Mod 2- Enzymes 1. Enzymes generally make good drug targets because a specific re

Question

Mod 2- Enzymes 1. Enzymes generally make good drug targets because a specific reaction of interest can be targeted with a high degree of selectivity. Consider the following three drugs and explain why, although does not. A. Statins inhibit HMG CoA reductase to block intracellular B. Methotrexate inhibits dihydrofolate reductase, which C. Gleevec® inhibits BCR, a kinase that is only produced in reaionspcific. he iwroduce sde ffects, while h hid cholesterol synthesis. subsequently leads to blocked DNA replication. certain types of leukemia cells.

Explanation / Answer

Enzyme reactions are specific. The same enzyme can involve in different pathways. When the drug is consumed to inhibit one pathway, it can affect other pathways in which the specific enzyme is involved. Not only the involvement of the same enzyme in different pathways, but the ligand enzyme interaction specificity, free binding energy, vander Waals interaction stabilizing the ligand in the binding pocket of the enzyme are other factors affecting the drug enzyme specificity.

For example, statins inhibit the enzyme HMG-CoA reductase that makes cholesterol, statins also inhibit the other processes of this enzyme, such as CoQ10 production. CoQ10 production is important for muscle cells and in blood sugar regulation. This leads to adverse effects such as muscle problems, liver damage, increased risk of diabetes.

Methotrexate competitively inhibits dihydrofolate reductase (DHFR), an enzyme that participates in the tetrahydrofolate synthesis. It is effectively used in chemotherapy. The same drug can interact with other enzymes involved in multiple mechanisms. The drug causes the inhibition of enzymes involved in purine metabolism, leading to accumulation of adenosine; inhibition of T cell activation and suppression of intercellular adhesion molecule expression by T cells; selective down-regulation of B cells; increasing CD95 sensitivity of activated T cells; and inhibition of methyltransferase activity, leading to deactivation of enzyme activity relevant to immune system function. Another mechanism of MTX is the inhibition of the binding of interleukin 1-beta to its cell surface receptor. The affinity of the same drug with different enzyme binding sites, makes them susceptible to inhibit different pathways leading to adverse effects.

Ragarding Gleevec, a well-known therapeutic and potent agent against chronic myelogenous leukemia, is an effective inhibitor of Abl tyrosine kinase. However, Gleevec fails to inhibit closely homologous tyrosine kinases, such as c-Src. Studies show that this is because, in Gleevec, many structural features of the binding site are conserved, The molecular determinants responsible for binding specificity are not immediately apparent. Some have attributed the difference in binding specificity of Gleevec to subtle variations in ligand–protein interactions. Also the vander Waals interaction stabilizes the ligand Gleevec well in the binding pocket of tyrosine kinase.

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