In silico Drug Screening Approach Using L1000-Based Connectivity Map and Its Application to COVID-19

Abstract

Conventional drug screening methods search for a limited number of small molecules that directly interact with the target protein. This process can be slow, cumbersome and has driven the need for developing new drug screening approaches to counter rapidly emerging diseases such as COVID-19. We propose a pipeline for drug repurposing combining in silico drug candidate identification followed by in vitro characterization of these candidates. We first identified a gene target of interest, the entry receptor for the SARS-CoV-2 virus, angiotensin converting enzyme 2 (ACE2). Next, we employed a gene expression profile database, L1000-based Connectivity Map to query gene expression patterns in lung epithelial cells, which act as the primary site of SARS-CoV-2 infection. Using gene expression profiles from 5 different lung epithelial cell lines, we computationally identified 17 small molecules that were predicted to decrease ACE2 expression. We further performed a streamlined validation in the normal human epithelial cell line BEAS-2B to demonstrate that these compounds can indeed decrease ACE2 surface expression and to profile cell health and viability upon drug treatment. This proposed pipeline combining in silico drug compound identification and in vitro expression and viability characterization in relevant cell types can aid in the repurposing of FDA-approved drugs to combat rapidly emerging diseases.

Novel small molecules inhibit proteotoxicity and inflammation: Mechanistic and therapeutic implications for Alzheimer’s Disease, healthspan and lifespan- Aging as a consequence of glycolysis

“…To clarify mechanisms mediating these broad protective effects of GM310 and its FDA-approved tricyclic congeners, we assessed effects of these congeners on gene expression in human neuronal cell lines using the CMAP/L1000 database [141]. Although of course GM310 was not in the database, since it is novel, the effects of 14 tricyclic congeners of GM310, FDA-approved tricyclic compounds zapproved by the FDA to treat either psychosis or depression, on gene expression in 2 neuronal cell lines (NEU and NPC) were available in the database.…”

“…The same combination is currently in clinical trials to treat AD, with promising results so far on surrogate measures https://www.amylyx.com/pipeline. It is also of some interest that, based on the CMAP database [141],…”

“…The same combination is currently in clinical trials to treat AD, with promising results so far on surrogate measures https://www.amylyx.com/pipeline. It is also of some interest that, based on the CMAP database [141], phenylbutyrate alone reversed the expression of 36% of the genes differentially expressed in microglia in AD [151]. Quetiapine combined with valproate, like phenylbutyrate an HDAC inhibitor, also improves symptoms in patients with AD [180].…”

Major Facilitator Superfamily Domain Containing 5 Inhibition Reduces Lipoprotein(a) Uptake and Calcification in Valvular Heart Disease

“…Next, small-molecule inhibition of MFSD5 Lp(a) uptake was conducted through the L1000 platform, 31,32 in which genes and drugs are connected by common gene-expression signatures enabling prediction of compounds that modulate genes of interest. L1000 analysis supported aminopurvalanol A, a cyclin-dependent kinase inhibitor, as a top, commercially available compound that could modulate MFSD5 expression.…”

Drug repurposing based on the similarity gene expression signatures to explore for potential indications of quercetin: a case study of multiple sclerosis

“…Moreover, based on cell experiments also proved that this result of drug repurposing is indeed effective (Ren et al, 2022). The CMapbased drug repurposing approach is also widely used to quickly identify potential drugs for Corona Virus Disease 2019 (COVID-19) (Loganathan et al, 2020;Asano et al, 2022). These successful precedents suggest that this method can be applied to more drug repurposing studies that are widely used in clinical practice or withdrawn due to serious adverse reactions.…”