期刊名称：Computational and Structural Biotechnology Journal
印刷版ISSN：2001-0370
出版年度：2021
卷号：19
页码：934-948
DOI：10.1016/j.csbj.2021.01.026
出版社：Computational and Structural Biotechnology Journal
摘要：A growing body of research has demonstrated that targeting intrinsically disordered proteins (IDPs) and intrinsically disordered protein regions (IDPRs) is feasible and represents a new trending strategy in drug discovery. However, the number of inhibitors targeting IDPs/IDPRs is increasing slowly due to limitations of the methods that can be used to accelerate the discovery process. We have applied structure-based methods to successfully develop the first peptidic inhibitor ( HIPe - H istone I nhibitory Pe ptide) that targets histone H4 that are released from NETs (Neutrophil Extracellular Traps). HIPe binds stably to the disordered N-terminal tail of histone H4, thereby preventing histone H4-induced cell death. Recently, by utilisation of the same state-of-the-art approaches, we have developed a novel peptidic inhibitor ( CHIP - C yclical H istone H2A I nterference P eptide) that binds to NET-resident histone H2A, which results in a blockade of monocyte adhesion and consequently reduction in atheroprogression. Here, we present comprehensive details on the computational methods utilised to design and develop HIPe and CHIP. We have exploited protein–protein complexes as starting structures for rational peptide design and then applied binding free energy methods to predict and prioritise binding strength of the designed peptides with histone H4 and H2A. By doing this way, we have modelled only around 20 peptides and from these were able to select 4–5 peptides, from a total of more than a trillion candidate peptides, for functional characterisation in different experiments. The developed computational protocols are generic and can be widely used to design and develop novel inhibitors for other disordered proteins.
关键词：Disordered proteins ; Peptides ; Computer-aided molecular design (CAMD) ; Protein-protein interactions (PPIs) ; Histones ; Neutrophil extracellular traps (NETs) ; aMD accelerated molecular dynamics ; ARDS acute respiratory distress syndrome ; BFE binding free energy ; BRCA-1 breast cancer type1 susceptibility protein ; CCL5 chemokine ligand 5 ; CHIP cyclical histone H2A interference peptide ; DC decomposition ; H2A histone H2A ; H2B histone H2B ; H3 histone H3 ; H4 histone H4 ; HIPe histone inhibitory peptide ; HNP1 human neutrophil peptide 1 ; IDPs intrinsically disordered proteins ; IDPRs intrinsically disordered protein regions ; MD molecular dynamics ; MM/GBSA molecular mechanics/generalised born surface area ; NETs neutrophil extracellular traps ; p53 tumor protein 53 ; PDB protein data bank ; PPIs protein-protein interactions ; PTP1B protein tyrosine phosphatase 1B ; SMCs smooth muscle cells
