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"In silico" estimation of encapsulation-induced pKa shifts in drugs.
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1  Centro de Química e Bioquímica and BioISI - Biosystems and Integrative Sciences Institute, Faculdade de Ciências, Universidade de Lisboa, 1749-016 Lisboa, Portugal


Molecular machines have recently been associated with the development of molecular carriers to enhance drug properties, such as solubility or bioavailability. One possible approach is the drug encapsulation by a host molecule, such as cucurbituril (CB) rings, modifying the environment of the guest molecule. CB rings are able to encapsulate guest molecules providing a hydrophobic cavity and several carbonyl groups that stabilize cationic hosts that interact with this region. This will result in significant pKa shifts for drugs with titrable (cationic) groups that  can be exploited in order to improve drug bioavailability, whether by enhancing their solubility, stabilizing their active form or by protecting them against external agents. This approach can be used for medical targeting, such as cancer therapy, by designing carriers that deliver guest molecules at specific conditions, knowing the target properties.
Computational tools are a powerful way to help the rational design of CB-guest complexes. In particular, the stochastic titrations constant-pH MD (CpHMD) method allows a molecular dynamics simulation to have the pH value as an external parameter and, consequently, obtain full titration curves and pKa values. The main goal here is to develop a strategy to model benzimidazole (BZ) pKa shifts, our «proof-of-concept» molecule, and then extrapolate this process to other host-guest complexes. BZ has a well-known shift of ~3.5 pKa units when encapsulated by a CB ring and, with the refinement and fine tuning of this process, it is possible to elucidate the molecular details of these host-guest interactions.

We acknowledge financial support from FCT through project UID/MULTI/00612/2013 and grant SFRH/BPD/110491/2015.

Keywords: cucurbituril benzimidazole encapsulation pKa-shifts bioavailability