Frequently Asked Questions

Delivery?
The compounds in our library collections are provided at 10mM concentrations in DMSO solution in microplate format. The micro plates containing these solutions are sealed in Dry-Shield packages, and shipped frozen with dry ice (-70°C).

Two factors are important on receipt of the plates: 

• Keep them frozen. DMSO freezes at 18°C; the solutions will stay frozen to approximately 10°C.
• Keep the plates horizontal. The plates are packed horizontally in a Styrofoam box with dry ice, surrounded by ice packs and Styrofoam chips. This arrangement keeps the plates frozen, horizontal and immobile. Upon receipt, transfer the plates to a freezer and store horizontally.

Stability Of The Test Compounds?
All compound solutions are prepared at room temperature and stored frozen at < -20°C under nitrogen. The solutions are stable, although a few compounds may decompose through oxidation or addition reactions with DMSO if kept at room temperature for long periods. Compounds that are notorious for this behavior are reactive conjugated ketones, alkyl halides, anhydrides, and the like. Fortunately, because of the rigors of the drug approval process, stability is usually built in. Nevertheless, several important drugs (e.g., certain anticancer agents) fall into this class.

We conducted a study on this problem several years ago and discovered that approximately 5% of compounds in DMSO solution showed significant change over one year at room temperature under nitrogen. This incidence is halved when the solutions were stored at -20°C, and enhanced through oxidation if the wells are not flushed with nitrogen or another inert gas between use.

We therefore recommend the following procedure after use and prior to storage:

• Flush the wells containing the compound solutions with nitrogen or argon, by using a gently stream of nitrogen as the wells are recapped. A glove box is even more efficient.
• Store the resealed plates at -20°C or lower.
• When the plates are retrieved for another run, do not remove the caps until the plates are at room temperature; reseal (as above) and return immediately to storage.

Under such conditions the collection should be stable (>95%) for several years.

Handling and Solubility?
More than half of the drugs used today are poorly soluble or insoluble in water. Solubility is not a reasonable criteria for compound selection. Fortunately, dimethylsulfoxide (DMSO) is a powerful solvent that has little effect on test systems at concentrations less than 1%. Dilution of the compound solutions from 100% DMSO to 0.1% DMSO can be effected in a single step and thereby provide a stable solution of the compound for most screening purposes. That concentration of DMSO has little effect on most test procedures. Please note that stepwise dilution, for example, 10:1 per step, is often not effective. Such dilution invariably leads to deposition of an insoluble drug on the walls of the tube at the first or subsequent step. Often, such deposition is not visible.

Drug-Like Molecules?
This is a meaningless term used commercially without justification. The receptors associated with the action of a drug are diverse without limit. It is an impossible task to predict what combination of chemical functionality and molecular topography is optimal for drug action. In contrast, it is highly probable to predict - often elegantly - the structural requirements for a specific receptor and confidently propose the molecular geometry necessary for activity. That is a primary medicinal chemical principle. But that information is meaningless when you approach a totally new drug target or receptor, known or otherwise. One needs only to review the diversity of structures in bioactive molecules to quickly appreciate the total absence of rules. But, we can make some meaningful contribution at a de novo stage, by eliminating non-drug molecules.

Non-Drug-Like Molecules?
There are many classes of compounds that should not be found in a drug screening library. These are the source of wasted screening time, false positives, and non-specific activities. These include:

• Compounds devoid of chemical functionality: alkanes or planar aromatic systems represent this category. The notorious carcinogens, benzpyrene and its relatives, are exceptions to this rule, but still are compounds to be avoided except as single representatives to profile their effect;
• Monofunctional compounds such as alkyl or aryl carboxylic acids, alcohols, and the like, that are without at least one additional functional moiety. Monoethers and esters can similarly be included in this category. Ethanol and diethyl ether may be viewed as exceptions but these are effective only at macrodoses.
• Compounds that have reactive groups: e.g., alpha-keto halogens, facile leaving groups, anhydrides, beta and gamma lactones, Michael addition candidates, and the like. Most of these will be found in commercial macro-libraries but are rarely represented in a drug collection. Michael addition candidates may be an exception here, since a number of important steroids have this character. Certain anti-cancer drugs also use such groups as a basis for the mechanism of action and are important constituents in a primary screen;
• Heavy metal components: mercury, lead, gold, platinum, copper and other metals are occasionally found in drugs that have important physiological properties. It is important to include representatives of these in a test system, but only in the context of an actual drug and with demonstrated utility. Synthetic variations abound especially, once more, in macro-libraries; these are to be avoided.
• Polyhalogen compounds: these are easy to make but useless in therapy or screening. Their structures impart lipophilicity which invariably translates into membrane solubility. Sadly, this character also leads to major toxicological concerns for the same reasons.