Journal
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
Volume 9, Issue 2, Pages 1272-1281Publisher
AMER CHEMICAL SOC
DOI: 10.1021/ct300899n
Keywords
-
Ask authors/readers for more resources
Aminoadamantane derivatives, such as amantadine and rimantadine, have been reported to block the M2 membrane protein of influenza A virus (A/M2TM), but their use has been discontinued due to reported resistance in humans. Understanding the mechanism of action of amantadine derivatives could assist the development of novel potent inhibitors that overcome A/M2TM resistance. Here, we use Free Energy Perturbation calculations coupled with Molecular Dynamics simulations (FEP/MD) to rationalize the thermodynamic origin of binding preference of several aminoadamantane derivatives inside the A/M2TM pore. Our results demonstrate that apart from crucial protein-ligand intermolecular interactions, the flexibility of the protein, the water network around the ligand, and the desolvation free energy penalty to transfer the ligand from the aqueous environment to the transmembrane region are key elements for the binding preference of these compounds and thus for lead optimization. The high correlation of the FEP/MD results with available experimental data (R-2 = 0.85) demonstrates that this methodology holds predictive value and can be used to guide the optimization of drug candidates binding to membrane proteins.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available