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Chemical structures of cefuroxime (3) and cefuroxime prodrugs, amoxicillin (4) and amoxicillin prodrugs, cephalexin (5) and cephalexin prodrugs.
Source publication
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 r...
Contexts in source publication
Context 1
... the drug suffers from relatively low bioavailability of 25% to 52%. Based on the acid-catalyzed hydrolysis of several maleamic acid amides, four different cefuroxime prodrugs ( Figure 6) were designed using DFT calculations. The calculations revealed that the calculated t1/2 for the conversion of these prodrugs ranged between 12 and 200 min and that the reaction rate-limiting step was determined on the nature of the amine leaving group [156]. ...
Context 2
... the drug suffers from relatively low bioavailability of 25% to 52%. Based on the acid-catalyzed hydrolysis of several maleamic acid amides, four different cefuroxime prodrugs ( Figure 6) were designed using DFT calculations. The calculations revealed that the calculated t1/2 for the conversion of these prodrugs ranged between 12 and 200 min and that the reaction rate-limiting step was determined on the nature of the amine leaving group [156]. ...
Context 3
... calculations revealed that the calculated t1/2 for the conversion of these prodrugs ranged between 12 and 200 min and that the reaction rate-limiting step was determined on the nature of the amine leaving group [156]. Amoxicillin ( Figure 6, 4) and cephalexin ( Figure 6, 5) suffer from low stability in aqueous media, where they might undergo hydrolysis when they are standing in solutions due to the reactivity of the strained lactam ring in which the carbonyl group undergoes nucleophilic attack by water to form the inactive penicilloic acid. Besides, both drugs have a bitter taste, which results in poor patient compliance, especially in pediatric and geriatric formulations. ...
Context 4
... both drugs have a bitter taste, which results in poor patient compliance, especially in pediatric and geriatric formulations. Based on Kirby's enzyme model, two linkers have been used for the design of novel amoxicillin and cephalexin prodrugs ( Figure 6). This is to mask the bitterness of the parent drugs and to afford chemical devices with the potential to release the antibacterial agent in a controlled manner. ...
Context 5
... (4-(2-hydroxy-isopropylaminopropoxy)-phenylacetamide) (Figure 7, 6) is a cardioselective beta1-adrenergic receptor antagonist used for the treatment of hypertension, angina pectoris, and cardiac arrhythmias. Atenolol is available as a tablet dosage Figure 6. ...
Context 6
... (4-(2-hydroxy-isopropylaminopropoxy)-phenylacetamide) (Figure 7, 6) is a cardioselective beta1-adrenergic receptor antagonist used for the treatment of hypertension, angina pectoris, and cardiac arrhythmias. Atenolol is available as a tablet dosage Figure 6. Chemical structures of cefuroxime (3) and cefuroxime prodrugs, amoxicillin (4) and amoxicillin prodrugs, cephalexin (5) and cephalexin prodrugs. ...
Context 7
... (4-(2-hydroxy-isopropylaminopropoxy)-phenylacetamide) (Figure 7, 6) is a cardioselective beta1-adrenergic receptor antagonist used for the treatment of hypertension, angina pectoris, and cardiac arrhythmias. Atenolol is available as a tablet dosage form for oral administration and not formulated for easy administration to children because of its instability in aqueous solutions, so the preparation of liquid formulation of atenolol remains a challenge [159,160]. ...
Context 8
... the drug suffers from relatively low bioavailability of 25% to 52%. Based on the acid-catalyzed hydrolysis of several maleamic acid amides, four different cefuroxime prodrugs ( Figure 6) were designed using DFT calculations. The calculations revealed that the calculated t1/2 for the conversion of these prodrugs ranged between 12 and 200 min and that the reaction rate-limiting step was determined on the nature of the amine leaving group [156]. ...
Context 9
... the drug suffers from relatively low bioavailability of 25% to 52%. Based on the acid-catalyzed hydrolysis of several maleamic acid amides, four different cefuroxime prodrugs ( Figure 6) were designed using DFT calculations. The calculations revealed that the calculated t1/2 for the conversion of these prodrugs ranged between 12 and 200 min and that the reaction rate-limiting step was determined on the nature of the amine leaving group [156]. ...
Context 10
... calculations revealed that the calculated t1/2 for the conversion of these prodrugs ranged between 12 and 200 min and that the reaction rate-limiting step was determined on the nature of the amine leaving group [156]. Amoxicillin ( Figure 6, 4) and cephalexin ( Figure 6, 5) suffer from low stability in aqueous media, where they might undergo hydrolysis when they are standing in solutions due to the reactivity of the strained lactam ring in which the carbonyl group undergoes nucleophilic attack by water to form the inactive penicilloic acid. Besides, both drugs have a bitter taste, which results in poor patient compliance, especially in pediatric and geriatric formulations. ...
Context 11
... both drugs have a bitter taste, which results in poor patient compliance, especially in pediatric and geriatric formulations. Based on Kirby's enzyme model, two linkers have been used for the design of novel amoxicillin and cephalexin prodrugs ( Figure 6). This is to mask the bitterness of the parent drugs and to afford chemical devices with the potential to release the antibacterial agent in a controlled manner. ...
Context 12
... (4-(2-hydroxy-isopropylaminopropoxy)-phenylacetamide) (Figure 7, 6) is a cardioselective beta1-adrenergic receptor antagonist used for the treatment of hypertension, angina pectoris, and cardiac arrhythmias. Atenolol is available as a tablet dosage Figure 6. ...
Context 13
... (4-(2-hydroxy-isopropylaminopropoxy)-phenylacetamide) (Figure 7, 6) is a cardioselective beta1-adrenergic receptor antagonist used for the treatment of hypertension, angina pectoris, and cardiac arrhythmias. Atenolol is available as a tablet dosage Figure 6. Chemical structures of cefuroxime (3) and cefuroxime prodrugs, amoxicillin (4) and amoxicillin prodrugs, cephalexin (5) and cephalexin prodrugs. ...
Context 14
... (4-(2-hydroxy-isopropylaminopropoxy)-phenylacetamide) (Figure 7, 6) is a cardioselective beta1-adrenergic receptor antagonist used for the treatment of hypertension, angina pectoris, and cardiac arrhythmias. Atenolol is available as a tablet dosage form for oral administration and not formulated for easy administration to children because of its instability in aqueous solutions, so the preparation of liquid formulation of atenolol remains a challenge [159,160]. ...
Citations
... In order to overcome pharmacokinetic or pharmacodynamic obstacles, for example, conjugation with another moiety can be used to modify the drug's physicochemical properties. The goal is to release the parent drug once the prodrug has been activated or degraded [11,[44][45][46][47][48][49][50][51][52][53][54]. Depending on the kind of prodrug generated, different techniques for the synthesis of L-dopa and dopamine prodrugs are highlighted in this chapter. ...
Parkinson's disease is a neurodegenerative disorder that progresses aggressively and depletes the central nervous system of dopamine (DA). Dopamine replacement therapy has several issues, such as poor blood-brain barrier penetration and a progressive decline in treatment responsiveness. The primary components of this treatment are the initial prodrug L-dopa (LD) and actual dopamine. This chapter discusses prodrugs produced and generated chemically, such as amide, dimeric amide, carrier-mediated, peptide transport-mediated, cyclic, and enzyme-model prodrugs. The bioavailability of these kinds of prodrugs in animals was studied. A promising ester prodrug has been invented for intranasal delivery. LD methyl ester is currently in phase III clinical studies. Many amide prodrugs have been developed with better stability than ester prodrugs. Amide and dimeric amide prodrugs offer enhanced pharmacokinetics and greater blood-brain barrier (BBB) penetration. Linking LD to carbohydrates is one approach that draws advantages from the brain's glucose transport mechanisms. While there isn't a DA prodrug on the market at present, prodrugs seem to have a bright future in Parkinson's disease treatment. Prodrugs that contain LD ester, for instance, demonstrate promises in the intranasal delivery of LD, facilitating the absorption of therapeutic agents by the brain. Most DA prodrugs delivered by amide, cyclic, peptidyl, or chemical routes demonstrated better pharmacokinetic properties.
... The support refers to the substance in a catalyst that does not directly participate in the chemical reaction but can still play a vital role in multiple ways, such as dispersing the active component, increasing the surface area, etc. Various adjustments to either the active component or support have been suggested to improve the performance of catalysts. For example, the active component can adopt the form of nanoparticles [12][13][14][15] or isolated single atoms (single-atom catalyst, SAC) [16][17][18][19]; some catalysts use metal oxides, graphene, or biomolecules as a support to achieve good dispersion of the active component or bring together and orient the reactants so that the reaction can proceed with a minimum energy barrier [20][21][22]. ...
Surface geometry at the atomic level is an important factor related to the activity of a catalytic site. It is important to identify sites with high activity to comprehend the performance of a given catalyst. In this work, it is proposed that the optimal surface for a given reaction step should satisfy the condition ∂E∂xi|TS=0, where E is the transition state energy and xi is any variable characterizing the surface. Taking three elementary steps as examples, it is shown that the optimal site found by this method has significantly reduced TS (transition state) energy compared with facets commonly applied in previous studies, and, thus, it can be several orders more active. The method provides an insight into the geometric impact of catalysis, gives a blueprint for an ideal catalyst surface structure, and, thus, provides guidance for catalyst development.
... Plenty of mechanistic-chemistry-and physics-based phenomenological and empirical models have been presented so far to simulate the kinetics of microbial biomass growth and product synthesis [7][8][9]; to quantify metabolic flux analysis [10,11]; for bioprocess optimization and biomanufacturing [12][13][14][15][16]; for bioreactor design, modelling and scale-up [17][18][19][20]; for the design of bioseparation units [20][21][22]; for protein and enzyme design [23][24][25][26]; and to characterize the kinetics of enzyme catalysis [24,[27][28][29][30]. Nevertheless, and despite advanced mathematical theories such as optimization and statistical analysis, both the research community and industry are still short of efficient and robust modelling models that can accurately translate the complex knowledge of the bioengineering domain into mathematical formulation [2]. However, in recent years, there has been a shift from physical modelling to data-driven modelling with the application of machine training techniques and a large number of data recorded and stored by the biochemical industry. ...
... Plenty of mechanistic-chemistry-and physics-based phenomenological and empirical models have been presented so far to simulate the kinetics of microbial biomass growth and product synthesis [7][8][9]; to quantify metabolic flux analysis [10,11]; for bioprocess optimization and biomanufacturing [12][13][14][15][16]; for bioreactor design, modelling and scale-up [17][18][19][20]; for the design of bioseparation units [20][21][22]; for protein and enzyme design [23][24][25][26]; and to characterize the kinetics of enzyme catalysis [24,[27][28][29][30]. Nevertheless, and despite advanced mathematical theories such as optimization and statistical analysis, both the research community and industry are still short of efficient and robust modelling models that can accurately translate the complex knowledge of the bioengineering domain into mathematical formulation [2]. ...
Biocatalysis is currently a workhorse used to produce a wide array of compounds, from bulk to fine chemicals, in a green and sustainable manner. The success of biocatalysis is largely thanks to an enlargement of the feasible chemical reaction toolbox. This materialized due to major advances in enzyme screening tools and methods, together with high-throughput laboratory techniques for biocatalyst optimization through enzyme engineering. Therefore, enzyme-related knowledge has significantly increased. To handle the large number of data now available, computational approaches have been gaining relevance in biocatalysis, among them machine learning methods (MLMs). MLMs use data and algorithms to learn and improve from experience automatically. This review intends to briefly highlight the contribution of biocatalysis within biochemical engineering and bioprocesses and to present the key aspects of MLMs currently used within the scope of biocatalysis and related fields, mostly with readers non-skilled in MLMs in mind. Accordingly, a brief overview and the basic concepts underlying MLMs are presented. This is complemented with the basic steps to build a machine learning model and followed by insights into the types of algorithms used to intelligently analyse data, identify patterns and develop realistic applications in biochemical engineering and bioprocesses. Notwithstanding, and given the scope of this review, some recent illustrative examples of MLMs in protein engineering, enzyme production, biocatalyst formulation and enzyme screening are provided, and future developments are suggested. Overall, it is envisaged that the present review will provide insights into MLMs and how these are major assets for more efficient biocatalysis.
... Prodrugs are chemically inert compounds that the body metabolizes into active medications. They are utilized to circumvent a drug's unstable pharmacokinetic qualities, toxicity, site specificity, and formulation issues [225]. They also help with solubility, absorption, and distribution issues. ...
The necessity for the discovery of innovative antimicrobials to treat life-threatening diseases has increased as multidrug-resistant bacteria has spread. Due to antibiotics' availability over the counter in many nations, antibiotic resistance is linked to overuse, abuse, and misuse of these drugs. The World Health Organization (WHO) recognized 12 families of bacteria that present the greatest harm to human health, where options of antibiotic therapy are extremely limited. Therefore, this paper reviews possible new ways for the development of novel classes of antibiotics for which there is no pre-existing resistance in human bacterial pathogens. By utilizing research and technology such as nanotechnology and computational methods (such as in silico and Fragment-based drug design (FBDD)), there has been an improvement in antimicrobial actions and selectivity with target sites. Moreover, there are antibiotic alternatives, such as antimicrobial peptides, essential oils, anti-Quorum sensing agents, darobactins, vitamin B6, bacteriophages, odilorhabdins, 18β-glycyrrhetinic acid, and cannabinoids. Additionally, drug repurposing (such as with ticagrelor, mitomycin C, auranofin, pen-tamidine, and zidovudine) and synthesis of novel antibacterial agents (including lactones, piperidinol, sugar-based bactericides, isoxazole, carbazole, pyrimidine, and pyrazole derivatives) represent novel approaches to treating infectious diseases. Nonetheless, prodrugs (e.g., siderophores) have recently shown to be an excellent platform to design a new generation of antimicrobial agents with better efficacy against multidrug-resistant bacteria. Ultimately, to combat resistant bacteria and to stop the spread of resistant illnesses, regulations and public education regarding the use of antibiotics in hospitals and the agricultural sector should be combined with research and technological advancements.
... Pauling first tried to use the transition state theory to clarify the essence of enzyme catalysis. He believed that the fundamental reason for the enzyme catalysis process was that it can specifically bind and stabilize the transition state in the reaction process, thereby reducing the energy level of the reaction [27]. Therefore, a new idea for the design of artificial enzymes has been triggered. ...
Selenium exists in the form of selenocysteines in selenoproteins and plays a pivotal role in the catalytic process of the antioxidative enzymes. In order to study the structural and functional properties of selenium in selenoproteins, explore the significance of the role of selenium in the fields of biology and chemistry, scientists conducted a series of artificial simulations on selenoproteins. In this review, we sum up the progress and developed strategies in the construction of artificial selenoenzyme. Using different mechanisms from different catalytic angles, selenium-containing catalytic antibodies, semi-synthetic selenonezyme, and the selenium-containing molecularly imprinted enzymes have been constructed. A variety of synthetic selenoenzyme models have been designed and constructed by selecting host molecules such as cyclodextrins, dendrimers, and hyperbranched polymers as the main scaffolds. Then, a variety of selenoprotein assemblies as well as cascade antioxidant nanoenzymes were built by using electrostatic interaction, metal coordination, and host–guest interaction. The unique redox properties of selenoenzyme glutathione peroxidase (GPx) can be reproduced.
... The rapid increase in computer capabilities and storage in conjunction with the theory and algorithm development, increase the size of the molecular systems which can be calculated via multiscaling approaches. The most populous ones need the use of highperformance computer facilities employing QM/MM and QM/MM/MD approaches, which have been developed not only for biomolecular systems but also for modeling a variety of complex systems, i.e., inorganic/organometallic, liquids, solid-state, etc., see for instance [179][180][181][182][183][184][185][186][187][188][189][190][191]. ...
The multiscaling quantum mechanics/molecular mechanics (QM/MM) approach was introduced in 1976, while the extensive acceptance of this methodology started in the 1990s. The combination of QM/MM approach with molecular dynamics (MD) simulation, otherwise known as the QM/MM/MD approach, is a powerful and promising tool for the investigation of chemical reactions’ mechanism of complex molecular systems, drug delivery, properties of molecular devices, organic electronics, etc. In the present review, the main methodologies in the multiscaling approaches, i.e., density functional theory (DFT), semiempirical methodologies (SE), MD simulations, MM, and their new advances are discussed in short. Then, a review on calculations and reactions on metalloproteins is presented, where particular attention is given to nitrogenase that catalyzes the conversion of atmospheric nitrogen molecules N₂ into NH₃ through the process known as nitrogen fixation and the FeMo-cofactor.
... Prodrugs are pharmacologically inactive molecules that can be metabolized to originate their active counterpart, usually by enzymatic cleavage of one or more promoieties. Prodrug development is a strategy used to overcome several problems that can be associated with active molecules, such as instability, poor absorption or distribution, toxicity, and poor solubility [79]. ...
Intranasal administration is a promising route for brain drug delivery. However, it can be difficult to formulate drugs that have low water solubility into high strength intranasal solutions. Hence, the purpose of this work was to review the strategies that have been used to increase drug strength in intranasal liquid formulations. Three main groups of strategies are: the use of solubilizers (change in pH, complexation and the use cosolvents/surfactants); incorporation of the drugs into a carrier nanosystem; modifications of the molecules themselves (use of salts or hydrophilic prodrugs). The use of high amounts of cosolvents and/or surfactants and pH decrease below 4 usually lead to local adverse effects, such as nasal and upper respiratory tract irritation. Cyclodextrins and (many) different carrier nanosystems, on the other hand, could be safer for intranasal administration at reasonably high concentrations, depending on selected excipients and their dose. While added attributes such as enhanced permeation, sustained delivery, or increased direct brain transport could be achieved, a great effort of optimization will be required. On the other hand, hydrophilic prodrugs, whether co-administered with a converting enzyme or not, can be used at very high concentrations, and have resulted in a fast prodrug to parent drug conversion and led to high brain drug levels. Nevertheless, the choice of which strategy to use will always depend on the characteristics of the drug and must be a case-by-case approach.
... A deeper progression on enzyme models and the computational methods will assist in understanding enzyme catalysis concepts and will eventually contribute to the development of efficient prodrugs. [17,18] A novel prodrug [(1m), {3-(5-methyl-2-oxo-1, 3-dioxol-4-yl) methyloxy-2 trans-[(4-chloro phenyl) cyclohexyl]-1, 4-naphthoquinone}] was prepared to treat Pneumocystis carinni, Plasmodia, tachyzoite and cyst forms of Toxoplasma gondii. It was synthesized by treating (1) with 5-methyl, 4-chloromethyldioxalone in the presence of Potassium carbonate, purified and characterized. ...
Naphthoquinone ring forms a prominent structural feature in many pharmaceutical compounds having therapeutic efficacy for various pathogens. Both Atovaquone and Buparvaquone drugs belong to this class, these drugs were predominantly used for treating malaria and protozoal infections. Both the parent drug molecules have very low bioavailability due to poor solubility, contributing to the need of inducing high dose during the treatment. Various studies have been carried out to overcome these issues, with a considerable focus on reducing the particle size or to introduce the novel prodrugs of these molecules. Noticeable work has been done to reduce the particle size, whereas very less volume of published literature is available on the prodrugs of these two under-focus drug molecules. In this review, efforts were put in to compile the available literature towards the progressive disclosures on the synthesis and the therapeutic advantages of Atovaquone and Buparvaquone prodrugs.
