1.2.4. Optimisation of candidates

The number of pharmacological compounds that survive the screening phase has to be further reduced and optimised according to key criteria.
To accomplish the largest possible reduction in the number of drug candidates, researchers characterise the way the compounds bind to their targets. This optimisation process is therefore, only applied to the first technique we discussed previously, the target-based approach.
Due to the limited knowledge about the mechanism of action of the chemical compounds in the phenotypic approach, the validation of this optimisation process is quite hard to carry out using this method.
Among the main factors affecting drug-target binding, we find:

      Affinity degree between drug and target.

      How many different targets the drug can bind to.

      How long the chemical compound (drug) can be bound to the target.

These criteria will help to discover the most effective drug dose and detect any undesirable side effects that may occur.
Further, those candidates that present toxicity at therapeutic levels have to be eliminated, as well as those which are highly unstable in solution or solid state, and finally those which are highly expensive to synthesise.
The compounds that meet the necessary requirements are examined by chemists, who produce a certain type of compound called analogs, structurally similar but with improvements in the mentioned criteria.

One of the major tasks during the optimisation process is to determine the correlation between the chemical structure of the compound and its activity (QSAR[1]) and in what way the first factor affects the second one.
Another aspect to evaluate is compound’s drugability, which describes the ability of the drug to reach its target, bind to it and be capable of producing some measurable effect. To find out the drugability of a candidate, scientists use Lipinski’s rule of five, which establishes that an oral medicine fulfils its pharmacological function if:

      It does not contain more than five hydrogen bond donors (total number of nitrogen-hydrogen and oxygen-hydrogen bonds).

      It does not contain more than ten hydrogen bond acceptors (total number of oxygen or nitrogen atoms).

      Its molecular mass is less than 500 uma.

      An octanol-water partition coefficient[2] (log P) less than five.

[1] Quantitative structure-activity relationship is the process whereby the chemical structure of a compound is related to the biological activity of a receptor.
[2] Ratio between the concentration of a certain substance (solute) in two solvents in equilibrium (octanol and water): log P = log ( [solute]octanol / [solute]water ).

Sources: UTAustinX: UT.4.01x Take Your Medicine - The Impact of Drug Development.

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