Bioisosteres are chemical groups with similar physical or chemical properties that produce broadly similar biological effects within a compound. This involves swapping molecular fragments to maintain a desired biological outcome while altering other characteristics. Molecules with comparable shapes and electron arrangements can interact with biological targets similarly.
Why Bioisosteres Matter in Medicine
Bioisosteres are a fundamental strategy in medicinal chemistry, used to optimize pharmaceutical agents by enhancing their therapeutic profiles, improving effectiveness, reducing side effects, or extending a drug’s presence in the body.
One primary purpose is to improve a drug’s potency, meaning a smaller dose is needed to achieve the desired effect. They also refine a drug’s selectivity, ensuring it acts on its intended biological target and minimizes interactions that could lead to side effects. Bioisosteric replacements can also make a drug last longer by increasing its metabolic stability, preventing premature breakdown. This leads to a more sustained therapeutic effect and less frequent dosing.
Bioisosteres also improve a drug’s pharmacokinetic properties, including absorption, distribution, metabolism, and excretion. Adjustments can enhance solubility for easier dissolution and absorption, or improve permeability to cross biological membranes more effectively. This optimizes bioavailability, meaning more drug reaches the bloodstream and its site of action. Additionally, bioisosteric changes can reduce toxicity by replacing problematic chemical groups with safer alternatives or preventing harmful metabolic byproduct formation.
Different Kinds of Bioisosteres
Bioisosteres are categorized into two main types: classical and non-classical. These classifications help medicinal chemists understand the nature and extent of structural changes in a bioisosteric replacement. The distinction lies in how closely the replacement group resembles the original in basic atomic structure and electron arrangement.
Classical bioisosteres involve substituting atoms or small groups with very similar size, shape, and electron configurations. This often means replacing elements from the same periodic table group or groups with identical valence electron structures. For instance, replacing hydrogen with fluorine is a common classical exchange, as fluorine is similar in size and can influence metabolic stability without significantly altering the molecule’s shape. Other examples include replacing a hydroxyl group (-OH) with an amino group (-NH2) or a sulfur atom (-S-) with an oxygen atom (-O-).
Non-classical bioisosteres, in contrast, involve more complex structural modifications where the replacement group may not have obvious atom-for-atom or group-for-group similarity to the original. Despite structural differences, these replacements achieve comparable biological effects by mimicking the original group’s electronic properties or spatial arrangement. Examples include replacing entire ring structures, such as substituting a benzene ring with a thiophene or pyridine ring, or replacing a linear functional group with a cyclic one. They maintain a similar interaction profile with biological targets, even if their chemical appearance is distinct.
How Bioisosteres Change Drug Behavior
Bioisosteric replacements influence a drug’s properties by subtly altering its molecular characteristics, affecting its interaction with biological systems. These changes can modify a molecule’s size, shape, lipophilicity (fat-solubility), and electronic properties, all crucial for a drug’s journey.
For instance, a small change in atomic radius from a bioisosteric swap can slightly adjust the molecule’s shape, affecting how it fits into a protein target’s binding pocket. Changes in lipophilicity (a molecule’s affinity for fats) directly impact how easily a drug crosses cell membranes, which are primarily composed of lipids. Increasing lipophilicity can improve gut absorption and distribution into fatty tissues, while decreasing it might enhance water solubility, aiding excretion.
Electronic properties, such as charge distribution or hydrogen bond formation, dictate how strongly and specifically a drug interacts with its biological target, like an enzyme or receptor. These interactions are governed by forces such as hydrogen bonding, van der Waals forces, and electrostatic attractions.
These molecular alterations directly impact a drug’s ADME profile: absorption, distribution, metabolism, and excretion. For example, replacing a metabolically unstable group with a bioisostere more resistant to enzymatic breakdown can significantly prolong a drug’s half-life, requiring less frequent dosing. Conversely, a bioisosteric modification might introduce a site for easier metabolism, leading to a shorter duration of action or active metabolite formation. Strategic deployment of bioisosteres allows medicinal chemists to fine-tune these parameters, optimizing the drug’s journey from administration to elimination and enhancing its therapeutic benefit.
Bioisosteres in Action: Examples
The application of bioisosteres has led to numerous successful drugs, showcasing their practical utility in medicinal chemistry. These replacements often address specific challenges during drug development, such as improving oral absorption, reducing metabolic breakdown, or minimizing side effects.
One notable example involves replacing a carboxylic acid group with a tetrazole ring in developing angiotensin II receptor blockers like losartan. The original carboxylic acid compound had good activity but poor oral absorption. Substituting it with a tetrazole, which is more lipophilic and has a similar acidic proton, significantly improved the drug’s oral bioavailability, making it a viable oral medication for hypertension. This illustrates how a bioisosteric change can dramatically enhance a drug’s pharmacokinetic properties, allowing convenient oral administration.
Another illustration involves replacing hydrogen atoms with fluorine atoms in drug molecules. Fluorine is similar in size to hydrogen, so it does not drastically alter the molecule’s shape or how it interacts with its target. However, the strong carbon-fluorine bond makes the molecule more resistant to certain metabolic enzymes, increasing drug stability and prolonging its action. This strategy improves the half-life of various drug candidates by preventing rapid breakdown.