On May 2021, Rafik Karaman published a new study in Molecules titled Enzyme Models—From Catalysis to Prodrugs. The article aimed to design and developnovel prodrugs in order to improve the effectiveness and pharmacokinetics of commonly used drugs, such as anti-Parkinson (dopamine), antiviral (acyclovir), antimalarial (atovaquone), anticancer (azanucleosides), antifibrinolytic (tranexamic acid), antihyperlipidemia (statins), vasoconstrictors (phenylephrine), antihypertension (atenolol), antibacterial agents (amoxicillin, cephalexin, and cefuroxime axetil), paracetamol, and guaifenesin. The design was based on the study of intramolecular processes (enzyme models) with the aid of computational methods. The results of this study demonstrated that (Enzymes are complex systems, and comprehending their mode of action and the factors responsible for accelerating the speed of the reactions they catalyze is essential in studying their biochemical processes. Molecular modeling and simulation methods are increasingly used to illustrate the mechanisms of enzyme-catalyzed reactions and the determinant factors of specificity and efficiency, which can greatly contribute to the development of drugs and catalysts alike. Despite the advances in experimental studies, a comprehensive understanding of enzyme catalysis can be reached only through the integration of experiments and computer modeling approaches. Several chemical models have been presented by scientists to mimic the high acceleration rates achieved by enzymes, such as Koshland in his “orbital steering” theory, Bruice in his intramolecular cyclization of dicarboxylic semi-esters (NAC), Milstien and Cohen in their gem-tri-methyl lock systems (stereopopulation control), Kirby’s enzyme models of proton transfer in systems containing two heteroatoms, and Menger in his spatiotemporal hypothesis. In addition to the goals achieved by these pioneers in understanding enzyme catalysis, the enzyme models invoked by them can be used as linkers to commonly used drugs for making more bioavailable prodrugs. Understanding the chemistry of many organic mechanisms is effective in the development and design of an efficient chemical device to be used as a prodrug linker where the resulting prodrug can undergo conversion by chemical and not enzymatic means to liberate the active drug in a controlled manner. Based on the above-mentioned enzyme models, different linkers were investigated for the design of a large number of prodrugs to improve the pharmacokinetics and patient compliance of some important currently marketed drugs. These include anti-Parkinson (dopamine), antiviral (acyclovir), antimalarial (atovaquone), anticancer (azanucleosides), antifibrinolytic (tranexamic acid), antihyperlipidemia (statins), vasoconstrictors (phenylephrine), and antihypertension (atenolol). Besides, this approach was used to mask the bitter taste of several drugs, such as antibacterial agents (amoxicillin, cephalexin, and cefuroxime axetil), paracetamol, and guaifenesin. Molecular revolution has changed the vision to the prodrug approach, in particular, from merely a chemical modification to solve problems associated with parent compounds to a modern, promising, safe, and efficacious approach that considers molecular/cellular factors to deliver active small-molecule and biotherapeutics).
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