Merits and pitfalls of conventional and covalent docking in identifying new hydroxyl aryl aldehyde like compounds as human IRE1 inhibitors

Abstract

IRE1 is an endoplasmic reticulum (ER) bound transmembrane bifunctional kinase and endoribonuclease protein crucial for the unfolded protein response (UPR) signaling pathway. Upon ER stress, IRE1 homodimerizes, oligomerizes and autophosphorylates resulting in endoribonuclease activity responsible for excision of a 26 nucleotide intron from the X-box binding protein 1 (XBP1) mRNA. This unique splicing mechanism results in activation of the XBP1s transcription factor to specifically restore ER stress. Small molecules targeting the reactive lysine residue (Lys907) in IRE1α’s RNase domain have been shown to inhibit the cleavage of XBP1 mRNA. Crystal structures of murine IRE1 in complex with covalently bound hydroxyl aryl aldehyde (HAA) inhibitors show that these molecules form hydrophobic interactions with His910 and Phe889, a hydrogen bond with Tyr892 and an indispensable Schiff-base with Lys907. The availability of such data prompted interest in exploring structure-based drug design as a strategy to develop new covalently binding ligands. We extensively evaluated conventional and covalent docking for drug discovery targeting the catalytic site of the RNase domain. The results indicate that neither computational approach is fully successful in the current case, and we highlight herein the potential and limitations of the methods for the design of novel IRE1 RNase binders.

Interaction of small molecules with the SARS-CoV-2 main protease in silico and in vitro validation of potential lead compounds using an enzyme-linked immunosorbent assay

“…The M pro enzyme is a cysteine protease and the inhibitors specifically interact with Cys145 covalently ( Zhu et al, 2020 ; Zhang et al, 2020a ). Covalent docking tools have been made available however, the success of this screening approach depends on a number of factors ( Carlesso et al, 2019 ; Scarpino et al, 2018 ). This includes the contribution of non-covalent interactions and the mechanism of covalent bonding ( Carlesso et al, 2019 ; Scarpino et al, 2018 ).…”

“…Covalent docking tools have been made available however, the success of this screening approach depends on a number of factors ( Carlesso et al, 2019 ; Scarpino et al, 2018 ). This includes the contribution of non-covalent interactions and the mechanism of covalent bonding ( Carlesso et al, 2019 ; Scarpino et al, 2018 ). In the current study, conventional docking methods were used and there is evidence to suggest that noncovalent docking is successful in elucidating the interactions that are occurring within protein-ligand complexes at the molecular level ( Saikia and Bordoloi, 2019 ; Meng et al, 2011 ; Wang et al, 2016 ).…”

Computational studies of drugs for possible action against Covid-19 infections

“…Docking study is a direct drug design approach using structure of a target (protein) to identify the essential amino acid interactions between the selected protein and drug with low energy and best dock conformation 18 . Amino acid residues Phe 3, Arg4 and Lys5 are formed hydrogen bond (appear in blue dotted line) with azithromycin ( Figure 1) and dexamethsone ( Figure 2).…”

Deciphering the selectivity of inhibitor MKC9989 towards residue K907 in IRE1α; a multiscalein silicoapproach

“…5 The structure of the four covalently bound MKC9989 molecules (space filling model) to the four selected lysine residues of the cytosolic part of IRE1. CovDock program to reproduce the exact crystallographic pose of MKC9989 towards K907, 50 we decided to use the structure from PDB ID 4PL3 at this particular site in the further investigations.…”