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• Three major types of chemical forces/bonds:

  • Covalent--very strong

    • Frequently, a covalent bond is described as essentially "irreversible" under biological conditions. The term "irreversible" is in fact in quotes because all reactions are reversible.  However, once a covalent bond is formed, the resulting structure is typically extremely stable and although the reverse reaction occurs its occurrence may be highly improbable.

    • Examples:

      • A covalent bond is formed between the activated form of phenoxybenzamine (Dibenzyline) (a receptor antagonist) and the alpha adrenergic-receptor.

        •  The covalent interaction explains the drug's long duration of action.

        •  To overcome the alpha-adrenergic receptor blockade, new alpha receptor protein must be synthesized in the inhibited receptor internalized by the cell and degraded.  This process may take 48 hours.

      • Another example of drugs that interact covalently with their targets are the DNA-alkylating chemotherapy agents.

        •  These drugs are chemically highly reactive, forming covalent bonds with DNA functional groups

        •  Such covalently-modified DNA may be incompatible with successful tumor cell division.

  • Electrostatic:-- weaker than covalent

    • Electrostatic interactions tend to be much more common than the covalent bonding in drug-receptor interactions

    • The interaction strength is variable:

      •  Strong electrostatic interactions occur between between permanently charged ionic molecules

      •  Weaker interactions all are due to hydrogen bonding

      •  Still weaker interactions are called induced-dipole interactions, e.g. van der Waals forces

  • Hydrophobic interactions referred to interactions between molecules in which the interactions are less driven by molecule to molecule attraction and more by the tendency of molecules to wish to avoid the aqueous (water) environments:

    • Hydrophobic interactions are generally weak, but important.

    • Hydrophobic interactions are probably significant in driving interactions:

      •  between lipophilic drugs and the lipid component of biological membranes

      •  between drugs and relatively nonpolar (not charged) receptor regions