Halogen bonds, sigma-holes and molecular mechanics of modern drug candidates
Michal H. Kolar, Paolo Carloni, and Pavel Hobza, Forschungszentrum Jülich, Jülich, Germany
Pair-additive atom-centered force fields are widely used in modeling biochemical phenomena in aqueous phase such as biomolecular conformational changes or inhibitor-enzyme binding. For a long time, halogens has been playing a prominent role in drug discovery and nowadays it is estimated that as much as 35 % of approved drugs contain a halogen atom.
Halogen bond is a recently recognized type of noncovalent interaction between a halogen and a Lewis base (e.g. carbonyl oxygen). This interaction facilitates binding of numerous organic molecules (drug candidates) to proteins related to certain types of cancer, HIV infection or diabetes. Using classical force fields halogen bonding is impossible to model, because of an inherent charge anisotropy of the halogen, called σ-hole.
We aim at extending the capabilities of the current biomolecular classical force field to faithfully describe halogen bonding. An extended analysis of halogen σ-holes has been done in order to get insight into what the σ-hole actually is from spatial point of view. Using off-centered massless charge we developed a σ-hole model (called explicit σ-hole) which notably improves both the biomolecular geometries as well as energetics.
The application of ESH model goes, however, beyond the biomolecular simulations, since halogen bonding is a widely used concept also in self-assembling materials and crystal engineering.
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