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Modelling the behavior of 5-aminolevulinic acid and its alkyl esters in a lipid bilayer
Institutionen för naturvetenskap and Modelling and Simulation Research Center, Örebro University, Sweden.ORCID iD: 0000-0001-9455-9558
i. Med. UL/Institute for Medicine and Pharmaceutical Sciences, Faculty of Pharmacy, University of Lisbon. Av. Prof. Gama Pinto, Lisbon, Portugal.
Head- and Neck Oncology Center, Örebro University Hospital, Örebro, Sweden.
Örebro universitet, Institutionen för naturvetenskap.
2008 (English)In: Chemical Physics Letters, ISSN 0009-2614, E-ISSN 1873-4448, Vol. 463, no 1-3, p. 178-182Article in journal (Refereed) Published
Abstract [en]

5-Aminolevulinic acid (5ALA) and ester derivates thereof are used as prodrugs in photodynamic therapy (PDT). The behavior of 5ALA and three esters of 5ALA in a DPPC lipid bilayer is investigated. In particular, the methyl ester displays a very different free energy profile, where the highest barrier is located in the region with highest lipid density, while the others have their peak in the middle of the membrane, and also displays a considerably lower permeability coefficient than neutral 5ALA and the ethyl ester. The zwitterion of 5ALA has the highest permeability constant, but a significant free energy minimum in the polar head-group region renders an accumulation in this region.

Place, publisher, year, edition, pages
Amsterdam: North-Holland Publishing Co , 2008. Vol. 463, no 1-3, p. 178-182
Keywords [en]
Molecular-dynamics simulations, photodynamic therapy, adenocarcinoma cells, beta transporters, hydrated DPPC, derivates, permeation, protoporphyrin, transition, membranes
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Medicinal Chemistry Physical Chemistry Theoretical Chemistry
Identifiers
URN: urn:nbn:se:liu:diva-150071DOI: 10.1016/j.cplett.2008.08.021ISI: 000259150400035Scopus ID: 2-s2.0-51349091343OAI: oai:DiVA.org:liu-150071DiVA, id: diva2:1237562
Available from: 2008-10-13 Created: 2018-08-09 Last updated: 2018-08-09
In thesis
1. 5-Aminolevulinic acid and derivatives thereof: properties, lipid permeability and enzymatic reactions
Open this publication in new window or tab >>5-Aminolevulinic acid and derivatives thereof: properties, lipid permeability and enzymatic reactions
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

5-aminolevulinic acid (5-ALA) and derivatives thereof are widely usedprodrugs in treatment of pre-malignant skin diseases of the cancer treatmentmethod photodynamic therapy (PDT). The target molecule in 5-ALAPDTis protoporphyrin IX (PpIX), which is synthesized endogenously from5-ALA via the heme pathway in the cell. This thesis is focused on 5-ALA,which is studied in different perspectives and with a variety of computationalmethods. The structural and energetic properties of 5-ALA, itsmethyl-, ethyl- and hexyl esters, four different 5-ALA enols, and hydrated5-ALA have been investigated using Quantum Mechanical (QM) first principlesdensity functional theory (DFT) calculations. 5-ALA is found to bemore stable than its isomers and the hydrolysations of the esters are morespontaneous for longer 5-ALA ester chains than shorter. The keto-enoltautomerization mechanism of 5-ALA has been studied, and a self-catalysismechanism has been proposed to be the most probable. Molecular Dynamics(MD) simulations of a lipid bilayer have been performed to study themembrane permeability of 5-ALA and its esters. The methyl ester of 5-ALAwas found to have the highest permeability constant (PMe-5-ALA = 52.8 cm/s).The mechanism of the two heme pathway enzymes; Porphobilinogen synthase(PBGS) and Uroporphyrinogen III decarboxylase (UROD), have beenstudied by DFT calculations and QM/MM methodology. The rate-limitingstep is found to have a barrier of 19.4 kcal/mol for PBGS and 13.7kcal/mol for the first decarboxylation step in UROD. Generally, the resultsare in good agreement with experimental results available to date.

Place, publisher, year, edition, pages
Örebro: Örebro universitet, 2010. p. 76
Series
Örebro Studies in Life Science, ISSN 1653-3100 ; 6
Keywords
5-Aminolevulinic acid, tautomerization, PDT, DFT, MM, QM/MM, Porphobilinogen synthase, Uroporphyrinogen III decarboxylase, membrane penetration, enzyme mechanism
National Category
Physical Chemistry Theoretical Chemistry Theoretical Chemistry
Identifiers
urn:nbn:se:liu:diva-150067 (URN)9789176687185 (ISBN)
Public defence
2010-04-28, Hörsal M, Musikhögskolan, Örebro Universitet, 10:15 (English)
Opponent
Supervisors
Available from: 2018-08-09 Created: 2018-08-09 Last updated: 2018-08-09Bibliographically approved
2. A theoretical study of 5-Aminolevulinic acid and its esters: properties and lipid permeability
Open this publication in new window or tab >>A theoretical study of 5-Aminolevulinic acid and its esters: properties and lipid permeability
2008 (English)Licentiate thesis, comprehensive summary (Other academic)
Abstract [en]

5-aminolevulinic acid (5ALA) is a widely used prodrug in Photodynamic therapy (PDT). The target molecule in 5ALA-PDT is Protoporphyrin IX (PpIX), which is synthesized endogenously via the heme pathway in the cell. In this thesis; the structural and energetic properties of 5ALA, its methyl-, ethyl- and hexyl esters, four different 5ALA enols, and hydrated 5ALA have been investigated using Quantum Mechanical (QM) first principles calculations. The vacuum proton affinity (PA) of 5ALA is found to be in good agreement with other similar compounds. The keto-enol tautomerization mechanism of 5ALA has been studied, and a self-catalysis mechanism has been proposed to be the most probable. Molecular Dynamics (MD) simulations of a lipid bilayer have been performed to study the membrane permeability of 5ALA and its esters. In the simulations the molecules were inserted in the middle of the membrane, equilibrated, and then simulated in 20 ns. It has been found that there are some differences in penetration between the molecules studied. The methyl ester of 5ALA is diverging from the others by having its barrier not in the middle of the membrane, as the others have.

Place, publisher, year, edition, pages
Örebro: Örebro Universitet, 2008. p. 37
Series
Licentiate Thesises in Life Science, ISSN 1653-9516 ; 5
National Category
Physical Chemistry
Identifiers
urn:nbn:se:liu:diva-150068 (URN)
Presentation
2008-03-06, Örebro, 00:00 (English)
Opponent
Supervisors
Available from: 2008-10-13 Created: 2018-08-09 Last updated: 2018-08-09Bibliographically approved

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