The COVID-19 pandemic was controlled due to the rapid development of new vaccines and anti-viral drugs. However, the emergence of new variants and drug resistant strains of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) potentially threatens this progress. A new study, published in eLife, described a computational approach to rational drug development that has identified potentially ‘druggable’ pockets in a SARS-CoV-2 protein.
A new therapeutic target
The emergence of drug-resistant strains of SARS-CoV-2 necessitates the development of new treatments. In most cases, proteins are the ideal therapeutic target. These proteins are usually important structural components or viral factors involved in replication.
Non-structural protein 1 (Nsp1) is a protein produced by SARS-CoV-2 (and other coronaviruses) early on in infection. The protein blocks host ribosomes, preventing translation and inhibiting the synthesis of proteins that are important in the innate immune response.
Until now, Nsp1 was not considered a serious drug target due to a supposed lack of ‘druggable’ pockets. Researchers at the University of Geneva (UNIGE), in collaboration with University College London (UCL) and the University of Barcelona, have revealed ‘hidden’ pockets in Nsp1.
Francesco Luigi Gervasio, Professor of Pharmaceutical Sciences at UNIGE and Professor of Chemistry at UCL said, “Nsp1 is an important infectious agent of SARS-CoV-2. This small viral protein selectively blocks ribosomes – the protein factories of our cells – making them unusable by our cells and thus preventing the immune response. At the same time, via ribosomes, Nsp1 stimulates the production of viral proteins.”
Using simulations (outside of the Matrix)
First, a pocket detection algorithm was used to identify the cavities in a 3D crystal structure of the protein. Further structural analysis using a molecular dynamics simulation identified secondary protein structures (α-helices, β-strands and β-barrels) within Nsp1. Another simulation was then used to analyse the volumes of the pockets identified.
The researchers identified four pockets altogether. Two were more hidden and were called “cryptic” pockets (pocket 3 and 4 on figure 1).
The binding ability of 59 small fragments to the pockets was then tested using an experimental screening approach known as crystal soaking. One fragment, called 2E10, interacted with pocket 1 (figure 2).
Rational drug design in the future
Using the approach described in the study, key molecular and structural data that could aid in rational drug development were revealed. This could be applied to other unexplored proteins with as-yet unknown and potentially druggable cavities.
Professor Gervasio said, “These results pave the way for the development of new treatments targeting the Nsp1 protein, not only against SARS-CoV-2 and its variants but also against other coronaviruses in which Nsp1 is present.”
