Influence of a lipid bilayer on the conformational behavior of amphotericin B derivatives — A molecular dynamics study

Neumann, Anna; Borowski, Edward; Bagiński, Maciej

doi:10.1016/j.bpc.2009.01.001

Cited by 26 publications

(21 citation statements)

References 57 publications

(94 reference statements)

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“…To better understand the interactions between AmB and living cells, it is important to understand how AmB interacts with lipids, including the arrangement of AmB in lipid–sterol environments (Matsumori et al 2006 ; Gagoś and Arczewska 2010 ), the function of fungal cell walls, and the effects of AmB aggregation in biological systems (Barwicz et al 1992 ; Barwicz and Tancrede 1997 ). Only a full understanding of these phenomena can lead to the design of forms of AmB with lower toxicity and greater efficacy (Bolard et al 1980b ; Bolard and Cheron 1982 ; Paquet et al 2002 ; Matsuoka and Murata 2003 ; Sternal et al 2004 ; Gabrielska et al 2006 ; Hac-Wydro and Dynarowicz-Łątka 2006 ; Foglia et al 2011 ), not only by appropriate formulation (Brogden et al 1998 ; Andres et al 2001 ; Hac-Wydro et al 2005c ; Menez et al 2006 ; Moen et al 2009 ; Hamill 2013 ; Pham et al 2013 ) but also by molecular modification (Hac-Wydro et al 2005c ; Paquet and Carreira 2006 ; Czub et al 2009 ; Croatt and Carreira 2011 ; Tevyashova et al 2013 ; Wilcock et al 2012 , 2013 ). For instance, toxicity can be reduced by using appropriate cationic derivatives of AmB (Slisz et al 2004 ).…”

Section: Introductionmentioning

confidence: 99%

Recent progress in the study of the interactions of amphotericin B with cholesterol and ergosterol in lipid environments

2014

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In the past decade substantial progress has been made in understanding the organization and biological activity of amphotericin B (AmB) in the presence of sterols in lipid environments. This review concentrates mainly on interactions of AmB with lipids and sterols, AmB channel formation in membranes, AmB aggregation, AmB modifications important for understanding its biological activity, and AmB models explaining its mechanism of action. Most of the reviewed studies concern monolayers at the water–gas interface, monolayers deposited on a solid substrate by use of the Langmuir–Blodgett technique, micelles, vesicles, and multi-bilayers. Liposomal AmB formulations and drug delivery are intentionally omitted, because several reviews dedicated to this subject are already available.

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Section: Introductionmentioning

confidence: 99%

Recent progress in the study of the interactions of amphotericin B with cholesterol and ergosterol in lipid environments

2014

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“…In relation to PAs, MD simulations have been extensively used in the conformational analysis of the AmB in aqueous [48,49,50] and lipidic [51,52] media, characterizing the molecular aspects of AmB-biomembranes interactions [50,53,54,55,56,57], elucidating the mechanism of action of the drug [58,59], and understanding the nature of relationship between its molecular organization and selective toxicity [58,60,61,62]. Despite, however, MD simulations are not applied thus far in exploring the factors contributing to the solubilization of PAs, in contrast for instance to anticancer drugs such as paclitaxel [46,63].…”

Section: Introductionmentioning

confidence: 99%

Solubilization Behavior of Polyene Antibiotics in Nanomicellar System: Insights from Molecular Dynamics Simulation of the Amphotericin B and Nystatin Interactions with Polysorbate 80

et al. 2015

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Amphotericin B (AmB) and Nystatin (Nys) are the drugs of choice for treatment of systemic and superficial mycotic infections, respectively, with their full clinical potential unrealized due to the lack of high therapeutic index formulations for their solubilized delivery. In the present study, using a coarse-grained (CG) molecular dynamics (MD) simulation approach, we investigated the interaction of AmB and Nys with Polysorbate 80 (P80) to gain insight into the behavior of these polyene antibiotics (PAs) in nanomicellar solution and derive potential implications for their formulation development. While the encapsulation process was predominantly governed by hydrophobic forces, the dynamics, hydration, localization, orientation, and solvation of PAs in the micelle were largely controlled by hydrophilic interactions. Simulation results rationalized the experimentally observed capability of P80 in solubilizing PAs by indicating (i) the dominant kinetics of drugs encapsulation over self-association; (ii) significantly lower hydration of the drugs at encapsulated state compared with aggregated state; (iii) monomeric solubilization of the drugs; (iv) contribution of drug-micelle interactions to the solubilization; (v) suppressed diffusivity of the encapsulated drugs; (vi) high loading capacity of the micelle; and (vii) the structural robustness of the micelle against drug loading. Supported from the experimental data, our simulations determined the preferred location of PAs to be the core-shell interface at the relatively shallow depth of 75% of micelle radius. Deeper penetration of PAs was impeded by the synergistic effects of (i) limited diffusion of water; and (ii) perpendicular orientation of these drug molecules with respect to the micelle radius. PAs were solvated almost exclusively in the aqueous poly-oxyethylene (POE) medium due to the distance-related lack of interaction with the core, explaining the documented insensitivity of Nys solubilization to drug-core compatibility in detergent micelles. Based on the obtained results, the dearth of water at interior sites of micelle and the large lateral occupation space of PAs lead to shallow insertion, broad radial distribution, and lack of core interactions of the amphiphilic drugs. Hence, controlled promotion of micelle permeability and optimization of chain crowding in palisade layer may help to achieve more efficient solubilization of the PAs.

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“…Though experimental (15)(16)(17) and theoretical studies (18)(19)(20) have been carried out in the past for investigating drug permeability, Molecular Dynamics Simulations (MDS) is now widely used for the estimation of partition of a drug in a membrane (21,22). Since in vivo studies of intestinal membrane permeability are expensive and may prove potentially harmful for the volunteers, the in vitro models such as partitioning in isotropic system (23, 24), transport across artificial membranes (25) and transport across cultured epithelial cell monolayer (26,27) have been the valuable tools.…”

Section: Introductionmentioning

confidence: 99%

Computational and experimental evidence to the permeability of withanolides across the normal cell membrane

Wadhwa¹,

Yadav

Katiyar

et al. 2019

Preprint

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Poor bioavailability due to the inability to cross the cell membrane is one of the major reasons for the failure of a drug in the clinical trials. We have used molecular dynamics simulations to predict the membrane permeability of natural drugs -withanolides (withaferin-A and withanone) that have similar structures but remarkably differ in their cytotoxicity. We found that withaferin-A, but not withanone, could proficiently transverse through the model membrane. The free energy profiles obtained were in accordance with the physico-chemical properties of the investigated drug molecules. It was observed that the polar head group of the bilayer exhibits high resistance for the passage of withanone as compared to withaferin-A, while the interior of the membrane behaves similarly for both withanolides. The solvation analysis revealed that the high solvation of terminal O5 oxygen of withaferin-A was the major driving force. The impact of the favorable interaction of terminal oxygen (O5) of withaferin-A with the phosphate of the membrane led to its smooth passage across the bilayer. The computational predictions were validated by raising and recruiting unique antibodies that react to withaferin-A and withanone.Further, the time-lapsed analyses of control and treated human normal and cancer cells, demonstrated proficient permeation of withaferin-A, but not withanone, through normal cells.These data strongly validated our computational method for predicting permeability and hence bioavailability of candidate compounds in the drug development process. Statement of significanceWhat determines the bioavailability of a drug? Does the ability to cross cell membrane determine this? A combined simulation/experimental study of the permeability of two natural drugswithanolides (Wi-A and Wi-N) across the cell membrane was conducted. In the computational portion of the study, steered MD simulations were performed to investigate the propensity of the two molecules to permeate across the cell. It is found that Wi-A proceeds relatively simply across the cell compared to Wi-N. This trend was found to be consistent with experiment. This work is an important step towards understanding the molecular basis of permeability of natural drug molecules.

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Influence of a lipid bilayer on the conformational behavior of amphotericin B derivatives — A molecular dynamics study

Cited by 26 publications

References 57 publications

Recent progress in the study of the interactions of amphotericin B with cholesterol and ergosterol in lipid environments

Recent progress in the study of the interactions of amphotericin B with cholesterol and ergosterol in lipid environments

Solubilization Behavior of Polyene Antibiotics in Nanomicellar System: Insights from Molecular Dynamics Simulation of the Amphotericin B and Nystatin Interactions with Polysorbate 80

Computational and experimental evidence to the permeability of withanolides across the normal cell membrane

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