Bioisosterism & Lead Optimisation

Bioisosterism & Lead Optimisation

Lead optimisation is the iterative process of modifying a lead compound to improve its drug-like properties while maintaining or enhancing pharmacological activity. Bioisosterism is one of the most powerful strategies available to medicinal chemists for this purpose.

What Is a Bioisostere?

Bioisosteres are atoms, groups, or fragments that can replace one another in a drug molecule with retention of similar biological activity. The concept extends beyond simple physical similarity — bioisosteres may differ in size, charge, or hydrogen-bonding capacity, yet produce comparable receptor interactions because they occupy similar binding space or mimic the electronic environment of the original group.

Classical bioisosteres (Grimm's hydride displacement law) include substitutions such as: -OH for -NH₂; -CH₂- for -O-; -F for -H; -Cl for -CH₃. These share similar atomic radii and valence electron counts.

Non-classical bioisosteres go beyond size and electron number. Common examples include: tetrazole as a bioisostere for carboxylic acid (same pKa, better metabolic stability, improved membrane permeability); phosphate for sulfate; and amide for ester (resistant to hydrolysis). The replacement of a carboxylic acid with a tetrazole ring in losartan illustrates how bioisosterism can improve oral bioavailability and half-life.

Scaffold Hopping

Scaffold hopping replaces the core ring system of a lead compound with a different framework while preserving the spatial arrangement of pharmacophoric features. This strategy is used to: escape intellectual property restrictions around a competitor's core scaffold; improve physicochemical properties; or address selectivity problems. Computational tools including pharmacophore modelling and shape-based virtual screening identify candidate replacements. The move from sulfonamide to sulfonyl-urea scaffolds in sulfonylurea antidiabetics illustrates scaffold hopping in practice.

Lipinski's Rule of Five

Lipinski's Rule of Five (Ro5) predicts oral bioavailability based on four physicochemical parameters derived from the World Drug Index. A compound is predicted to have poor oral absorption if it violates more than one of: molecular weight > 500 Da; calculated logP (cLogP) > 5; hydrogen bond donors > 5; hydrogen bond acceptors > 10. The rules reflect the constraints of passive transcellular membrane permeation and gastrointestinal absorption.

Exceptions include substrates of active transporters (e.g., macrolide antibiotics) and natural products. Extended rules such as the Rule of Three (for fragment-based drug discovery) and Veber's rules (polar surface area < 140 Ų, rotatable bonds ≤ 10) supplement the Ro5 for specific compound classes.

Application in Lead Optimisation

A systematic lead optimisation campaign tracks structure-activity relationships (SAR) in a table, modifying one variable at a time. Bioisosteric replacements and scaffold hops are proposed based on SAR data, then synthesised and tested in binding, selectivity, and ADMET assays. The goal is a pre-clinical candidate with adequate potency (IC₅₀ < 100 nM), selectivity (>100-fold over off-targets), acceptable logD (1–3), plasma half-life > 2 h, and no structural alerts for toxicity.