This assignment gives you the opportunity to discover potential new medicines to treat human disease. Once you have formed your company and selected your target disease, you will be able to apply your knowledge of chemistry to the design of molecules for testing. Throughout the assignment, you will receive feedback on how your research programme is doing and you see how an understanding of molecular interactions and an appreciation of competitive advantage are central to the discovery of new medicines.
Good luck with your assignment.
Lipophilicity (literally, 'fat-liking') is a measure of how 'greasy' a compound is. Lipophilic compounds tend to have poor solubility in water and typically include groups such as aliphatic chains, aromatic rings. The longer and larger these groups are, the more lipophilic they tend to be. Compounds that dissolve easily in water are described as being polar or hydrophilic (literally, 'water-loving'). Such compounds typically include heteroatoms such as oxygen and nitrogen.
Regions (or pockets) of an enzyme active site can also be described as lipophilic or polar, depending on whether they comprise amino acids with largely lipophilic or polar groups respectively.
In this assignment, the lipophilic pockets of the enzyme active site are colour-coded blue and the polar pockets red. Similarly, lipophilic groups for design purposes are colour-coded blue and polar groups red.
The potency of an enzyme inhibitor depends on a number of factors. The size and shape of the compound need to be such that it fits snugly within the enzyme. Although enzymes are generally quite elastic and can accommodate a range of sizes and shapes, if the compound deviates too far from the ideal fit, it will no longer bind and will lose biological activity. It is also important for the polarity/lipophilicity of the inhibitor to match the properties of the regions of the enzyme active site as far as possible. In practice, this means potency will tend to increase if a lipophilic group on the inhibitor binds to a lipophilic pocket of the enzyme (or if a polar group on the inhibitor binds to a polar pocket of the enzyme).
Don't forget you can view how your designed compound is likely to bind to the enzyme by viewing the molecular model. You can also look at a 3D stereoview of your design - you will need red-green stereospecs to see these properly. These are available free-of-charge from the RSC.
Drug-like Properties - Absorption
In order for a compound to be well absorbed via the oral route, it has to be sufficiently polar to dissolve in the gut. However, if a compound is too polar, it will be unable to pass across the lipophilic cell wall lining the gut and will be excreted from the body before it is absorbed. This will tend to reduce its drug-like property score.
Drug-like Properties - Metabolism
In order for a compound to work effectively in the body for a long time (i.e. 24 hours following each daily dose), it must be stable to proteins in the liver that are designed to remove the compound from the body by a process called metabolism. In general, the more lipophilic a compound is, the more likely it is to be metabolised. Therefore, if a compound becomes too lipophilic, its drug-like properties score will start to go down.
In this assignment, the drug-like properties of the groups you can select from decrease in the following order:
Hydrogen; Methyl; Carboxylic acid; Amine; Amide; Phenyl; Propyl; Alcohol; Benzyl
Structure-Activity Relationships (SAR)
When designing new compounds, chemists use all the information they have generated on previous compounds to inform their decisions. Occasionally, patterns emerge and the chemist can start to predict what might happen to the test results if they replace one group with another. Such patterns are called Structure-Activity Relationships and can really help accelerate medicinal chemistry programmes. Although such relationships are not always reliable in the industrial setting (there are many complex variables involved), in this activity, reliable structure activity relationships (with respect to both potency and drug-like properties) will emerge if you study the history plots. And remember, you can use any of your tested compounds as the basis for your next design/test cycle, not just the most recent one.