和力，这与生物活性数据相吻合和相关。这些相互作用通过限制残基运动，显著稳定 pfDHODH 的结构构象，这可能支撑了它相对于 DSM265 的增强抑制活性。CF-吡啶基基团与残基 Ser236、Ile237 和 Phe188 的活性位点相互作用，其特征是强 π-π 堆积和卤键相互作用，也稳定了它的定位，这共同解释了它对 pfDHODH 的增强抑制作用。相反，DSM265 结合的相互作用较少且较弱，这可以解释其相对较低的结合亲和力。这些发现将有助于设计具有增强特性的新型 pfDHODH 抑制剂。
