Molecular Bio-Computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban 4001, South Africa.
School of Chemistry and Physics, University of KwaZulu-Natal, Private Bag X01, Pietermaritzburg 3209, South Africa.
Phys Chem Chem Phys. 2019 Jul 10;21(27):15120-15132. doi: 10.1039/c9cp02112d.
The concept of chirality has become prominent over the years, particularly with regards to the design of therapeutic molecules. This phenomenon was recently reported for pro-carcinogenic fibroblast growth factor receptor 1 (FGFR1), wherein two inhibitors exhibited disparate inhibitory potencies due to the effects of chirality. Therefore, the ability of the R-enantiomer (R-21c) to possess a potency 10.44 times that of the S-enantiomer (S-21c) leaves us with a curiosity to investigate the underlying mechanisms using computational methods. Hence, presented in this study are insights that clearly explain the systematic effects of chirality on the differential activities of (R)-21c and (S)-21c towards FGFR1. The findings showed that the "R-configured" (R)-21c induced a notable conformational change in the active site P-loop, which enhanced its motion, as complemented by rotation of two dihedral angles: φ1(CNCC) and φ2(CC*OC), providing a favorable orientation. Likewise, optimal positioning of (R)-21c at the binding cavity allowed adequate interspaces that facilitated the formation of strong interactions with target residues. Moreover, the estimated ΔG binding correlated with bioactivity data (IC50) and, when decomposed, we observed that van der Waals (vdW) interactions were the major highlight of the binding process of both 21c enantiomers and also accounted for their differential activities. Active site interactions of (R)-21c with residues Phe489 and Arg629 stabilized its two benzimidazole motifs, while Arg570 and Pro663 formed two strong NH-N hydrogen bonds and one π-alkyl interaction, which altogether accounted for its inhibitory prowess towards FGFR1. In contrast, these interactions were not observed in (S)-21c due to its non-flexible S-configuration, which disallowed its extension into the active site region and prevented interaction with crucial residues. These results are expected to facilitate the discovery and rational design of novel and specific FGFR1 inhibitors.
手性的概念近年来变得越来越重要，尤其是在治疗分子的设计方面。最近有报道称，致癌的成纤维细胞生长因子受体 1（FGFR1）存在这种现象，两种抑制剂由于手性的影响表现出不同的抑制效力。因此，R-对映体（R-21c）的效力是 S-对映体（S-21c）的 10.44 倍，这让我们产生了使用计算方法研究其潜在机制的好奇心。因此，本研究提供了一些见解，这些见解清楚地解释了手性对（R）-21c 和（S）-21c 对 FGFR1 活性差异的系统影响。研究结果表明，“R 构型”（R）-21c 引起活性位点 P 环的显著构象变化，增强了其运动，同时补充了两个二面角 φ1（CNCC）和 φ2（CC*OC）的旋转，提供了有利的取向。同样，（R）-21c 在结合腔中的最佳定位允许足够的间隔，从而促进其与靶标残基形成强相互作用。此外，估计的 ΔG 结合与生物活性数据（IC50）相关，并且当分解时，我们观察到手性相互作用是两个 21c 对映体结合过程的主要亮点，并且也解释了它们的差异活性。（R）-21c 与残基 Phe489 和 Arg629 的活性位点相互作用稳定了其两个苯并咪唑基序，而 Arg570 和 Pro663 形成了两个强 NH-N 氢键和一个 π-烷基相互作用，这些相互作用共同解释了其对 FGFR1 的抑制能力。相比之下，由于其非柔性 S 构型，（S）-21c 没有观察到这些相互作用，这使其无法延伸到活性位点区域，并阻止与关键残基的相互作用。这些结果有望促进新型和特异性 FGFR1 抑制剂的发现和合理设计。
