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

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 (ΔG_bind) 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

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.

Keywords:

• Fibroblast growth factor receptors
• C11
• selective inhibition
• interaction dynamics
• free binding energy

Acknowledgments

The authors would like the thank the School of Health Sciences, University of KwaZulu-Natal for providing infrastructural support and the Center for High Performance Computing (CHPC), Cape town, South Africa for computational resources.

Disclosure statement

There are no conflicts of interest to declare.

Funding

This study received no funding.

Authors’ contributions

FAO performed the design, method implementation, result analyses and interpretation, and wrote the manuscript. MES proof-read and approved for submission.