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Unbinding pathways of VEGFR2 inhibitors revealed by steered molecular dynamics
Anna Maria Capelli1, Gabriele Costantino
1Chemistry Research and Drug Design Department, Chiesi Farmaceutici S.p.A. , Largo F. Belloli 11a, 43122 Parma, Italy.
Abstract:
A detailed atomistic description of the unbinding process of sorafenib and sunitinib, two known VEGFR2 inhibitors clinically used to treat renal cell carcinoma, was unraveled by using steered molecular dynamics (SMD) simulations. While sunitinib is a fast-dissociating binder, sorafenib exhibits quite a long residence time at this enzyme, which might impact its duration of action in vivo. In order to gain insights into the kinetically different behaviors of the two inhibitors, an SMD study was carried out, which involved a careful optimization of the force and velocity parameters. We were able to identify two different binding pathways for the two inhibitors, as sunitinib exited the ATP binding site from the cavity entrance without a rupture point while sorafenib moved opposite to the ATP binding site entrance. Furthermore, the calculated ΔGoff values clearly reflect on a qualitative level the distinct off-rates of the two inhibitors, thus suggesting that this protocol could be tried on other VEGFR2 ligands to assess its robustness and then used to rank structural analogues of these derivatives.
Insights
Steered molecular dynamics revealed distinct unbinding pathways for VEGFR2 inhibitors sorafenib and sunitinib. Sunitinib dissociates rapidly, while sorafenib has a longer residence time, impacting their therapeutic duration in renal cell carcinoma treatment.
Area of Science:
- Biochemistry
- Pharmacology
- Computational Chemistry
Background:
- Sorafenib and sunitinib are clinically used VEGFR2 inhibitors for renal cell carcinoma.
- Understanding their distinct binding kinetics is crucial for optimizing cancer therapy.
Purpose of the Study:
- To elucidate the atomistic details of sorafenib and sunitinib unbinding from VEGFR2.
- To investigate the molecular basis for their differing residence times and dissociation rates.
Main Methods:
- Utilized steered molecular dynamics (SMD) simulations with optimized force and velocity parameters.
- Analyzed binding pathways and calculated binding free energies (ΔGoff) for both inhibitors.
Main Results:
- Identified unique unbinding pathways for sunitinib (cavity entrance) and sorafenib (opposite direction).
- Sunitinib demonstrated fast dissociation, whereas sorafenib exhibited a significantly longer residence time.
- Calculated ΔGoff values qualitatively correlated with the observed distinct off-rates.
Conclusions:
- The study provides atomistic insights into the differential binding kinetics of VEGFR2 inhibitors.
- The developed SMD protocol shows promise for assessing and ranking other VEGFR2 ligands and their analogues.
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