CHEM-E4220 - Medicinal Chemistry D, 27.10.2020-03.12.2020

Amino acids represent one of the key building blocks of Nature as the form the basis of all proteins. Natural alpha-amino acids all feature a common structural element that is the alpha-amino acetic acid moiety (=glycine). 

Substituents on the alpha-position define the nature and reactivity of amino acids, and we can distinguish between e.g. aliphatic amino acids (alanine, valine, leucine, isoleucine), aromatic amino acids (phenylalanine, tyrosine, histidine), sulfur-containing amino acids (methionine, cysteine) etc.

The sterical demand, polarity, charge, and possible dipol interactions define not only the shape of a proteinogenic biomolecule, but are also key parameters to be considered in the interaction of a biomolecular target and its designated drug molecule. 

Bile (or gall) is a dark green to brownish fluid produced by the liver and stored in the gallbladder (a small green hollow organ between the liver and the small intestines). Bile, that is consistent of so-called bile salts (anions of the steroid-derived bile acids), acts as a surfactant to bind and excrete fats, but also many liver metabolites of drugs, into the gastrointestinal system.

The efficiency of binding to a biomolecular target can be expressed by various different (but somewhat similar) quantitative descriptors, depending on the target and the activity assay performed. 

Common descriptors for the assessment of inhibitors include the 

• IC50 (the half-maximal inhibitory concentration, i.e. the concentration of a molecule that results in a 50% decrease in observable response from a biomolecular process), or the
  
• Ki (the inhibition constant that is related to the IC50 but takes into account the art of inhibition, i.e. competitive vs non-competitive inhibition).

• EC50 (the half-maximal effective concentration, i.e. the concentration of a molecule that yields a 50% response on a dose/response curve).

The temperature regulation of the body is an essential factor for the survival in mammals. The key role in these processes play the hypothalamus, the part of the brain that links the nervous system with the endocrine system (everything related to hormonal messengers). Depending on the sensation that sensors across our body transmit to the hypothalamus, cooling or heating can be induced.

If critically high temperatures are sensed, the following effects are induced: Sweating (to cool the skin by evaporation of water from the surface) and vasodilation (widening of blood vessels to transport more blood to the skin where the body loses heat through radiation).

If critically low temperatures are sensed, the following effects are induced: Vasoconstriction (narrowing of blood vessels leads to reduction of blood flow in the extremities to keep the warm blood closer to the vital organs), shivering (heating through increased muscle movement) and hormonal thermogenesis (where the thyroid gland releases hormones to upregulate the metabolism).

The complex interaction of all factors in hypothalamic thermoregulation is still not fully elucidated. Take home message for this course is the fact that the low temperature sensation triggers a cascade to induce fever via biosynthesis of prostaglandines. COX inhibitors suppress the eicosanoid biosyntesis and thus help against critically high fever.

Pharmacokinetics combines all aspects related to the distribution, metabolism, and excretion of medicines. In drug development, pharmacokinetics deals with the way how our body affects drugs before and after their actual desired pharmacological effect. Pharmacokinetics are a key parameter to understand and modulate toxicity of drug molecules.

See also ADME

Prostaglandins belong to the class of eicosanoids (natural products derived from C20 fatty acids). Prostaglandins are biosynthetically produced from arachidonic acid by cyclooxygenases. The family of prostaglandines includes a variety of structurally related but differently functionalized molecules that share the cyclopentane core with two vicinal long hydrocarbon chains as common motif.

In our body, prostaglandines act in various ways as hormones by specific agonistic binding to prostaglandin receptors. Among the different responses arising from agonistic binding, prostaglandins induce vaso- and bronchodilation, smooth muscle contraction, pyrogenesis, pain sensation and inflammatory immune response.

The prostaglandin biosynthesis is a target of many non-steroidal anti-inflammatory drugs that act as inhibitors of cyclooxygenases.

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