Lipinski Rule-of-Five LRoF

There are, in addition to these simple functional group filters, a number of property-based filters that may be applied. These fdters take the form of calculated metrics, such as the Lipinski Rule of Five (LRoF Hydrogen-bond donors. Hydrogen-bond acceptors, Lipophilicity, Molecular weight). Solubility, total Polar Surface Area (tPS A), Blood-brain-barrier (BBB) Permeability, calculated metabolic filters (cADMET Absorption-Distribution-Metabolism-Excretion-Toxicity) and Bioavailability. 

The Lipinski Rule-of-Five almost certainly represents the first real attempt to identify a drug-like filter for molecular databases. Lipinski analysed the compounds within the World Drag Index that had progressed to Phase II clinical trials or better and discovered a simple set of rales that have been used extensively since their publication in 1997. The LRoF states that a compound may have lower membrane permeability or poorer absorption if two or more of the rules are violated. These rules are a compound should have no more than 5 hydrogen-bond donors, no more than 

10 hydrogen bond acceptors, a calculated log P of 5 or less, and a molecular weight of 500 or less. Log P is the logarithm of the octanol-water partition coefficient, and thus is a measure of the lipophilicity of a molecule. The rule derives its name from the fact that all of the individual requirements are divisible by five (although there are only four rales ). 

Not all drugs need to have a high level of permeability, nor do all drags obey the rales, so the pass rate for marketed drugs is not 100% (compounds with active transport mechanisms of delivery are also excluded from the rules). Therefore, while the LRoF is a very useful decision-support tool for drug-likeness, it is not really a standalone function and, like many other tools, it should be used in conjunction with other filters, especially those based on structural requirements. 

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