What is the rule of three in drug discovery?

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The Rule of Three in drug discovery is a guideline used to identify promising chemical compounds during the early stages of drug development, particularly in the context of fragment-based drug discovery (FBDD). It helps researchers evaluate whether a small molecule, or "fragment," is likely to serve as a good starting point for developing a drug.

Key Criteria of the Rule of Three:

Molecular Weight: The compound should have a molecular weight of 300 Daltons or less.

Hydrogen Bond Donors and Acceptors: It should have no more than 3 hydrogen bond donors and 3 hydrogen bond acceptors.

LogP (Partition Coefficient): The LogP, which indicates the compound’s lipophilicity, should be 3 or lower to ensure good solubility and permeability.

Rotatable Bonds: Typically, the molecule should have a low number of rotatable bonds (often fewer than 3) to maintain structural rigidity.

Purpose and Importance:

The Rule of Three provides a framework to screen for small, simple molecules that are likely to bind to target proteins with sufficient affinity and specificity. These fragments can then be optimized into more complex molecules that exhibit improved drug-like properties.

By adhering to this rule, researchers focus on compounds that balance size, solubility, and binding potential, improving the efficiency of lead optimization in the drug discovery process.