Abstract
In the last year, the COVID-19 pandemic has highly affected the lifestyle of the world population, encouraging the scientific community towards a great effort on studying the infection molecular mechanisms. Several vaccine formulations are nowadays available and helping to reach immunity. Nevertheless, there is a growing interest towards the development of novel anti-covid drugs. In this scenario, the main protease (Mpro) represents an appealing target, being the enzyme responsible for the cleavage of polypeptides during the viral genome transcription. With the aim of sharing new insights for the design of novel Mpro inhibitors, our research group developed a machine learning approach using the support vector machine (SVM) classification. Starting from a dataset of two million commercially available compounds, the model was able to classify two hundred novel chemo-types as potentially active against the viral protease. The compounds labelled as actives by SVM were next evaluated through consensus docking studies on two PDB structures and their binding mode was compared to well-known protease inhibitors. The best five compounds selected by consensus docking were then submitted to molecular dynamics to deepen binding interactions stability. Of note, the compounds selected via SVM retrieved all the most important interactions known in the literature.
Highlights
The COVID-19 pandemic, known as Severe Acute Respiratory SyndromeCoronavirus-2 (SARS-CoV-2) is afflicting the health and routines of billions of people worldwide.During the last few months, we are witnessing a race against time to vaccinate as many people as possible; the disparities in vaccine distribution between countries and the new emerging variants represent a further public health concern, making it hard to reach a full immunization [1,2].SARS-CoV-2 is a member of the betacoronavirus family, together with SARS-CoV and Middle East Respiratory Syndrome (MERS-CoV)
The enormous scientific effort worldwide led to a better understanding of SARS-CoV-2 structure and the infection mechanism, spotting four main druggable targets, namely the Spike (S) protein, Papain-like protease (PLpro), RNA-dependent RNA polymerase (RdRp) and the main protease/3C-like protease (Mpro/3CLpro) [3,4]
Feature selection was carried out on the training set, in order to identify the crucial molecular descriptors able to explain the possible correlation between Mpro inhibitors activity and their chemical structures
Summary
The COVID-19 pandemic, known as Severe Acute Respiratory SyndromeCoronavirus-2 (SARS-CoV-2) is afflicting the health and routines of billions of people worldwide.During the last few months, we are witnessing a race against time to vaccinate as many people as possible; the disparities in vaccine distribution between countries and the new emerging variants represent a further public health concern, making it hard to reach a full immunization [1,2].SARS-CoV-2 is a member of the betacoronavirus family, together with SARS-CoV and Middle East Respiratory Syndrome (MERS-CoV). The COVID-19 pandemic, known as Severe Acute Respiratory Syndrome. Coronavirus-2 (SARS-CoV-2) is afflicting the health and routines of billions of people worldwide. SARS-CoV-2 is a member of the betacoronavirus family, together with SARS-CoV and Middle East Respiratory Syndrome (MERS-CoV). The enormous scientific effort worldwide led to a better understanding of SARS-CoV-2 structure and the infection mechanism, spotting four main druggable targets, namely the Spike (S) protein, Papain-like protease (PLpro), RNA-dependent RNA polymerase (RdRp) and the main protease/3C-like protease (Mpro/3CLpro) [3,4]. SARS-CoV-2 Mpro leads a crucial role in the viral replication process. Mpro is a cysteine protease responsible for the cleavage of polypeptides during the viral genome transcription, promoting the generation of non-structural proteins, which can assemble to form new infectious virions.
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
