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Disaggregation of Amylin Aggregate by Novel Conformationally Restricted Aminobenzoic Acid containing ?/? and ?/? Hybrid Peptidomimetics.

ABSTRACT: Diabetes has emerged as a threat to the current world. More than ninety five per cent of all the diabetic population has type 2 diabetes mellitus (T2DM). Aggregates of Amylin hormone, which is co-secreted with insulin from the pancreatic ?-cells, inhibit the activities of insulin and glucagon and cause T2DM. Importance of the conformationally restricted peptides for drug design against T2DM has been invigorated by recent FDA approval of Symlin, which is a large conformationally restricted peptide. However, Symlin still has some issues including solubility, oral bioavailability and cost of preparation. Herein, we introduced a novel strategy for conformationally restricted peptide design adopting a minimalistic approach for cost reduction. We have demonstrated efficient inhibition of amyloid formation of Amylin and its disruption by a novel class of conformationally restricted ?-sheet breaker hybrid peptidomimetics (BSBHps). We have inserted ?, ? and ? -aminobenzoic acid separately into an amyloidogenic peptide sequence, synthesized ?/?, ?/? and ?/? hybrid peptidomimetics, respectively. Interestingly, we observed the aggregation inhibitory efficacy of ?/? and ?/? BSBHps, but not of ?/? analogues. They also disrupt existing amyloids into non-toxic forms. Results may be useful for newer drug design against T2DM as well as other amyloidoses and understanding amyloidogenesis.

SUBMITTER: Paul A

PROVIDER: S-EPMC5214534 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Disaggregation of Amylin Aggregate by Novel Conformationally Restricted Aminobenzoic Acid containing α/β and α/γ Hybrid Peptidomimetics.

Paul Ashim A Kalita Sourav S Kalita Sujan S Sukumar Piruthivi P Mandal Bhubaneswar B

Scientific reports 20170105

Diabetes has emerged as a threat to the current world. More than ninety five per cent of all the diabetic population has type 2 diabetes mellitus (T2DM). Aggregates of Amylin hormone, which is co-secreted with insulin from the pancreatic β-cells, inhibit the activities of insulin and glucagon and cause T2DM. Importance of the conformationally restricted peptides for drug design against T2DM has been invigorated by recent FDA approval of Symlin, which is a large conformationally restricted peptid ...[more]

PMID: 28054630

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Project description:ContextMicro-hydration of the aminobenzoic acid is essential to understand its interaction with surrounding water molecules. Understanding the micro-hydration of the aminobenzoic acid is also essential to study its remediation from wastewater. Therefore, we explored the potential energy surfaces (PESs) of the para-aminobenzoic acid-water clusters, ABW[Formula: see text], [Formula: see text], to study the microsolvation of the aminobenzoic acid in water. In addition, we performed a quantum theory of atoms in molecules (QTAIM) analysis to identify the nature of non-covalent bondings in the aminobenzoic acid-water clusters. Furthermore, temperature effects on the stability of the located isomers have been examined. The located structures have been used to calculate the hydration free energy and the hydration enthalpy of the aminobenzoic acid using the cluster continuum solvation model. The hydration free energy and the hydration enthalpy of the aminobenzoic acid at room temperature are evaluated to be -7.0 kcal/mol and -18.1 kcal/mol, respectively. The hydration enthalpy is in perfect agreement with a previous experimental estimate. Besides, temperature effects on the calculated hydration enthalpy and free energy are reported. Finally, we calculated the gas phase binding energies of the most stable structures of the ABW[Formula: see text] clusters using twelve functionals of density functional theory (DFT), including empirical dispersion. The DFT functionals are benchmarked against the DLPNO-CCSD(T)/CBS. We have found that the three most suitable DFT functionals are classified in the following order: PW6B95D3 > MN15 > [Formula: see text]B97XD. Therefore, the PW6B95D3 functional is recommended for further study of the aminobenzoic acid-water clusters and similar systems.MethodsThe exploration started with classical molecular dynamics simulations followed by complete optimization at the PW6B95D3/def2-TZVP level of theory. Optimizations are performed using Gaussian 16 suite of codes. QTAIM analysis is performed using the AIMAll program.

Dataset Information

Disaggregation of Amylin Aggregate by Novel Conformationally Restricted Aminobenzoic Acid containing ?/? and ?/? Hybrid Peptidomimetics.

Publications

Disaggregation of Amylin Aggregate by Novel Conformationally Restricted Aminobenzoic Acid containing α/β and α/γ Hybrid Peptidomimetics.

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