A Multi-Pronged Approach Targeting SARS-CoV-2 Proteins Using Ultra-Large Virtual Screening

Abstract

<p>Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), previously known as 2019 novel coronavirus (2019-nCoV), has spread rapidly across the globe, creating an unparalleled global health burden and spurring a deepening economic crisis. As of July 7th, 2020, almost seven months into the outbreak, there are no approved vaccines and few treatments available. Developing drugs that target multiple points in the viral life cycle could serve as a strategy to tackle the current as well as future coronavirus pandemics. Here we leverage the power of our recently developed <i>in silico</i> screening platform, VirtualFlow, to identify inhibitors that target SARS-CoV-2. VirtualFlow is able to efficiently harness the power of computing clusters and cloud-based computing platforms to carry out ultra-large scale virtual screens. In this unprecedented structure-based multi-target virtual screening campaign, we have used VirtualFlow to screen an average of approximately 1 billion molecules against each of 40 different target sites on 17 different potential viral and host targets in the cloud. In addition to targeting the active sites of viral enzymes, we also target critical auxiliary sites such as functionally important protein-protein interaction interfaces. This multi-target approach not only increases the likelihood of finding a potent inhibitor, but could also help identify a collection of anti-coronavirus drugs that would retain efficacy in the face of viral mutation. Drugs belonging to different regimen classes could be combined to develop possible combination therapies, and top hits that bind at highly conserved sites would be potential candidates for further development as coronavirus drugs. Here, we present the top 200 <i>in silico</i> hits for each target site. While in-house experimental validation of some of these compounds is currently underway, we want to make this array of potential inhibitor candidates available to researchers worldwide in consideration of the pressing need for fast-tracked drug development.</p>

High Throughput Virtual Screening and Validation of a SARS-CoV-2 Main Protease Non-Covalent Inhibitor

“…Without the ability to quickly obtain a compound and experimentally validate it, computational results alone will not be a solution. Virtual screens against M pro have ranged from small libraries of existing approved pharmaceuticals to natural product libraries and billion-scale combinatorial libraries (27, 28). Studies such as (29) use drug repurposing databases that are smaller (<50k) but have potential for faster lead to drug time.…”

Establishing an Analogue Based In Silico Pipeline in the Pursuit of Novel Inhibitory Scaffolds against the SARS Coronavirus 2 Papain-Like Protease

“…Although molecules obtained from virtual screens have previously been deposited in the literature for prospective testing against PL pro [ 84 , 85 , 86 , 87 , 88 ], these were mainly docking studies, and we could not find any paper where a ligand-based virtual screen of such scale had been performed against GRL-0617 before docking. Additionally, and in contrast to our work, the docking had commonly been performed against the PL pro catalytic site and not the GRL-0617 binding site, which is distinctly different.…”

Identification of low micromolar SARS-CoV-2 Mproinhibitors from hits identified byin silicoscreens

“…We described recently two in silico screens of one billion compounds using M pro as a target [20]. The first screen, hereafter referred to as screen 1A, used the three-dimensional coordinates of M pro described by Jin et al [5] (pdb id: 6lu7).…”

“…The first screen, hereafter referred to as screen 1A, used the three-dimensional coordinates of M pro described by Jin et al [5] (pdb id: 6lu7). The second screen, hereafter referred to as screen 1B, used the coordinates of M pro described by Dai et al [3] (pdb id: 6m0k), except that different rotamers were used for residues S46, M49 and C145, in the hope of expanding the active site and capturing a larger repertoire of chemical compounds [20]. Comparison of the top 1,000 hits identified by screens 1A and 1B, revealed an overlap of only 12 compounds.…”

“…Finally, many groups have used the reported crystal structure of M pro to identify inhibitors by in silico screening. Two of these studies screened more than one billion compounds [20,21]. As our group participated in one of these endeavors, we followed upon this work by examining whether some of the top hits could actually inhibit the protease activity of SARS-CoV-2 M pro in vitro.…”