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Investigation of Degarelix aggregation behaviour using All Atom Molecular Dynamics Simulations – effect of counterions
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci. (Pharmaceutics and Biopharmaceutics)
2021 (engelsk)Independent thesis Advanced level (degree of Master (Two Years)), 20 poäng / 30 hpOppgave
Abstract [en]

The aggregation propensity of peptide drug can affect its development, dosage forms, and route of administration. This behaviour can be influenced by other components in the system such as ions or charged molecules which interact with the amino acid residues. Therefore, understanding these interactions is important in developing a therapeutic peptide formulation. Molecular dynamic simulations can be an important computational tool in the understanding of peptide aggregation behaviours. It can provide conformational, structural, and chemical properties which are important to understand the aggregation kinetics and propensity of the peptides. In this study, All-Atom Molecular Dynamics (AA-MD) method were applied to investigate the detail of molecular-level interaction patterns between Degarelix and different counterions i.e. chloride, acetate and gluconate. Each simulation system were consisted of 20 peptide molecules representing 10 mM concentration. Simulations with two different peptide-counterion concentration ratios i.e. 1:1 and 1:2 were performed for acetate and gluconate, while for chloride, the simulation was performed only at 1:1 peptide-counterion ratio. At a specific peptide-counterion ratio, we did not observe significant differences in aggregation behaviour of Degarelix in terms of aggregations size distribution, percentage of free monomers or number of aggregates in the presence of different counterions. However, the detailed contact map between peptide amino acids and counterions as well as hbonds and radial distribution function analysis showed that gluconate and chloride interact the most and least with the Degarelix peptides respectively. The increase of counterion concentration (from 1:1 to 1:2 peptide-counterion ratio) for acetate and gluconate in the system showed an increased peptide-counterion interaction i.e. higher number of peptide-counterion hbonds and contacts as well as an increased aggregation tendency of Degarelix. Overall, the results from our study suggest that AA-MD simulations are capable of capturing the different interaction pattern between Degarelix and different counterions at the molecular-level. Also, the results showed that counterion concentration can impact the aggregation propensity of Degarelix.

sted, utgiver, år, opplag, sider
2021. , s. 22
HSV kategori
Identifikatorer
URN: urn:nbn:se:uu:diva-444326OAI: oai:DiVA.org:uu-444326DiVA, id: diva2:1561048
Fag / kurs
Pharmacy
Utdanningsprogram
Master's Programme in Pharmaceutical Modelling
Presentation
2021-06-03, Uppsala, 15:30 (engelsk)
Veileder
Examiner
Tilgjengelig fra: 2021-06-14 Laget: 2021-06-05 Sist oppdatert: 2021-06-14bibliografisk kontrollert

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