Directly Binding Rather than Induced-Fit Dominated Binding Affinity Difference in (S)- and (R)-Crizotinib Bound MTH1

Area of Science:

• Pharmacology
• Molecular Biology
• Computational Chemistry

Background:

• Crizotinib is an effective anticancer drug targeting MTH1, a key player in RAS-dependent cancers.
• Stereospecificity in drug binding is crucial for therapeutic efficacy, yet the mechanisms driving enantiomeric affinity differences are not always clear.
• Previous studies indicated similar binding modes for crizotinib enantiomers to MTH1, despite observed affinity differences.

Purpose of the Study:

• To investigate the molecular basis for the stereospecific binding of crizotinib enantiomers to MTH1.
• To elucidate the mechanism underlying the significant binding affinity difference between (S)- and (R)-crizotinib.
• To explore the role of direct binding versus induced-fit processes in drug enantioselectivity.

Main Methods:

• All-atom molecular dynamics simulations were employed.
• Free energy surfaces of the binding/unbinding processes for both (S)- and (R)-crizotinib enantiomers to MTH1 were characterized.
• Binding modes of the enantiomers were analyzed in detail.

Main Results:

• The study revealed that the direct binding process, rather than induced fit, significantly impacts the binding affinity difference between crizotinib enantiomers.
• (S)-crizotinib exhibits a higher binding affinity to MTH1 compared to (R)-crizotinib.
• The simulations provided a detailed characterization of the free energy landscapes governing enantiomer binding.

Conclusions:

• The findings suggest a common mechanism of stereoselectivity for enantiomers, driven by direct binding dynamics.
• Understanding these dynamics is critical for designing more selective and potent anticancer drugs targeting MTH1.
• This research offers insights into the subtle structural variations that lead to substantial differences in drug-target interactions.