Abstract：
The specific inhibition of aberrant Fibroblast Growth Factor Receptors (FGFRs) has been identified as a feasible strategy to therapeutically ameliorate their respective carcinogenic involvements. High homology among these proteins has however limited efforts towards the discovery of selective small-molecule compounds due to undesirable effects elicited by pan-FGFR inhibitors. A recent study showed the selective activity of a new compound C11 which was >52 times more potent against FGFR1 than FGFR2 and FGFR3, and 4 times than FGFR4. This C11 selective non-covalency was investigated in this study using computational methods since it has remained unresolved. Structural findings revealed that C11 enhanced structural perturbations in FGFR1 with less prominent effects in other FGFRs. High deviations also characterized the C11-bound active pocket of FGFR1 with notable fluctuations across the constituent P-loop, αC helix, hinge region, catalytic, and activation loops. These induced motions were essential for optimal C11 motion an d positioning of its phenalenone ring and prop-2-en-l-yl moiety at the FGFR1 active pocket to interact stably and strongly with A564FGFR1, L484FGFR1, Y563FGFR1, and E562FGFR1 which as well had high energy contributions. C11 exhibited highly unstable binding in F GFRs2-3 with a more steady interaction with FGFR4. Free binding energy (ΔGbind) analyses further estimated the highest interaction energy for C11-FGFR1 with favorable desolvation energy that indicated a deep hydrophobic pocket binding for C11 in FGFR1 compared to other FGFRs. We believe rational insights from this study will contribute to the structure-based design of highly specific FGFR1 inhibitors.Communicated by Ramaswamy H. Sarma.
摘要：
异常成纤维细胞生长因子受体（FGFR）的特异性抑制已被确定为治疗性改善其各自致癌参与的可行策略。然而,由于pan-FGFR抑制剂引起的不希望的作用,这些蛋白质之间的高度同源性限制了对发现选择性小分子化合物的努力。最近的研究显示新化合物C11对FGFR1的选择性活性比FGFR2和FGFR3强>52倍,比FGFR4强4倍。在本研究中使用计算方法研究了这种C11选择性非共价,因为它仍未解决。结构发现表明，C11增强了FGFR1的结构扰动，而在其他FGFRs中的影响则不太明显。高偏差还表征了FGFR1的C11结合活性口袋，在组成P环中具有明显的波动，αC螺旋,铰链区,催化,和激活循环。这些诱发的运动对于最佳的C11运动以及其菲那酮环和丙-2-烯-1-基部分在FGFR1活性口袋中的定位至关重要，以与A564FGFR1，L484FGFR1，Y563FGFR1和E562FGFR1稳定而强烈地相互作用也具有高能量贡献。C11在FGFRs2-3中表现出高度不稳定的结合，与FGFR4的相互作用更稳定。自由结合能(ΔGbind)分析进一步估计了C11-FGFR1的最高相互作用能,具有有利的去溶剂化能量,表明与其他FGFRs相比,FGFR1中C11的深疏水口袋结合。我们相信来自本研究的合理见解将有助于高度特异性FGFR1抑制剂的基于结构的设计。由RamaswamyH.Sarma沟通。
