Hit-to-lead short peptides against dengue type 2 envelope protein: Computational and experimental investigations

Zaidi, Norburhanuddin Johari and Abdullah, Adib Afandi and Heh, Choon Han and Lin, Chun-Hung and Othman, Rozana and Ahmad Fuaad, Abdullah Al Hadi (2022) Hit-to-lead short peptides against dengue type 2 envelope protein: Computational and experimental investigations. Molecules, 27 (10). ISSN 1420-3049, DOI https://doi.org/10.3390/molecules27103233.

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Data from the World Health Organisation show that the global incidence of dengue infection has risen drastically, with an estimated 400 million cases of dengue infection occurring annually. Despite this worrying trend, there is still no therapeutic treatment available. Herein, we investigated short peptide fragments with a varying total number of amino acid residues (peptide fragments) from previously reported dengue virus type 2 (DENV2) peptide-based inhibitors, DN58wt (GDSYIIIGVEPGQLKENWFKKGSSIGQMF), DN58opt (TWWCFYFCRRHHPFWFFYRHN), DS36wt (LITVNPIVTEKDSPVNIEAE), and DS36opt (RHWEQFYFRRRERKFWLFFW), aided by in silico approaches: peptide-protein molecular docking and 100 ns of molecular dynamics (MD) simulation via molecular mechanics using Poisson-Boltzmann surface area (MMPBSA) and molecular mechanics generalised Born surface area (MMGBSA) methods. A library of 11,699 peptide fragments was generated, subjected to in silico calculation, and the candidates with the excellent binding affinity and shown to be stable in the DI-DIII binding pocket of DENV2 envelope (E) protein were determined. Selected peptides were synthesised using conventional Fmoc solid-phase peptide chemistry, purified by RP-HPLC, and characterised using LCMS. In vitro studies followed, to test for the peptides' toxicity and efficacy in inhibiting the DENV2 growth cycle. Our studies identified the electrostatic interaction (from free energy calculation) to be the driving stabilising force for the E protein-peptide interactions. Five key E protein residues were also identified that had the most interactions with the peptides: (polar) LYS36, ASN37, and ARG350, and (nonpolar) LEU351 and VAL354; these residues might play crucial roles in the effective binding interactions. One of the peptide fragments, DN58opt_8-13 (PFWFFYRH), showed the best inhibitory activity, at about 63% DENV2 plague reduction, compared with no treatment. This correlates well with the in silico studies in which the peptide possessed the lowest binding energy (-9.0 kcal/mol) and was maintained steadily within the binding pocket of DENV2 E protein during the MD simulations. This study demonstrates the use of computational studies to expand research on lead optimisation of antiviral peptides, thus explaining the inhibitory potential of the designed peptides.

Item Type: Article
Funders: SATREPS Project under the Ministry of Higher Education (MOHE), Malaysia [Grant No: IF070-2020]
Uncontrolled Keywords: Peptide; Dengue; Envelope protein; Molecular docking; Molecular dynamics; Plaque assay
Subjects: Q Science > QD Chemistry
Q Science > QH Natural history > QH301 Biology
Divisions: Faculty of Science
Faculty of Pharmacy
Depositing User: Ms. Juhaida Abd Rahim
Date Deposited: 13 Oct 2023 02:02
Last Modified: 13 Oct 2023 02:02
URI: http://eprints.um.edu.my/id/eprint/42252

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