A greener pharmaceutical industry 

Drug discovery

During drug discovery a lot of data is collected to characterise the compounds of interest. The data describes the following attributes: 

• pharmacology;

• physical chemistry;

• ADME (Absorption, Distribution, Metabolism, Excretion); and

• toxicity.

Their key parameters are explained below. Pharmacology and toxicity assays are informative of the cellular response and safety of drug candidates. ADME and physical chemistry properties determine what proportion of the administered compound reaches the biological target (e.g. an enzyme or other receptor). These properties are interconnected. For example, gut permeability, as part of the ADME profile, depends on the physical chemistry properties of solubility and lipophilicity. Therefore, drug discovery is only complete after multi-parameter optimisation. 

Potency on target and target selectivity (pharmacology)

Potency, expressed as the concentration required to produce a pharmacological effect of a specified strength, is a defining attribute of a drug molecule. Generally, high potency results in lower doses. A low dose provides a larger safety window for possible unwanted side effects (off-target effects). Thus, it is usually beneficial to the patient. In vitro assays with proteins or cells are used to assess potency in the first instance. If the 3D structure of the receptor is well characterised in silico then the binding affinity between drug candidate and biological target can be modeled to assist drug design.

Target selectivity describes the specificity of the interaction of a drug with the biological target in comparison to other off-targets (targets where interaction with the drug compound may lead to off-target effects). To find good target selectivity, compounds are tested against a panel of known off-targets. To minimise potential safety risks for the patient, thresholds are defined for each off-target.

Overall, a good drug candidate should be potent and selective, meaning it has a high affinity for the intended receptor and a poor affinity for other possible interaction sites.

Physical chemistry properties

Physico-chemical parameters, that determine plasma solubility and gut permeability (amongst other attributes) and thus the ADME and pharmacokinetic profile, are predicted in silico early in the drug discovery process to guide the candidate selection process. Later the predictions are validated in vitro for the more promising compounds. Key parameters include lipophilicity (expressed as the logarithmic KOW at physiological pH, i.e. log D), solubility (physiological relevant), acid-base character, and the electrochemical redox potential. These parameters determine if the drug reaches the effective concentration at the biological target. For example, optimal absorption of an orally administered drug in the small intestine requires the compound to be soluble and have intestinal permeability. Lipinski’s rule-of-five aims to balance solubility and permeability (for orally administered small molecule APIs) (Lipinski et al., 2001).

Absorption, distribution, metabolism, excretion

ADME properties are assessed in vitro to evaluate a compound’s effective concentration at the biological target. Additionally, it is important that dosing is limited to once or twice daily. The drug candidate must be metabolically stable enough to be an effective treatment, but not so much that it results in accumulation in the body (as measured by excretion rate). Assessed are, for example, gut permeability, metabolic and plasma stability, plasma protein binding, CYP450 inhibition, and blood-brain barrier penetration. More advanced and very promising compounds are tested in more elaborate in vivo pharmacokinetic and pharmacodynamic studies.

After metabolic and plasma stability, chemical stability under storage conditions is also required to secure quality, safety and efficacy of the drug. For example, the impact of pH and temperature on the compound’s stability is assessed during drug discovery. More comprehensive tests, e.g. on the impact of light and oxidation, are performed later during the development phase.

Drug safety (toxicity)

Drug safety is a collective term for adverse drug effects and their frequency. Depending on the severity of the unmet medical need, specific safety requirements are defined. For example, for a new anti-cancer drug, the threshold of tolerable safety is different to that of a general use painkiller. Typical in vitro safety tests are the Ames test (for mutagenicity), a micronucleus test (for genotoxicity), cytotoxicity and a phototoxicity assay. There are additional assays depending on the nature of the drug candidate.