Abstract
Enzymes are highly specific biological catalysts that accelerate the rate of chemical reactions within the cell. Our knowledge of how enzymes work remains incomplete. Computational methodologies such as molecular mechanics (MM) and quantum mechanical (QM) methods play an important role in elucidating the detailed mechanisms of enzymatic reactions where experimental research measurements are not possible. Theories invoked by a variety of scientists indicate that enzymes work as structural scaffolds that serve to bring together and orient the reactants so that the reaction can proceed with minimum energy. Enzyme models can be utilized for mimicking enzyme catalysis and the development of novel prodrugs. Prodrugs are used to enhance the pharmacokinetics of drugs; classical prodrug approaches focus on alternating the physicochemical properties, while chemical modern approaches are based on the knowledge gained from the chemistry of enzyme models and correlations between experimental and calculated rate values of intramolecular processes (enzyme models). A large number of prodrugs have been designed and developed 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. This article describes the works done on enzyme models and the computational methods used to understand enzyme catalysis and to help in the development of efficient prodrugs.
Highlights
The quantum mechanical (QM) and molecular mechanics (MM) approach was first developed by Warshel and Levitt, where QM simulates the active site of an enzyme at the electronic level, while MM simulates the rest of the system at the atomistic level [21,22]
Several chemical models have been presented by scientists to mimic the high rate of acceleration achieved by enzymes, including (1) Koshland in his “orbital steering” theory (Figure 1), which describes reactive atoms with at least one spherical asymmetry in their valence orbitals, which are constrained by binding to the active site or by the superstructure of the molecule in an intramolecular reaction to react along specific pathways
Comprehending their mode of action and the factors responsible for accelerating the speed of the reactions they catalyze is essential in Acyclovir (Figure 9, 13) is a synthetic purine nucleoside antiviral drug used to treat infections caused by the herpes simplex virus (HSV), herpes zoster, and varicellazoster by inhibiting DNA synthesis and viral replication after conversion to acyclovir triphosphate by cellular or viral enzymes
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. N–H moieties in the oxyanion hole (an arrangement of hydrogen bond donors) These moieties support the functional role of the active site residues in reducing the activation energy by participating in H-bonding with reaction intermediates and transition states [6,7]. Numerous computer simulations of enzymatic reactions have indicated that the stabilization of the transition state is the main catalytic factor [13]. The rate of drug release is dependent solely on the rate-limiting step of the interconversion reaction. In this approach, no enzyme is needed to catalyze the interconversion reaction
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