Abstract
The global pandemic of coronavirus disease (COVID-19) caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) created a rush to discover drug candidates. Despite the efforts, so far no vaccine or drug has been approved for treatment. Artificial intelligence offers solutions that could accelerate the discovery and optimization of new antivirals, especially in the current scenario dominated by the scarcity of compounds active against SARS-CoV-2. The main protease (Mpro) of SARS-CoV-2 is an attractive target for drug discovery due to the absence in humans and the essential role in viral replication. In this work, we developed a deep learning platform for de novo design of putative inhibitors of SARS-CoV-2 main protease (Mpro). Our methodology consists of 3 main steps: (1) training and validation of general chemistry-based generative model; (2) fine-tuning of the generative model for the chemical space of SARS-CoV- Mpro inhibitors and (3) training of a classifier for bioactivity prediction using transfer learning. The fine-tuned chemical model generated > 90% valid, diverse and novel (not present on the training set) structures. The generated molecules showed a good overlap with Mpro chemical space, displaying similar physicochemical properties and chemical structures. In addition, novel scaffolds were also generated, showing the potential to explore new chemical series. The classification model outperformed the baseline area under the precision-recall curve, showing it can be used for prediction. In addition, the model also outperformed the freely available model Chemprop on an external test set of fragments screened against SARS-CoV-2 Mpro, showing its potential to identify putative antivirals to tackle the COVID-19 pandemic. Finally, among the top-20 predicted hits, we identified nine hits via molecular docking displaying binding poses and interactions similar to experimentally validated inhibitors.
Highlights
IntroductionThe global pandemic of coronavirus disease (COVID-19) caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) created a rush to discover drug candidates against the virus [1,2,3]
The global pandemic of coronavirus disease (COVID-19) caused by SARS-CoV-2 created a rush to discover drug candidates against the virus [1,2,3]
The active site is located on the cleft between domains I and II and features the catalytic dyad Cys-His [2, 17]. Main protease (Mpro) is conserved among coronaviruses, sharing ~ 76% sequence similarity with Structure–activity relationship (SAR)-CoV-1 Mpro, and there are no homologs in humans, making it an attractive target for drug discovery [2, 7, 18]
Summary
The global pandemic of coronavirus disease (COVID-19) caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) created a rush to discover drug candidates against the virus [1,2,3]. Coronaviruses are enveloped, single-stranded RNA viruses members of the family Coronaviridae [7]. Their genome is approximately 30 kb and contains a variable number of open reading frames (ORFs) which encode 16 nonstructural (nsp), 4 structural and several accessory proteins [8,9,10,11,12]. In SARS-CoV-2 the nonstructural protein 5 (nsp 5) is the main protease and is essential for viral replication [2, 16]. Mpro is conserved among coronaviruses, sharing ~ 76% sequence similarity with SAR-CoV-1 Mpro, and there are no homologs in humans, making it an attractive target for drug discovery [2, 7, 18].
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