A Simple Molecular Model to Study the Substrate Diffusion into the Active Site of a Lipase-Catalyzed Esterification of Ibuprofen and Ketoprofen with Glycerol

Toledo, María Victoria; Briand, Laura E.; Ferreira, Marı́a Luján

doi:10.1007/s11244-022-01636-z

Cited by 6 publications

(4 citation statements)

References 26 publications

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“…The Autodock Vina tool [24] integrated into Chimera software [25] was used for the docking. The grid box was set by using the center of mass calculated in PyMol software, based on the catalytic triads of the enzymes (Ser105, Asp 187, and His 224 for CalB [8], and Ser 144, Asp 203, and His 257 for RM [26,27]) and by considering that the ligand's extended conformations fit well in the grid box (25 × 25 × 25 Å). The best candidates were visualized and further analyzed (distances, interactions, and surface hydrophobicities) using the Chimera software.…”

Section: Computational Analysismentioning

confidence: 99%

“…In this regard, the literature reports studies on the esterification of racemic ibuprofen with glycerol. Toledo et al published a study on the diffusion of ibuprofen into the active site of Candida antarctica lipase type B (CalB) [8], as well as investigations into the esterification at the molecular level through concentration-modulated infrared spectroscopy [9]. Ravelo et al reported the kinetic model of the esterification of racemic ibuprofen with CalB in solventless [10] and biphasic [11] systems, both for immobilized [12] and free [13] biocatalysts.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Biocatalytic Insights for The Synthesis of New Potential Prodrugs: Design of two Ibuprofen Derivatives

Zappaterra,

Presini,

Venturi

et al. 2023

Applied Sciences

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Due to its effectiveness, ibuprofen is one of the most popular anti-inflammatory drugs worldwide. However, the poor water solubility of this active ingredient severely limits its spectrum of pharmaceutical formulations (and often results in severe adverse effects due to high administered doses). To overcome these limitations, in this work, we enzymatically synthesized more hydrophilic derivatives of ibuprofen through its covalent attachment to two biobased polyalcohols: erythritol and glycerol. Herein, we report the optimized reaction conditions to produce an IBU–erythritol ester (82% ± 4% of conversion) by using Candida antarctica lipase B (CalB). Furthermore, we also report the enantioselective solventless esterification of (S)-ibuprofen with glycerol (83% ± 5% of conversion), exploiting immobilized Rhizomucor miehei lipase as a biocatalyst. The full NMR characterizations of the prodrug esters were performed via 1H, 13C-NMR, DEPT, COSY, HSQC, and HMBC-NMR. The approach reported in this work can be extended to a large variety of poorly water-soluble active pharmaceutical ingredients (APIs).

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Section: Computational Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Biocatalytic Insights for The Synthesis of New Potential Prodrugs: Design of two Ibuprofen Derivatives

Zappaterra,

Presini,

Venturi

et al. 2023

Applied Sciences

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“…The PM3 approach is based on the use of a set of empirical parameters to describe the electronic structure of a molecule [ 48 ]. The key feature of the PM3 is that it offers the chance to accurately predict the geometrical conformation of large molecules, including enzymes [ 49 ] and polymers [ 50 ].…”

Section: Introductionmentioning

confidence: 99%

Computational Investigation of Interactions between Carbon Nitride Dots and Doxorubicin

2023

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The study of carbon dots is one of the frontiers of materials science due to their great structural and chemical complexity. These issues have slowed down the production of solid models that are able to describe the chemical and physical features of carbon dots. Recently, several studies have started to resolve this challenge by producing the first structural-based interpretation of several kinds of carbon dots, such as graphene and polymeric ones. Furthermore, carbon nitride dot models established their structures as being formed by heptazine and oxidized graphene layers. These advancements allowed us to study their interaction with key bioactive molecules, producing the first computational studies on this matter. In this work, we modelled the structures of carbon nitride dots and their interaction with an anticancer molecule (Doxorubicin) using semi-empirical methods, evaluating both geometrical and energetic parameters.

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“…Novozym ® 435 (N435) is an industrial preparation of this enzyme on Lewatit VP OC 1600 manufactured by Novozymes A/S. This biocatalyst is most active in the esterification of profens [9] and, in particular, ibuprofen [10][11][12]. For several decades, immobilization techniques have been applied to lipases, profiting from their ability to act as interfacial biocatalysts, although there is still space for further enhancement [12,13].…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Ibuprofen Monoglyceride Using Novozym®435: Biocatalyst Activation and Stabilization in Multiphasic Systems

et al. 2022

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This work was focused on the enzymatic esterification of glycerol and ibuprofen at high concentrations in two triphasic systems composed of toluene+ibuprofene (apolar) and glycerol or glycerol–water (polar) liquid phases, and a solid phase with the industrial immobilized lipase B from Candida antarctica named Novozym®435 (N435) acting as the biocatalyst. Based on a preliminary study, the concentration of the enzyme was set at 30 g·L−1 and the stirring speed at 720 r.p.m to reduce external mass transfer limitations. To obtain more information on the reaction system, it was conducted at a wide range of temperatures (50 to 80 °C) and initial concentrations of ibuprofen (20–100 g·L−1, that is, 97 to 483 mM). Under these experimental conditions, the external mass transfer, according to the Mears criterion (Me = 1.47–3.33·10−4 << 0.15), was fast, presenting no limitation to the system productivity, regardless of the presence of water and from 50 to 80 °C. Considering that the enzyme is immobilized in a porous ion-exchange resin, limitations due to internal mass transfer can exist, depending on the values of the effectiveness factor (η). It varied from 0.14 to 0.23 at 50 to 80 °C and 0.32–1 mm particle diameter range in the absence of water, and in the same ranges, from 0.40 to 0.66 in the presence of 7.4% w/w water in the glycerol phase. Thus, it is evident that some limitation occurs due to mass transfer inside the pores, while the presence of water in the polar phase increases the productivity 3–4 fold. During the kinetic study, several kinetic models were proposed for both triphasic reacting systems, with and without first-order biocatalyst deactivation, and their fit to all relevant experimental data led to the observation that the best kinetic model was a reversible hyperbolic model with first-order deactivation in the anhydrous reaction system and a similar model, but without deactivation, for the system with added water at zero time. This fact is in sharp contrast to the use of N435 in a water-glycerol monophasic system, where progressive dissolution of ibuprofen in the reacting media, together with a notable enzyme deactivation, is observed.

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A Simple Molecular Model to Study the Substrate Diffusion into the Active Site of a Lipase-Catalyzed Esterification of Ibuprofen and Ketoprofen with Glycerol

Cited by 6 publications

References 26 publications

Biocatalytic Insights for The Synthesis of New Potential Prodrugs: Design of two Ibuprofen Derivatives

Biocatalytic Insights for The Synthesis of New Potential Prodrugs: Design of two Ibuprofen Derivatives

Computational Investigation of Interactions between Carbon Nitride Dots and Doxorubicin

Synthesis of Ibuprofen Monoglyceride Using Novozym®435: Biocatalyst Activation and Stabilization in Multiphasic Systems

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