Today, we find Chemical Abstracts with over two million compounds coded in a connectivity table system and ISI with close to a million compounds coded in WLN. The U.S. Patent Office has large files coded in the Hayward notation; the IDC has large numbers of compounds in its CT and GREMAS Code. Derwent has a sizable patent file coded in one fragment code, and many journal literature compounds coded in the Ring Code fragment code. There are a number of individual companies and government agencies with over 100,000 compounds coded in "a" system. And almost all companies synthesizing new compounds have some internal system for their compounds. Finally, there are many universities with a wide variety of coded structure files.

-Charles E. Granito J. Chem. Doc. 1973, 13, 72-74

The situation described by Granito in 1973 seems eerily familiar today. The names of the players, the technologies, and encoding systems have changed, but the problem of multiple incompatible molecular languages has persisted for over 30 years.

This problem will become even more pronounced in the near future as free chemistry databases on the Web continue their rapid proliferation. In Granito's world of closed, proprietary databases and unevenly distributed computer power, interoperability was an afterthought; in the coming world of free, open databases, and ubiquitous computer networks that connect to them, interoperability will be taken for granted.

Granito goes on to observe that "there is no one 'best' system" for molecular representation. And he's right. Molecular languages evolve within a particular problem domain, just as human languages evolve within a specific cultural context. This isn't to say that a molecular language can't be creatively adapted to serve purposes for which it was never designed. Trying to do so is, after all, how new languages are conceived.

Consider the case of InChI, which is both a molecular identification system and a line notation, or Chemical Markup Language (CML), an XML language. There are vast areas of chemistry in which using either InChI or CML will be problematic - particularly polymers, organometallics, and inorganic chemistry. And let's not ignore new molecular representation problems brewing on the horizon like small molecule tertiary structure. Yet for pure organic chemistry as most of us know it today, InChI and CML may well be optimal.

The problem is that both InChI and CML compete with simpler, entrenched alternatives - SMILES and molfile, respectively. Even MDL, the author of the original molfile specification, is having difficulty gaining acceptance for its new molfile format, despite significant technical advantages.

If history is any guide, we can look forward to at least as many molecular languages in the next thirty years as we've seen in the last thirty. It wasn't long ago that WLN was viewed as the language of the future. Now it just looks cryptic. For this we can thank a combination of technology advances and the emergence of a far simpler alternative, SMILES. A similar fate, more likely than not, awaits all molecular languages currently in use.

Will there ever be a universal molecular language and is there any point in trying to invent one? Every area of chemistry introduces its own peculiarities not shared by any of the others. Yet all users want the simplest language possible. These two contradictory forces ensure that a universal language is unlikely to ever appear. In other words, the most successful new molecular languages are likely to be agile - simple, easy to learn, cheap to implement, and quickly adaptable in the face of new chemical concepts and advances in computer technology.

Just two years ago, trying to find free online chemistry databases was an exercise in futility. Now, they're sprouting up all over the Web like wildflowers after a wet Spring. What follows is a far-from-complete roundup of some of the more interesting places to start your chemical search.

1. PubChem- The granddaddy of all free chemistry databases. Search over 8 million compounds by a variety of criteria. Although some PubChem records are linked into the primary literature through MeSH, most are not. But this doesn't seem to be PubChem's true calling. Instead, PubChem may well evolve into the world's largest online collection of molecular data sheets. Increasingly, the other databases in this list are cross-referencing their entries into PubChem. PubChem's entire database can be downloaded by FTP. CAS Registry are correct to see PubChem as the first real competition they've had in decades.

2. ZINC- A free database of commercially-available compounds for virtual screening. Search over 4.6 million compounds by structure, IUPAC name, InChI, and a host of calculated properties.

3. eMolecules- Google for molecules. With a simple interface and super fast search engine, eMolecules augments PubChem with other information sources, including specialty chemical catalogs. Although eMolecules' emphasis seems to be on commercially-available compounds, it's only possible to get a link directly into a supplier's online catalog for a limited number of molecules. Most of the links are to PubChem records. For this reason, I don't find eMolecules very useful in its current form. If you remember something called "Chmoogle", this is the same service (moral: don't mess with Google).

4. CHEBI- "A freely available dictionary of molecular entities focused on ‘small’ chemical compounds." CHEBI draws its information from two main sources: Integrated Relational Enzyme Database of the EBI and the Kyoto Encyclopedia of Genes and Genomes. Find out what proteins a molecule has been associated with and in what context. Provides cross-links to CAS registry numbers, Beilstein registry numbers, and Gmelin registry numbers.

5. NIST Chemistry WebBook- Physical data (thermochemical, thermophysical, and ion energetics) for mostly organic compounds. Search by formula, structure, CAS number, and IUPAC name.

6. BioCyc- A collection of about 3,500 compounds involved as enzyme substrates, products, inhibitors, and activators. On accepting a license agreement, the entire database can be freely downloaded in Chemical Markup Language format.

7. ChemExper- Find a supplier for your specialty chemical needs. Search by structure, name, molecular formula, and CAS number. After finding you compound, get an offer from one or more suppliers. I can't vouch for how this works in practice, but it sounds like a good idea.

8. Compendium of Pesticide Common Names- More than 1,100 commonly-used pesticides. Compounds are located by browsing indexed lists (IUPAC name, CAS number, and trade name) rather than searching. Each entry lists, among other pieces of information, a chemical structure and sub-classifications (repellents, antifeedants, synergists, etc.).

9. NMRShiftDB- Organic structures and their nuclear magnetic resonance (nmr) chemical shifts. NMRShiftDB contains chemical shift data for over 22,000 organic compounds and 19,000 spectra. Records can be searched by structure, chemical shift and nucleus. NMRShiftDB is truly open; it can be accessed programmatically and the source code for the software that runs the online database can be freely downloaded. Individual users can submit their own spectral shifts for peer review and subsequent inclusion into the database.

10. Chemical Structure Lookup Service (CSLS)- An address book for chemical structures. If you've ever used Metacrawler, then you'll recognize the idea behind SCLS, which is to aggregate several free chemistry databases. Search over 27 million molecules by IUPAC name, InChI, structure, SMILES, and a variety of molecular identifiers. Your results set will contain links into specific databases that host the molecules you find. The user interface isn't just unfriendly - it's downright antisocial. But if you can get past this, CSLS may well be one of the most useful services in this list.

11. DrugBank- Combines detailed drug data with comprehensive drug target information. Search over 4,300 drugs by trade name, SMILES, and InChI. Each record contains information on target of action, therapeutic indication, medications the drug is an ingredient of, and trade names. Searches can be limited to only approved drugs or experimental drugs. Both the concept and interface to this service are well thought-out.

12. Wikipedia- Wikipedia? Yes, Wikipedia. Wikipedia offers several kinds of chemical information produced by a knowledgeable, all-volunteer army. Looking for information on organic compounds? Consider this datasheet on morphine as an example. For those interested in synthesis, Wikipedia is increasingly being used to collaboratively author short reviews on the topic. Search capabilities are currently limited to text and don't appear to work with IUPAC names or CAS numbers. Where this quintessential disruptive technology and its offspring end up taking chemical publishing is unclear, but the ride will be spectacular.