Drugs transition state analogues

Competitive, reversible inhibitors are the most common type of inhibitor developed for pharmaceutical use. If the substrate of an enzyme is known, then a competitive inhibitor will likely somewhat resemble the substrate. The search for an inhibitor will typically start with molecules of similar structure to the substrate. Because enzymes theoretically bind most strongly to a transition state, competitive inhibitors are often designed to resemble a transition state or a high energy intermediate along the reaction coordinate. These types of drugs are called transition state analogues or transition state inhibitors. 

Lovastatin is a member of a class of drugs (atorvastatin and simvastatin are others in this class) called statins that are used to treat hypercholesterolemia. The statins act as competitive inhibitors of the enzyme HMG-CoA reductase. These molecules mimic the structure of the normal substrate of the enzyme (HMG-CoA) and act as transition state analogues. While the statins are bound to the enzyme, HMG-CoA cannot be converted to mevalonic acid, thus inhibiting the whole cholesterol biosynthetic process. Recent studies indicate that there may be important secondary effects of statin therapy because some of the medical benefits of statins are too rapid to be a result of decreasing atherosclerotic lesions. Statin therapy has been associated with reduced risks of dementia, Alzheimer disease, ischemic cerebral stroke, and other diseases that are not correlated with high cholesterol levels. Although this is still an active area of research, it appears that the pleiotropic effects of statins may be a result of a reduction in the synthesis of isoprenoid intermediates that are formed in the pathway of cholesterol biosynthesis. 

Transition state analogues of enzymatic reaction as potential drugs, Drug Discovery (ed. Hany A. El-Shemy), ISBN 978-953-51-0906-8, InTech, DOI 10.5772/52504. Available from http //www.intechopen. com/books/drug-discovery/transition-state-analogues-of-enzymatic-reaction-as-potential-drugs. 

Independent from studies oriented towards the search for better anti-AIDS drugs, compounds of general formula 60 and 61, where R are natural aminoacid residues, were reacted with simple alcohols like methanol. In this way we prepared, with high purity and satisfactory yields, otherwise difficult to obtain phos-phorothioate [87] and phosphorodithioate [88] amidoesters 64 considered as the analogues of transition state for the cleavage of peptide bond by proteases [89]. 

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