Computational Assessment of the Pharmacological Profiles of Degradation Products of Chitosan

Abstract

Chitosan is a natural polymer revealing an increased potential to be used in different biomedical applications, including drug delivery systems, and tissue engineering. It implies the evaluation of the organism response to the biomaterial implantation. Low-molecular degradation products, the chito-oligomers, are resulting mainly from the influence of enzymes, which are found in the organism fluids. Within this study, we have performed the computational assessment of pharmacological profiles and toxicological effects on human health of small chito-oligomers with distinct molecular weights, deacetylation degrees, and acetylation patterns. Our approach is based on the fact that regulatory agencies and researchers in the drug development field rely on the use of modeling to predict biological effects and to guide decision making. To be considered as valid for regulatory purposes, every model that is used for predictions should be associated with a defined toxicological endpoint and has appropriate robustness and predictivity. Within this context, we have used FAF-Drugs4, SwissADME, and PreADMET tools to predict the oral bioavailability of chito-oligomers and SwissADME, PreADMET, and admetSAR2.0 tools to predict their pharmacokinetic profiles. The organs and genomic toxicities have been assessed using admetSAR2.0 and PreADMET tools but specific computational facilities have been also used for predicting different toxicological endpoints: Pred-Skin for skin sensitization, CarcinoPred-EL for carcinogenicity, Pred-hERG for cardiotoxicity, ENDOCRINE DISRUPTOME for endocrine disruption potential and Toxtree for carcinogenicity and mutagenicity. Our computational assessment showed that investigated chito-oligomers reflect promising pharmacological profiles and limited toxicological effects on humans, regardless of molecular weight, deacetylation degree, and acetylation pattern. According to our results, there is a possible inhibition of the organic anion transporting peptides OATP1B1 and/or OATP1B3, a weak potential of cardiotoxicity, a minor probability of affecting the androgen receptor, and phospholipidosis. Consequently, these results may be used to guide or to complement the existing in vitro and in vivo toxicity tests, to optimize biomaterials properties and to contribute to the selection of prototypes for nanocarriers.

In silico Assessment of Pharmacological Profile of Low Molecular Weight Oligo-Hydroxyalkanoates

“…Quite similar results with those emphasized in this study were obtained when assessing the pharmacological profiles of the short oligomers resulting from the degradation of other biopolymers that are used for medical applications: oligomers (up to 40 monomeric units) of lactic acid (OLAs) (Dascalu et al, 2020) and low molecular weight chito-oligosaccharides (Roman et al, 2019). OLAs were also predicted as being able to inhibit the organic anion transporting peptides OATP1B1 and/or OATP1B3.…”

“…The co-oligomers containing the sequences 3-hydroxybutyrate-3-hydroxyvalerate or 4-hydroxybutyrate-4hydroxyvalerate revealed to have the highest probabilities to bind to plasma proteins. Low probabilities to bind to plasma proteins have been also predicted for low molecular weight chitosan based oligomers (Roman et al, 2019) and low molecular weight oligomers of lactic acid (Dascalu et al, 2020). This outcome is also in good agreement with the information that the binding of 4HB to plasma proteins is negligible and its distribution on the human organism depends on its distribution in the total body water (Busardò and Jones, 2015).…”

“…the pharmacological profiles and toxicological endpoints of water-soluble chitosan derivatives (Isvoran et al, 2017), steroids (Roman et al, 2018a), parabens (Roman et al, 2018b), chito-oligomers (Roman et al, 2019), phthalates (Craciun et al, 2019), pesticides (Alves et al, 2018b;Gridan et al, 2019), and low molecular weight oligomers of lactic acid (Dascalu et al, 2020). These methods are summarized in Table 2.…”

In vitro bioassessment of novel δ- carboline derivatives as an antiproliferative agent

“…Carcinogenicity is one of the cell-killing property of the chemical compound. To know the carcinogenicity nature of the compound CarcinoPred-EL was used (Mady et al, 2018;Roman et al, 2019).…”

Computational Assessment of Chito-Oligosaccharides Interactions with Plasma Proteins

“…Pharmaceutical actions of COs proved to be strongly dependent on their physicochemical properties [18]. A computational study performed by our group [19] showed that COs reveal promising pharmacological profiles and limited toxicological effects on humans, regardless of MW, DD, and DAP. According to this study, the possible toxicological effects of COs in the human organism consist in the inhibition of the organic anion transporting peptides OATP1B1 and/or OATP1B3, a small probability of affecting the androgen receptor, a low potential of cardiotoxicity, and the possibility of COs characterized by high DD to produce phospholipidosis [19].…”