Three dimensional model of severe acute respiratory syndrome coronavirus helicase ATPase catalytic domain and molecular design of severe acute respiratory syndrome coronavirus helicase inhibitors

Abstract

The modeling of the severe acute respiratory syndrome coronavirus helicase ATPase catalytic domain was performed using the protein structure prediction Meta Server and the 3D Jury method for model selection, which resulted in the identification of 1JPR, 1UAA and 1W36 PDB structures as suitable templates for creating a full atom 3D model. This model was further utilized to design small molecules that are expected to block an ATPase catalytic pocket thus inhibit the enzymatic activity. Binding sites for various functional groups were identified in a series of molecular dynamics calculation. Their positions in the catalytic pocket were used as constraints in the Cambridge structural database search for molecules having the pharmacophores that interacted most strongly with the enzyme in a desired position. The subsequent MD simulations followed by calculations of binding energies of the designed molecules were compared to ATP identifying the most successful candidates, for likely inhibitors - molecules possessing two phosphonic acid moieties at distal ends of the molecule.

The interactome: Predicting the protein-protein interactions in cells

“…Proper selection of the protein domain is necessary [102][103][104][105][106][107][108]. In addition to pure chemical data [109][110][111][112][113][114][115][116] in the context of the Drug Discovery [117][118][119][120][121][122][123][124][125][126][127], there is also a need for some knowledge on protein-protein interactions, the high quality structural prediction of proteins [2,[128][129][130][131][132][133][134][135][136] and their inhibitors, and a detailed understanding of how those inhibitors affect the molecular recognition between proteins. The development of theoretical methods for function annotation clearly shows that a detailed analysis of local characteristics of the protein chain can significantly improve accuracy.…”

ATP Hydrolysis Analysis of Severe Acute Respiratory Syndrome (SARS) Coronavirus Helicase

“…Recent computerbased three dimensional model of SARS-CoV helicase showed that it has six conserved motifs that are characteristic for superfamily 1 helicases, and motif I and II, specifically Lys288 residue in motif I by contacting the β-phosphate of the bound NTP, play an important role when NTP-Mg 2+ complex binds the helicase and proceed to hydrolyze. 32 In addition, the complex ATP with SARS-CoV helicase closely resembles the crystal structure of PcrA helicase, another member of superfamily 1 helicases, which suggests that SARS-CoV helicase may follow similar divalent cation dependent ATP hydrolysis pattern of other superfamily 1 helicases. In previous studies of PcrA 33 , Mg 2+ binding can stabilize ATP-Mg 2+ complex in the correct conformation to hydrolyze ATP.…”

The Nonstructural Proteins Directing Coronavirus RNA Synthesis and Processing

“…The substrate preferences summarized earlier support a threedimensional model of the SARS-CoV HEL1 core domains (1A and 2A) that was based on structural information available for multiple cellular helicases (Hoffmann et al, 2006). The model predicts both the existence of multiple hydrogen bonding interactions with the βand γ-phosphates of the NTP and a lack of specific interactions with the nucleobase.…”

“…Despite its importance as a potential drug target, a CoV nsp13 or HEL1 crystal structure has not been obtained thus far due to technical complications with recombinant protein production and crystallization. Instead, several CoV helicase models have been described, mainly based on cellular helicase structures (Bernini et al, 2006;Hoffmann et al, 2006;Lehmann et al, 2015c). Given this limitation, and despite the large evolutionary distance between the two enzymes, it is interesting to have a closer look at the recently published EAV nsp10-helicase structure (Deng et al, 2014).…”