PolypharmDB, a Deep Learning-Based Resource, Quickly Identifies Repurposed Drug Candidates for COVID-19

Dar'ya S. Redka Stephen S. MacKinnon Melissa Landon Andreas Windemuth Naheed Kurji Vijay Shahani

10.26434/chemrxiv.12071271.v1

Research curated

Abstract

There is an immediate need to discover treatments for COVID-19, the pandemic caused by the SARS-CoV-2 virus. Standard small molecule drug discovery workflows that start with library screens are an impractical path forward given the timelines to discover, develop, and test clinically. To accelerate the time to patient testing, here we explored the therapeutic potential of small molecule drugs that have been tested to some degree in a clinical environment, including approved medications, as possible therapeutic interventions for COVID-19. Motivating our process is a concept termed polypharmacology, i.e. off-target interactions that may hold therapeutic potential. In this work, we used Ligand Design, our deep learning drug design platform, to interrogate the polypharmacological profiles of an internal collection of small molecule drugs with federal approval or going through clinical trials, with the goal of identifying molecules predicted to modulate targets relevant for COVID-19 treatment. Resulting from our efforts is PolypharmDB, a resource of drugs and their predicted binding of protein targets across the human proteome. Mining PolypharmDB yielded molecules predicted to interact with human and viral drug targets for COVID-19, including host proteins linked to viral entry and proliferation and key viral proteins associated with the virus life-cycle. Further, we assembled a collection of prioritized approved drugs for two specific host-targets, TMPRSS2 and cathepsin B, whose joint inhibition was recently shown to block SARS-CoV-2 virus entry into host cells. Overall, we demonstrate that our approach facilitates rapid response, identifying 30 prioritized candidates for testing for their possible use as anti-COVID drugs. Using the PolypharmDB resource, it is possible to identify repurposed drug candidates for newly discovered targets within a single work day. We are making a complete list of the molecules we identified available at no cost to partners with the ability to test them for efficacy, in vitro and/or clinically.

Source: ChemRxiv

Related molecules

Name	Synonyms	Genes
Temsirolimus
Everolimus
Deutetrabenazine
Latamoxef
Cefazolin
Cefoxitin
Enoxacin
Linezolid
Colchiceine
Ticarcillin
Meropenem
Antazoline
Tolazoline
Dihydralazine
Histrelin
Naphazoline
Disopyramide
Hydroxystilbamidine
Anastrozole
Amlodipine
Isocarboxazid
Phenacemide
Rivastigmine
Cefaclor
Phenoxybenzamine
Cephalexin
Selegiline
Cathepsin B	APP secretase, APPS, Cathepsin B1	CTSB, CPSB
Transmembrane serine 2-Cathepsin B interface
Chloramphenicol
Cefuroxime
Transmembrane serine 2	TMPRSS2, Serine protease 10	TMPRSS2, PRSS10
Mezlocillin
Angiotensin-converting enzyme 2-Spike glycoprotein interface
Bacampicillin
Sirolimus
Angiotensin-converting enzyme 2	ACE-related carboxypeptidase, ACE2	ACE2
3C-like protease	3CLpro, Mpro, SARS coronavirus main peptidase, 3CLpro-SARS-CoV-2	rep, ORF1a-1b
Bremelanotide
Spike glycoprotein	Spike protein, S glycoprotein, S-Protein, S1, S2, S3, Peplomer protein, E2	S, ORF2
Pentamidine
Pheneticillin
Phenelzine

Related interactions

Target	Drug	Type	Result
3C-like protease	Sirolimus	Computational	positive
3C-like protease	Temsirolimus	Computational	positive
Transmembrane serine 2-Cathepsin B interface	Rivastigmine	Computational	positive
Transmembrane serine 2-Cathepsin B interface	Selegiline	Computational	positive
Transmembrane serine 2-Cathepsin B interface	Cephalexin	Computational	positive
Transmembrane serine 2-Cathepsin B interface	Phenelzine	Computational	positive
Transmembrane serine 2-Cathepsin B interface	Phenoxybenzamine	Computational	positive
Transmembrane serine 2-Cathepsin B interface	Phenacemide	Computational	positive
Transmembrane serine 2-Cathepsin B interface	Chloramphenicol	Computational	positive
Transmembrane serine 2-Cathepsin B interface	Isocarboxazid	Computational	positive
Transmembrane serine 2-Cathepsin B interface	Disopyramide	Computational	positive
Cathepsin B	Phenelzine	Computational	positive
Cathepsin B	Selegiline	Computational	positive
Cathepsin B	Cephalexin	Computational	positive
Cathepsin B	Phenoxybenzamine	Computational	positive
Cathepsin B	Cefaclor	Computational	positive
Cathepsin B	Disopyramide	Computational	positive
Cathepsin B	Rivastigmine	Computational	positive
Cathepsin B	Phenacemide	Computational	positive
Cathepsin B	Chloramphenicol	Computational	positive
Transmembrane serine 2	Amlodipine	Computational	positive
Transmembrane serine 2	Anastrozole	Computational	positive
Transmembrane serine 2	Hydroxystilbamidine	Computational	positive
Transmembrane serine 2	Disopyramide	Computational	positive
Transmembrane serine 2	Naphazoline	Computational	positive
Cathepsin B	Isocarboxazid	Computational	positive
Transmembrane serine 2	Histrelin	Computational	positive
Transmembrane serine 2	Dihydralazine	Computational	positive
Transmembrane serine 2	Tolazoline	Computational	positive
Transmembrane serine 2	Pentamidine	Computational	positive
Transmembrane serine 2	Antazoline	Computational	positive
Angiotensin-converting enzyme 2-Spike glycoprotein interface	Meropenem	Computational	positive
Angiotensin-converting enzyme 2-Spike glycoprotein interface	Mezlocillin	Computational	positive
Angiotensin-converting enzyme 2-Spike glycoprotein interface	Cefuroxime	Computational	positive
Angiotensin-converting enzyme 2-Spike glycoprotein interface	Ticarcillin	Computational	positive
Angiotensin-converting enzyme 2-Spike glycoprotein interface	Pheneticillin	Computational	positive
Spike glycoprotein	Colchiceine	Computational	positive
Spike glycoprotein	Linezolid	Computational	positive
Spike glycoprotein	Enoxacin	Computational	positive
Angiotensin-converting enzyme 2	Pheneticillin	Computational	positive
Angiotensin-converting enzyme 2	Bacampicillin	Computational	positive
Angiotensin-converting enzyme 2	Cefoxitin	Computational	positive
Angiotensin-converting enzyme 2	Cefazolin	Computational	positive
Angiotensin-converting enzyme 2	Latamoxef	Computational	positive
3C-like protease	Deutetrabenazine	Computational	positive
3C-like protease	Everolimus	Computational	positive
3C-like protease	Bremelanotide	Computational	positive