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Medicinal Chemistry
Medicinal Chemistry
In the practice of medicinal chemistry, chemical knowledge is applied to design and synthesise therapeutic compounds. In lead optimisation, medicinal chemists collaborate with biologists and pharmacologists to gather assay data and understand the physiological impact of their molecules. This insight allows chemical adjustments to be made to the lead series template to improve target engagement, target exposure, and functional pharmacology. These criteria are known as the three pillars of candidate survival [A]; as well as binding with high affinity, the drug needs to reach the target and the binding event should effectively alter the pathogenesis of a disease.
In the practice of medicinal chemistry, chemical knowledge is applied to design and synthesise therapeutic compounds. In lead optimisation, medicinal chemists collaborate with biologists and pharmacologists to gather assay data and understand the physiological impact of their molecules. This insight allows chemical adjustments to be made to the lead series template to improve target engagement, target exposure, and functional pharmacology. These criteria are known as the three pillars of candidate survival [A]; as well as binding with high affinity, the drug needs to reach the target and the binding event should effectively alter the pathogenesis of a disease.
Patterns between structural motifs and potency are known as structure–activity relationships (SAR’s). SAR’s are essential tools that medicinal chemists use to rationally suggest analogues to explore in future synthetic iterations as potential improvements to the lead series. In the early stages of optimization the focus is mainly on improving the binding affinity, or potency. This leads to molecules which can produce the same effect at the target but at lower concentrations, so that the drug’s future dosage will be smaller. This is beneficial since less total drug present in cells reduces the chance of off-target binding which could cause side effects. A key tool in this process is bioisosterism; the replacement of a group for another which behaves a similar way at the target. This may improve pharmacological parameters such as metabolic stability or toxicity by varying physicochemical properties.
Patterns between structural motifs and potency are known as structure–activity relationships (SAR’s). SAR’s are essential tools that medicinal chemists use to rationally suggest analogues to explore in future synthetic iterations as potential improvements to the lead series. In the early stages of optimization the focus is mainly on improving the binding affinity, or potency. This leads to molecules which can produce the same effect at the target but at lower concentrations, so that the drug’s future dosage will be smaller. This is beneficial since less total drug present in cells reduces the chance of off-target binding which could cause side effects. A key tool in this process is bioisosterism; the replacement of a group for another which behaves a similar way at the target. This may improve pharmacological parameters such as metabolic stability or toxicity by varying physicochemical properties.
Over the years, as databases of druglike compounds have expanded, the effect of structural and physicochemical features on biological properties has become better understood. Correlations can be drawn between physicochemical and pharmacokinetic parameters; these are of particular interest as they can be used to predict the behaviour of a compound in animal models. Famously, Lipinski’s ‘Rule of Five’ [B] suggested that orally bioavailable drugs lie within certain limits of lipophilicity, polar surface area, hydrogen bond donors and acceptors, and molecular weight. The original 1997 publication triggered a movement to consider the impact of physicochemical properties as early as possible in the drug discovery process, to improve the quality of lead molecular frameworks and reduce the risk of attrition based on poor pharmacology.
Over the years, as databases of druglike compounds have expanded, the effect of structural and physicochemical features on biological properties has become better understood. Correlations can be drawn between physicochemical and pharmacokinetic parameters; these are of particular interest as they can be used to predict the behaviour of a compound in animal models. Famously, Lipinski’s ‘Rule of Five’ [B] suggested that orally bioavailable drugs lie within certain limits of lipophilicity, polar surface area, hydrogen bond donors and acceptors, and molecular weight. The original 1997 publication triggered a movement to consider the impact of physicochemical properties as early as possible in the drug discovery process, to improve the quality of lead molecular frameworks and reduce the risk of attrition based on poor pharmacology.
[A] Morgan P.; Van Der Graaf P. H.; Arrowsmith J.; Feltner D. E.; Drummond K. S.; Wegner C. D.; Street S. D. A. Can the flow of medicines be improved? Fundamental pharmacokinetic and pharmacological principles toward improving Phase II survival. Drug Discovery Today 2012, 17, 419–424
[A] Morgan P.; Van Der Graaf P. H.; Arrowsmith J.; Feltner D. E.; Drummond K. S.; Wegner C. D.; Street S. D. A. Can the flow of medicines be improved? Fundamental pharmacokinetic and pharmacological principles toward improving Phase II survival. Drug Discovery Today 2012, 17, 419–424
[B] Lipinski, C. L.; Lead and drug-like compounds - the rule of five revolution. Drug Discovery Today: Technologies 2004, 1, 337-341
[B] Lipinski, C. L.; Lead and drug-like compounds - the rule of five revolution. Drug Discovery Today: Technologies 2004, 1, 337-341
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