The assessment of a molecule to be “fit for purpose” is to determine the physiochemical parameters which will be used alongside the docking results to select the best possible candidates for synthesis.
The Absorption, Distribution, Metabolism, Excretion, Toxicity (ADMET) properties of molecules are in a sense generic, meaning they represent ‘the action of the body on the drug’ rather than a more specific process of ‘the action of the drug on the body’.[113] The calculation of these ADMET parameters are essential in the selection
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process, optimisation of ADMET properties from lead generation to optimising in vivo
profiles, is now a process that is carried out prior to candidate selection.[113] Within the ADMET setting, oral bioavailability is an important consideration for the development of a biological molecule as a therapeutic agent.[95] Correlation between the physical properties of an orally administered drug and drug candidate, with successful drug development was conducted by Lipinski and lead to the “rule of five” (RO5). This guideline proposed that an increased chance of drug absorption and
permeability, is more likely when the molecular weight is < 500 Da, logP is < 5, the
number of hydrogen bond acceptors is < 10 and the number of hydrogen bond donors
is < 5.[113] It was found that failing a single “rule of five” was acceptable, as there
was no statistical significance between not failing any and failing one. However, failing two was detrimental to the oral bioavailability of the drug with 90% of oral drugs
in phase II clinical trials meeting these criteria.[113] However, the “rule of five”
perhaps should be thought of as a guideline for oral bioavailability, rather than a strict rule for an “ideal drug”. In addition to the parameters set by Lipinski, molecular flexibility for membrane permeation was postulated as being desirable by Navia.[114] With the complexation of water to amide bonds as a negative factor for oral bioavailability deduced by Hirschmann.[115] Other negative factors towards oral bioavailability include the number of rotatable bonds within a compound which should be no more than 10, high polar surface area on intestinal absorption, failure to achieve membrane permeation, first pass metabolic processes and active transport from the blood into the excretory system such as to the gut or the liver.[95,116]
There has been great debate on the topic of “ideal drug-like compounds” since the
RO5 was suggested by Lipinski et al. almost two decades ago in 1997. The
guidelines for a good orally bioavailable drug remain clear, however the ideals of “the perfect drug-like molecule” are constantly changing as we learn more about the molecular targets and the ADMET properties of the compounds used to treat them. It has been suggested that perhaps we are too obsessed with the oral bioavailability of a compound and that we should consider drug space from the toxicological view point.[117] A number of guidelines have been developed from this point of view that relate toxicity to other physiochemical properties such as lipophilicity which is directly related to a drugs solubility profile and can be predicted through the computational
calculation of the partition coefficient ClogP.
One such rule has been developed by researchers at the pharmaceutical company Glaxo Smith Kline (GSK), where they screened 30,000 compounds and found a link
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parameters.[118] The rule is aptly named 4/ 400 as it relates to those more favourable
compounds having a ClogP < 4 and a molecular weight < 400.[118] Another
pharmaceutical company Pfizer investigated the in vivo tolerability of a group of 245
compounds and found a connection of ClogP and topological polar surface area
(TPSA) with a reduction of toxicity.[119] Those compounds with a ClogP < 3 and
TPSA > 75 were found to have a six fold reduction in toxicity, in comparison to those
compounds with a ClogP > 3 and TPSA < 75 where the reduction in toxicity was
increased to 24 fold and as such this became the Pfizer 3/75 rule.[119] A major cause of toxicity can be attributed to target promiscuity; a screen of 2133 compounds found
a direct correlation between ClogP and increased chances of compound
promiscuity.[120] Those compounds with a ClogP < 3 had a reduced chance of being
promiscuous whereas those with a ClogP > 4 were found to be less specific towards
their target and more promiscuous in nature.[120]
It has also been suggested that the higher the lipophilic nature of a compound, the more likely it is to be insoluble. The lipophilicity of a compound can be improved by reducing the number of aromatic rings, generally less than three is acceptable.[121] However if a compound is not lipophilic enough, then it may not be absorbed through the intestinal wall. Another way to improve the administration of a poorly soluble compound is through changes in the formulation, but by doing so the body will have to work much harder to metabolise and eventually excrete it. This would, therefore, result in the drugs needed for a longer duration of action and is an excellent example of the issues facing medicinal and computational chemists.
There is a fine balance needed for circumventing the issues associated with increasing lipophilicity in the search for improved drug potency. One method developed by medicinal and computational chemists to overcome these issues could be the use of a universally applicable index, the ligand efficiency. Ligand efficiency is defined as the energy of binding per non hydrogen atom and is very much dependent upon the size of the compound.[122] It is a direct correlation between the docking results and the physiochemical property of a ligand and can be useful for a more balanced selection of a subset of compounds.