Deciphering the molecular mechanisms of selective non-covalency demonstrated differentially by 9-Allylnaphtho[1, 8-ef]isoindole-7, 8, 10(9H)-trione (C11) against fibroblast growth factor receptors 1–4. Issue 6 (13th April 2023)

• Record Type: Journal Article
• Authors: Olotu, Fisayo A.; Soliman, Mahmoud E. S.
• Is Part Of: Journal of biomolecular structure & dynamics. Volume 41:Issue 6(2023)
• Page Start: 2419
• Page End: 2430
• Publication Date: 2023-04-13
• Subjects: Fibroblast growth factor receptors -- C11 -- selective inhibition -- interaction dynamics -- free binding energy; Biomolecules -- Periodicals; Molecular structure -- Periodicals; Molecular Biology -- Periodicals; Biomechanics -- Periodicals; 572
• DOI: 10.1080/07391102.2022.2032355
• Languages: English
• ISSNs: 0739-1102

Abstract

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 A564 FGFR1, L484 FGFR1, Y563 FGFR1, and E562 FGFR1 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 Graphical Abstract: UF0001 Figures showing the binding variations of 9-Allylnaphtho[1, 8-ef]isoindole-7, 8, 10(9 H)-trione (C11) at the catalytic pockets of FGFRs1-4.