Computationally designed prodrugs of statins based on Kirby’s enzyme model

Amly, Wajd; Scrano, Laura; Mecca, Gennaro; Bufo, Sabino Aurelio

doi:10.1007/s00894-013-1929-2

Cited by 10 publications

(6 citation statements)

References 63 publications

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“…In these examples, the prodrug moiety was linked to the hydroxyl group of the active drug such that the drug‐linker moiety (prodrug) has the potential to interconvert when exposed into physiological environments such as stomach, intestine, and/or blood circulation, with rates that are solely dependent on the structural features of the pharmacologically inactive promoiety (Kirby's enzyme model). Other different linkers such as Kirby's maleamic acid amide enzyme model was also explored for the design of a number of prodrugs such as tranexamic acid for bleeding conditions, acyclovir as antiviral drug for the treatment for herpes simplex , atenolol for treating hypertension with enhanced stability and bioavailability and statins for lowering cholesterol levels in the blood . In addition, prodrugs for masking the bitter taste of antibacterial drugs such as cefuroxime were also designed and synthesized .…”

Section: Calculation Methods Used In the Prodrugs Designmentioning

confidence: 99%

Prodrugs Design Based on Inter‐ and Intramolecular Chemical Processes

Karaman

2013

Chem Biol Drug Des

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This review provides the reader a concise overview of the majority of prodrug approaches with the emphasis on the modern approaches to prodrug design. The chemical approach catalyzed by metabolic enzymes which is considered as widely used among all other approaches to minimize the undesirable drug physicochemical properties is discussed. Part of this review will shed light on the use of molecular orbital methods such as DFT, semiempirical and ab initio for the design of novel prodrugs. This novel prodrug approach implies prodrug design based on enzyme models that were utilized for mimicking enzyme catalysis. The computational approach exploited for the prodrug design involves molecular orbital and molecular mechanics (DFT, ab initio, and MM2) calculations and correlations between experimental and calculated values of intramolecular processes that were experimentally studied to assign the factors determining the reaction rates in certain processes for better understanding on how enzymes might exert their extraordinary catalysis.

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Section: Calculation Methods Used In the Prodrugs Designmentioning

confidence: 99%

Prodrugs Design Based on Inter‐ and Intramolecular Chemical Processes

Karaman

2013

Chem Biol Drug Des

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“…The calculations demonstrated that the reaction rate is linearly correlated to the distance between the two reacting centers and the angle of hydrogen bonding, and the rate-limiting step is the transfer of a proton from the ammonium moiety to the acetal oxygen. Additionally, the interconversion of the simvastatin prodrug can be determined according to the promoiety (Kirby’s enzyme model) structural features [ 167 ].…”

Section: The Prodrug Approachmentioning

confidence: 99%

Enzyme Models—From Catalysis to Prodrugs

Breijyeh

2021

Molecules

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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.

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“…Unraveling the reaction mechanism would allow for an accurate design of an efficient chemical device to be used as a prodrug linker that can be covalently linked to a drug which can chemically, and not enzymatically be cleaved to release the active parent drug in a controlled manner. For instance, exploring the mechanism for a proton transfer in Kirby's acetals [47] has led to a design and synthesis of novel prodrugs of aza-nucleosides to treat myelodysplastic syndromes [48] and statins to treat high cholesterol levels in the blood [49]. In the above mentioned examples, the prodrug moiety was attached to the hydroxyl group of the active drug such that the drug promoiety (prodrug) has the potential to degrade upon exposure to physiological environment such as stomach, intestine, and/or blood circulation, with rates that are solely dependent on the structural features of the pharmacologically inactive promoiety (Kirby's enzyme model).…”

Section: Application Of Nanotechnology In Drug Deliverymentioning

confidence: 99%