# Rule of five in 2015 and beyond: Target and ligand structural limitations, ligand chemistry structure and drug discovery project decisions.
> Ro5（ファイブルール）の現代的意義：標的・リガンド構造の制約と創薬戦略への示唆


## Abstract

The rule of five (Ro5), derived from physicochemical data of phase II clinical compounds, aligns with structural constraints inherent to protein targets and their ligand-binding sites. Three of the four Ro5 parameters are fundamentally tied to the architecture of both targets and binding regions. Ligand chemical structure reflects two contrasting design philosophies: synthetic medicinal chemistry compounds developed without evolutionary input, and natural product (NP) metabolites shaped by evolutionary selection. Ro5 exceptions occur predominantly among NPs, with intramolecular hydrogen bonding—exemplified by cyclosporine A—enabling chameleon-like physicochemical behavior that underlies many NP outliers. The fragment-based drug Navitoclax illustrates the substantial expertise, time, and strategic decisions required to identify the rare non-NP Ro5 exception.

### Mechanism

In certain natural products such as cyclosporine A, intramolecular hydrogen bonding masks polar groups, enabling chameleon-like physicochemical behavior that circumvents the physicochemical boundaries defined by the rule of five.

## Bibliographic

- **Authors**: Lipinski CA
- **Journal**: Adv Drug Deliv Rev
- **Year**: 2016 (2016-06-01)
- **PMID**: [27154268](https://pubmed.ncbi.nlm.nih.gov/27154268/)
- **DOI**: [10.1016/j.addr.2016.04.029](https://doi.org/10.1016/j.addr.2016.04.029)
- **Study type**: review
- **Delivery route**: not specified
- **Effect reported**: not assessed

## Delivery context

The delivery route is not clearly identifiable from this paper. For hydrogen intake, inhalation is the most efficient route; inhalation, however, carries explosion risk (empirical LFL of 10%; high-concentration devices are not recommended).

## Safety notes

The delivery route is not clearly identifiable from this paper. For hydrogen intake, inhalation is the most efficient route; inhalation, however, carries explosion risk (empirical LFL of 10%; high-concentration devices are not recommended).

See also:
- [Inhalation concentration and LFL / UFL](https://h2-papers.org/en/safety-notes/inhalation-concentration)
- [Consumer Affairs Agency accident cases](https://h2-papers.org/en/safety-notes/accident-cases)

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> **Cite as**: H2 Papers — PMID 27154268. https://h2-papers.org/en/papers/27154268
> **Source**: PubMed PMID [27154268](https://pubmed.ncbi.nlm.nih.gov/27154268/)