Leadlike

Leadlike is a term used in medicinal chemistry to describe small organic molecules whose physicochemical properties make them suitable starting points for drug discovery and optimization. The concept contrasts with broader drug-like criteria by emphasizing a smaller, less complex, and more expandable chemical space. Leadlike compounds are intended to be readily elaborated into more potent and selective candidates while maintaining favorable developability characteristics.

Commonly cited leadlike guidelines note that these compounds tend to be smaller and less lipophilic than typical drug-like molecules. Typical ranges include molecular weight around 250–350 g/mol, a logP around 1–3, and a limited number of hydrogen bond donors (often 0–3) and acceptors (often 2–6). Rotatable bonds are usually kept low to moderate (roughly ≤ 6) to preserve three-dimensional integrity and facilitate optimization. Topological polar surface area is often in the moderate range. These criteria are used to balance synthetic accessibility with the potential for optimization during lead development.

Leadlike properties are particularly relevant in fragment-based drug discovery (FBLD). In FBLD, small fragments with MW roughly 150–250 are screened and then grown or linked to achieve the desired potency and selectivity, transitioning from leadlike starting points to more fully optimized drug candidates. Leadlike concepts also inform library design, guiding the selection of compounds that offer tractable growth paths while avoiding early accumulation of undesirable attributes.

Limitations and evolving practice: leadlike is a guideline rather than a fixed rule, and there are successful drugs that arise outside traditional leadlike ranges. The concept complements broader frameworks of drug-likeness, optimization strategies, and evolving understanding of developability.

See also: drug-likeness, Lipinski’s rule of five, fragment-based drug discovery, lead discovery.