Potential COVID-2019 3C-like Protease Inhibitors Designed Using Generative Deep Learning Approaches

Abstract

<div> <div> <p>The emergence of the 2019 novel coronavirus (COVID-19), for which there is no vaccine or any known effective treatment created a sense of urgency for novel drug discovery approaches. One of the most important COVID-19 protein targets is the 3C-like protease for which the crystal structure is known. Most of the immediate efforts are focused on drug repurposing of known clinically-approved drugs and virtual screening for the molecules available from chemical libraries that may not work well. For example, the IC50 of lopinavir, an HIV protease inhibitor, against the 3C-like protease is approximately 50 micromolar, which is far from ideal. In an attempt to address this challenge, on January 28th, 2020 Insilico Medicine decided to utilize a part of its generative chemistry pipeline to design novel drug-like inhibitors of COVID-19 and started generation on January 30th. It utilized three of its previously validated generative chemistry approaches: crystal-derived pocked-based generator, homology modelling-based generation, and ligand-based generation. Novel druglike compounds generated using these approaches were published at <a href="http://www.insilico.com/ncov-sprint/">www.insilico.com/ncov-sprint/</a>. Several molecules will be synthesized and tested using the internal resources; however, the team is seeking collaborations to synthesize, test, and, if needed, optimize the published molecules. <br></p> </div> </div>

Peptide-like and small-molecule inhibitors against Covid-19

“…Further studies are necessary on the application of data mining techniques like the expert system to classify the peptide-like inhibitors, cluster analysis by self-organizing map (SOM) to make a group of inhibitors, and to understand similarity and dissimilarity should (Yan et al, 2013, Rein et al, 2019 (Zhavoronkov et al, 2020). Molecules screened from FDA approved drugs may undergo directly for clinical trials against Covid-19 disease.…”

A review of modern technologies for tackling COVID-19 pandemic

“…The MIT specialists are utilizing an AI model trained on data about the ACE2 receptor to simulate the connection between the baits and the virus [36]. Some research focuses to find novel compounds for use in focusing on SARS-Cov2 by utilizing an exclusive pipeline to discover inhibitors for the 3Clike protease [37]. Such models utilize three sorts of information: the crystal structure of the protein, the co-crystalized ligands, and the homology model of the protein.…”

Geroprotective and senoremediative strategies to reduce the comorbidity, infection rates, severity, and lethality in gerophilic and gerolavic infections

“…When the news of SARS-CoV-2/COVID-19 emerged in early January 2020, it was difficult to justify a business case for small biotechnology companies to allocate resources to the effort. By January 28 th , however, Insilico Medicine allocated resources to generate and test small molecules against the SARS-CoV-2 3C-like protease [120,121]. As the scale of the current COVID-19 pandemic remains uncertain, it is still difficult to justify allocating scarce company resources to full-scale drug discovery and drug development programs, which may cost tens or even hundreds of millions of dollars [122].…”