{ "cells": [ { "cell_type": "markdown", "metadata": {}, "source": [ "# Using Connectivity map data and PharmacoGx R package to find drugs against coronaviruses" ] }, { "cell_type": "markdown", "metadata": {}, "source": [ "Connectivity map or Cmap is resource that uses gene expression data to connect disease transcriptomic signature with those of different types of cells after drug treatment. If the transcriptomic signature of a drug on cell line is opposite from disease signature, it can be expected that this drug could have a positive effect on amelioration of disease.\n", "\n", "\n", "References:\n", "Subramanian A, et al. A Next Generation Connectivity Map: L1000 Platform And The First 1,000,000 Profiles. Cell. 2017/12/1. 171(6):1437–1452.\n", "\n", "Lamb J, et al. The Connectivity Map: using gene-expression signatures to connect small molecules, genes, and disease. Science. 2006/9/29. 313(5795):1929-35, (2006)" ] }, { "cell_type": "markdown", "metadata": {}, "source": [ "Harmonizome is a collection of processed datasets from over 70 major online resources. I downloaded from Harmonizome \"GEO Signatures of Differentially Expressed Genes for Viral Infections\". For this analysis I used transcriptomics data of lungs from mice that were infected with icSARS CoV (GEO accesion number GSE50000;7th day of infection) and Calu-3 2B4 cells that were infected with Human Coronavirus EMC 2012 (GEO accession number GSE45042;24 hours after infection). For this analysis I havent used transcriptomic data of novel human coronavirus 2019 or SARS-2, but according to the literature all of these viruses (MERS,SARS1 and SARS2) are betacoronaviruses that have origin in bats and SARS-2 is shown to be very similar to SARS-01 according to phylogenic analysis. \n", "\n", "References:\n", "Rouillard AD, Gundersen GW, Fernandez NF, Wang Z, Monteiro CD, McDermott MG, Ma'ayan A. The harmonizome: a collection of processed datasets gathered to serve and mine knowledge about genes and proteins. Database (Oxford). 2016 Jul 3;2016. pii: baw100.\n", "\t\n", "Josset L, Menachery VD, Gralinski LE, Agnihothram S et al. Cell host response to infection with novel human coronavirus EMC predicts potential antivirals and important differences with SARS coronavirus. mBio 2013 Apr 30;4(3):e00165-13. PMID: 23631916\n", "\n", "Menachery VD, Eisfeld AJ, Schäfer A, Josset L et al. Pathogenic influenza viruses and coronaviruses utilize similar and contrasting approaches to control interferon-stimulated gene responses. mBio 2014 May 20;5(3):e01174-14. PMID: 24846384\n", "\n", "Yushun Wan, Jian Shang, Rachel Graham, Ralph S. Baric, Fang Li. Receptor recognition by novel coronavirus from Wuhan: An analysis based on decade-long structural studies of SARS. Journal of Virology, 2020; DOI: 10.1128/JVI.00127-20\n", "\n", "Yadi Zhou, Yuan Hou, Jiayu Shen, Yin Huang, William Martin, Feixiong Cheng.Network-based Drug Repurposing for Human Coronavirus\n", "doi: https://doi.org/10.1101/2020.02.03.20020263" ] }, { "cell_type": "markdown", "metadata": {}, "source": [ "For the analysis of Connectivity map data I used PharmacoGx R package.\n", "\n", "P Smirnov, Z Safikhani, N El-Hachem , D Wang, A She , C Olsen, MFreeman, H Selby, D Gendoo , P Grossman , A Beck , H Aerts ,\n", "M Lupien, A Goldenberg ,B Haibe-Kains PharmacoGx: an R package for analysis of large pharmacogenomic datasets Bioinformatics (2016)." ] }, { "cell_type": "code", "execution_count": 76, "metadata": {}, "outputs": [], "source": [ "library(PharmacoGx)" ] }, { "cell_type": "code", "execution_count": 77, "metadata": {}, "outputs": [ { "data": { "text/html": [ "\n", "\n", "\n", "\t\n", "\t\n", "\n", "\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\n", "
A data.frame: 11 × 5
PSet.NameDataset.TypeAvailable.Molecular.ProfilesDate.UpdatedURL
<fct><fct><fct><fct><fct>
CCLE_2013CCLE_2013 sensitivity rna/mutation Tue Sep 15 18:50:07 2015https://www.pmgenomics.ca/bhklab/sites/default/files/downloads/CCLE_Nature2013.RData
CCLECCLE sensitivity rna/rnaseq/mutation/cnv Thu Dec 10 18:17:14 2015https://www.pmgenomics.ca/bhklab/sites/default/files/downloads/CCLE.RData
GDSC_2013GDSC_2013 sensitivity rna/mutation Mon Oct 5 16:07:54 2015https://www.pmgenomics.ca/bhklab/sites/default/files/downloads/CGP_Nature2013.RData
GDSCGDSC sensitivity rna/rna2/mutation/fusion/cnvWed Dec 30 10:44:21 2015https://www.pmgenomics.ca/bhklab/sites/default/files/downloads/GDSC.RData
GDSC1000GDSC1000 sensitivity rna Thu Aug 25 11:13:00 2016https://www.pmgenomics.ca/bhklab/sites/default/files/downloads/GDSC1000.RData
gCSIgCSI sensitivity rnaseq/cnv Mon Jun 13 18:50:12 2016https://www.pmgenomics.ca/bhklab/sites/default/files/downloads/gCSI.RData
FIMMFIMM sensitivity Mon Oct 3 17:14:00 2016 https://www.pmgenomics.ca/bhklab/sites/default/files/downloads/FIMM.RData
CTRPv2CTRPv2 sensitivity Thu Aug 25 11:15:00 2016https://www.pmgenomics.ca/bhklab/sites/default/files/downloads/CTRPv2.RData
CMAPCMAP perturbationrna Mon Sep 21 02:38:45 2015https://www.pmgenomics.ca/bhklab/sites/default/files/downloads/CMAP.RData
L1000_compoundsL1000_compoundsperturbationrna Mon Jan 25 12:51:00 2016https://www.pmgenomics.ca/bhklab/sites/default/files/downloads/L1000_compounds.RData
L1000_geneticL1000_genetic perturbationrna Mon Jan 25 12:51:00 2016https://www.pmgenomics.ca/bhklab/sites/default/files/downloads/L1000_genetic.RData
\n" ], "text/latex": [ "A data.frame: 11 × 5\n", "\\begin{tabular}{r|lllll}\n", " & PSet.Name & Dataset.Type & Available.Molecular.Profiles & Date.Updated & URL\\\\\n", " & & & & & \\\\\n", "\\hline\n", "\tCCLE\\_2013 & CCLE\\_2013 & sensitivity & rna/mutation & Tue Sep 15 18:50:07 2015 & https://www.pmgenomics.ca/bhklab/sites/default/files/downloads/CCLE\\_Nature2013.RData\\\\\n", "\tCCLE & CCLE & sensitivity & rna/rnaseq/mutation/cnv & Thu Dec 10 18:17:14 2015 & https://www.pmgenomics.ca/bhklab/sites/default/files/downloads/CCLE.RData \\\\\n", "\tGDSC\\_2013 & GDSC\\_2013 & sensitivity & rna/mutation & Mon Oct 5 16:07:54 2015 & https://www.pmgenomics.ca/bhklab/sites/default/files/downloads/CGP\\_Nature2013.RData \\\\\n", "\tGDSC & GDSC & sensitivity & rna/rna2/mutation/fusion/cnv & Wed Dec 30 10:44:21 2015 & https://www.pmgenomics.ca/bhklab/sites/default/files/downloads/GDSC.RData \\\\\n", "\tGDSC1000 & GDSC1000 & sensitivity & rna & Thu Aug 25 11:13:00 2016 & https://www.pmgenomics.ca/bhklab/sites/default/files/downloads/GDSC1000.RData \\\\\n", "\tgCSI & gCSI & sensitivity & rnaseq/cnv & Mon Jun 13 18:50:12 2016 & https://www.pmgenomics.ca/bhklab/sites/default/files/downloads/gCSI.RData \\\\\n", "\tFIMM & FIMM & sensitivity & & Mon Oct 3 17:14:00 2016 & https://www.pmgenomics.ca/bhklab/sites/default/files/downloads/FIMM.RData \\\\\n", "\tCTRPv2 & CTRPv2 & sensitivity & & Thu Aug 25 11:15:00 2016 & https://www.pmgenomics.ca/bhklab/sites/default/files/downloads/CTRPv2.RData \\\\\n", "\tCMAP & CMAP & perturbation & rna & Mon Sep 21 02:38:45 2015 & https://www.pmgenomics.ca/bhklab/sites/default/files/downloads/CMAP.RData \\\\\n", "\tL1000\\_compounds & L1000\\_compounds & perturbation & rna & Mon Jan 25 12:51:00 2016 & https://www.pmgenomics.ca/bhklab/sites/default/files/downloads/L1000\\_compounds.RData\\\\\n", "\tL1000\\_genetic & L1000\\_genetic & perturbation & rna & Mon Jan 25 12:51:00 2016 & https://www.pmgenomics.ca/bhklab/sites/default/files/downloads/L1000\\_genetic.RData \\\\\n", "\\end{tabular}\n" ], "text/markdown": [ "\n", "A data.frame: 11 × 5\n", "\n", "| | PSet.Name <fct> | Dataset.Type <fct> | Available.Molecular.Profiles <fct> | Date.Updated <fct> | URL <fct> |\n", "|---|---|---|---|---|---|\n", "| CCLE_2013 | CCLE_2013 | sensitivity | rna/mutation | Tue Sep 15 18:50:07 2015 | https://www.pmgenomics.ca/bhklab/sites/default/files/downloads/CCLE_Nature2013.RData |\n", "| CCLE | CCLE | sensitivity | rna/rnaseq/mutation/cnv | Thu Dec 10 18:17:14 2015 | https://www.pmgenomics.ca/bhklab/sites/default/files/downloads/CCLE.RData |\n", "| GDSC_2013 | GDSC_2013 | sensitivity | rna/mutation | Mon Oct 5 16:07:54 2015 | https://www.pmgenomics.ca/bhklab/sites/default/files/downloads/CGP_Nature2013.RData |\n", "| GDSC | GDSC | sensitivity | rna/rna2/mutation/fusion/cnv | Wed Dec 30 10:44:21 2015 | https://www.pmgenomics.ca/bhklab/sites/default/files/downloads/GDSC.RData |\n", "| GDSC1000 | GDSC1000 | sensitivity | rna | Thu Aug 25 11:13:00 2016 | https://www.pmgenomics.ca/bhklab/sites/default/files/downloads/GDSC1000.RData |\n", "| gCSI | gCSI | sensitivity | rnaseq/cnv | Mon Jun 13 18:50:12 2016 | https://www.pmgenomics.ca/bhklab/sites/default/files/downloads/gCSI.RData |\n", "| FIMM | FIMM | sensitivity | | Mon Oct 3 17:14:00 2016 | https://www.pmgenomics.ca/bhklab/sites/default/files/downloads/FIMM.RData |\n", "| CTRPv2 | CTRPv2 | sensitivity | | Thu Aug 25 11:15:00 2016 | https://www.pmgenomics.ca/bhklab/sites/default/files/downloads/CTRPv2.RData |\n", "| CMAP | CMAP | perturbation | rna | Mon Sep 21 02:38:45 2015 | https://www.pmgenomics.ca/bhklab/sites/default/files/downloads/CMAP.RData |\n", "| L1000_compounds | L1000_compounds | perturbation | rna | Mon Jan 25 12:51:00 2016 | https://www.pmgenomics.ca/bhklab/sites/default/files/downloads/L1000_compounds.RData |\n", "| L1000_genetic | L1000_genetic | perturbation | rna | Mon Jan 25 12:51:00 2016 | https://www.pmgenomics.ca/bhklab/sites/default/files/downloads/L1000_genetic.RData |\n", "\n" ], "text/plain": [ " PSet.Name Dataset.Type Available.Molecular.Profiles\n", "CCLE_2013 CCLE_2013 sensitivity rna/mutation \n", "CCLE CCLE sensitivity rna/rnaseq/mutation/cnv \n", "GDSC_2013 GDSC_2013 sensitivity rna/mutation \n", "GDSC GDSC sensitivity rna/rna2/mutation/fusion/cnv\n", "GDSC1000 GDSC1000 sensitivity rna \n", "gCSI gCSI sensitivity rnaseq/cnv \n", "FIMM FIMM sensitivity \n", "CTRPv2 CTRPv2 sensitivity \n", "CMAP CMAP perturbation rna \n", "L1000_compounds L1000_compounds perturbation rna \n", "L1000_genetic L1000_genetic perturbation rna \n", " Date.Updated \n", "CCLE_2013 Tue Sep 15 18:50:07 2015\n", "CCLE Thu Dec 10 18:17:14 2015\n", "GDSC_2013 Mon Oct 5 16:07:54 2015\n", "GDSC Wed Dec 30 10:44:21 2015\n", "GDSC1000 Thu Aug 25 11:13:00 2016\n", "gCSI Mon Jun 13 18:50:12 2016\n", "FIMM Mon Oct 3 17:14:00 2016 \n", "CTRPv2 Thu Aug 25 11:15:00 2016\n", "CMAP Mon Sep 21 02:38:45 2015\n", "L1000_compounds Mon Jan 25 12:51:00 2016\n", "L1000_genetic Mon Jan 25 12:51:00 2016\n", " URL \n", "CCLE_2013 https://www.pmgenomics.ca/bhklab/sites/default/files/downloads/CCLE_Nature2013.RData\n", "CCLE https://www.pmgenomics.ca/bhklab/sites/default/files/downloads/CCLE.RData \n", "GDSC_2013 https://www.pmgenomics.ca/bhklab/sites/default/files/downloads/CGP_Nature2013.RData \n", "GDSC https://www.pmgenomics.ca/bhklab/sites/default/files/downloads/GDSC.RData \n", "GDSC1000 https://www.pmgenomics.ca/bhklab/sites/default/files/downloads/GDSC1000.RData \n", "gCSI https://www.pmgenomics.ca/bhklab/sites/default/files/downloads/gCSI.RData \n", "FIMM https://www.pmgenomics.ca/bhklab/sites/default/files/downloads/FIMM.RData \n", "CTRPv2 https://www.pmgenomics.ca/bhklab/sites/default/files/downloads/CTRPv2.RData \n", "CMAP https://www.pmgenomics.ca/bhklab/sites/default/files/downloads/CMAP.RData \n", "L1000_compounds https://www.pmgenomics.ca/bhklab/sites/default/files/downloads/L1000_compounds.RData\n", "L1000_genetic https://www.pmgenomics.ca/bhklab/sites/default/files/downloads/L1000_genetic.RData " ] }, "metadata": {}, "output_type": "display_data" } ], "source": [ "availablePSets()\n" ] }, { "cell_type": "code", "execution_count": 78, "metadata": {}, "outputs": [], "source": [ "CMAP.sigs <- downloadPertSig(\"CMAP\")" ] }, { "cell_type": "code", "execution_count": 80, "metadata": {}, "outputs": [], "source": [ " drug.perturbation <- CMAP.sigs" ] }, { "cell_type": "code", "execution_count": 82, "metadata": {}, "outputs": [], "source": [ "sars1_up_and_down_genes <-read.csv(\"icSARS_Cov_Day7_None_GSE50000.csv\",stringsAsFactors = F, header = T, sep=\";\")\n", "rownames(sars1_up_and_down_genes) <- sars1_up_and_down_genes$Feature\n", "sars1<- sars1_up_and_down_genes$Direction\n", "names(sars1) <- rownames(sars1_up_and_down_genes)\n" ] }, { "cell_type": "code", "execution_count": 83, "metadata": {}, "outputs": [], "source": [ "res_sars1 <- apply(drug.perturbation[,,c(\"tstat\", \"fdr\")], \n", " 2,function(x, sars1){\n", " return(connectivityScore(x=x, \n", " y=sars1,\n", " method=\"fgsea\", nperm=100))\n", " },sars1 = sars1)" ] }, { "cell_type": "code", "execution_count": 84, "metadata": {}, "outputs": [ { "data": { "text/html": [ "\n", "
  1. 'Connectivity'
  2. 'P_value'
\n" ], "text/latex": [ "\\begin{enumerate*}\n", "\\item 'Connectivity'\n", "\\item 'P\\_value'\n", "\\end{enumerate*}\n" ], "text/markdown": [ "1. 'Connectivity'\n", "2. 'P_value'\n", "\n", "\n" ], "text/plain": [ "[1] \"Connectivity\" \"P_value\" " ] }, "metadata": {}, "output_type": "display_data" } ], "source": [ "rownames(res_sars1) <- c(\"Connectivity\", \"P_value\")\n", "res_sars1 <- t(res_sars1)\n" ] }, { "cell_type": "code", "execution_count": 95, "metadata": {}, "outputs": [], "source": [ "con_score_sars <-res_sars1[order((res_sars1[,1]),decreasing = F),]\n", "p_value_sars <- res_sars1[order((res_sars1[,2]),decreasing = F),]" ] }, { "cell_type": "code", "execution_count": 96, "metadata": {}, "outputs": [ { "data": { "text/html": [ "\n", "\n", "\n", "\t\n", "\n", "\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\n", "
A matrix: 1288 × 2 of type dbl
ConnectivityP_value
valproic acid-0.3766250.003243431
rifabutin-0.3403800.003249652
levomepromazine-0.3299050.003363063
promazine-0.3384600.003408985
Prestwick-559-0.3322850.003453743
maprotiline-0.3459950.003483930
nicergoline-0.2979750.003540995
GW-8510-0.3657750.003643482
lasalocid-0.2879650.003653011
pyrvinium-0.3129200.003692544
nortriptyline-0.3469900.003785772
prochlorperazine-0.3602450.003809080
norcyclobenzaprine-0.3199600.003935323
fluphenazine-0.3517400.004089757
LY-294002-0.3581350.004118938
raloxifene-0.3017950.004218595
4,5-dianilinophthalimide-0.8093300.006282675
trichostatin A-0.3302450.006335983
eucatropine-0.2885550.006421429
syrosingopine-0.3188950.006459413
mebendazole-0.3003250.006618701
lycorine 0.3198950.006644780
rescinnamine-0.3232950.006987249
reserpine-0.2850800.007184183
sirolimus-0.3616850.007393165
trifluoperazine-0.3751950.007405285
vorinostat-0.3783100.008683363
methotrexate-0.3364050.008864197
fulvestrant-0.2812450.009065718
phenazopyridine-0.3214250.009136916
.........
PF-00562151-0001
pioglitazone01
PF-00539745-0001
valdecoxib01
PF-00539758-0001
orlistat01
570788501
C-7501
515587701
dinoprostone01
519444201
AG-02867101
6-bromoindirubin-3'-oxime01
Gly-His-Lys01
STOCK1N-3569601
STOCK1N-2845701
H-8901
SB-20219001
NS-39801
SB-20358001
AH-680901
alsterpaullone01
SC-1922001
0198306-000001
AR-A01441801
semustine01
CP-94462901
irinotecan01
BCB00003901
11-deoxy-16,16-dimethylprostaglandin E201
\n" ], "text/latex": [ "A matrix: 1288 × 2 of type dbl\n", "\\begin{tabular}{r|ll}\n", " & Connectivity & P\\_value\\\\\n", "\\hline\n", "\tvalproic acid & -0.376625 & 0.003243431\\\\\n", "\trifabutin & -0.340380 & 0.003249652\\\\\n", "\tlevomepromazine & -0.329905 & 0.003363063\\\\\n", "\tpromazine & -0.338460 & 0.003408985\\\\\n", "\tPrestwick-559 & -0.332285 & 0.003453743\\\\\n", "\tmaprotiline & -0.345995 & 0.003483930\\\\\n", "\tnicergoline & -0.297975 & 0.003540995\\\\\n", "\tGW-8510 & -0.365775 & 0.003643482\\\\\n", "\tlasalocid & -0.287965 & 0.003653011\\\\\n", "\tpyrvinium & -0.312920 & 0.003692544\\\\\n", "\tnortriptyline & -0.346990 & 0.003785772\\\\\n", "\tprochlorperazine & -0.360245 & 0.003809080\\\\\n", "\tnorcyclobenzaprine & -0.319960 & 0.003935323\\\\\n", "\tfluphenazine & -0.351740 & 0.004089757\\\\\n", "\tLY-294002 & -0.358135 & 0.004118938\\\\\n", "\traloxifene & -0.301795 & 0.004218595\\\\\n", "\t4,5-dianilinophthalimide & -0.809330 & 0.006282675\\\\\n", "\ttrichostatin A & -0.330245 & 0.006335983\\\\\n", "\teucatropine & -0.288555 & 0.006421429\\\\\n", "\tsyrosingopine & -0.318895 & 0.006459413\\\\\n", "\tmebendazole & -0.300325 & 0.006618701\\\\\n", "\tlycorine & 0.319895 & 0.006644780\\\\\n", "\trescinnamine & -0.323295 & 0.006987249\\\\\n", "\treserpine & -0.285080 & 0.007184183\\\\\n", "\tsirolimus & -0.361685 & 0.007393165\\\\\n", "\ttrifluoperazine & -0.375195 & 0.007405285\\\\\n", "\tvorinostat & -0.378310 & 0.008683363\\\\\n", "\tmethotrexate & -0.336405 & 0.008864197\\\\\n", "\tfulvestrant & -0.281245 & 0.009065718\\\\\n", "\tphenazopyridine & -0.321425 & 0.009136916\\\\\n", "\t... & ... & ...\\\\\n", "\tPF-00562151-00 & 0 & 1\\\\\n", "\tpioglitazone & 0 & 1\\\\\n", "\tPF-00539745-00 & 0 & 1\\\\\n", "\tvaldecoxib & 0 & 1\\\\\n", "\tPF-00539758-00 & 0 & 1\\\\\n", "\torlistat & 0 & 1\\\\\n", "\t5707885 & 0 & 1\\\\\n", "\tC-75 & 0 & 1\\\\\n", "\t5155877 & 0 & 1\\\\\n", "\tdinoprostone & 0 & 1\\\\\n", "\t5194442 & 0 & 1\\\\\n", "\tAG-028671 & 0 & 1\\\\\n", "\t6-bromoindirubin-3'-oxime & 0 & 1\\\\\n", "\tGly-His-Lys & 0 & 1\\\\\n", "\tSTOCK1N-35696 & 0 & 1\\\\\n", "\tSTOCK1N-28457 & 0 & 1\\\\\n", "\tH-89 & 0 & 1\\\\\n", "\tSB-202190 & 0 & 1\\\\\n", "\tNS-398 & 0 & 1\\\\\n", "\tSB-203580 & 0 & 1\\\\\n", "\tAH-6809 & 0 & 1\\\\\n", "\talsterpaullone & 0 & 1\\\\\n", "\tSC-19220 & 0 & 1\\\\\n", "\t0198306-0000 & 0 & 1\\\\\n", "\tAR-A014418 & 0 & 1\\\\\n", "\tsemustine & 0 & 1\\\\\n", "\tCP-944629 & 0 & 1\\\\\n", "\tirinotecan & 0 & 1\\\\\n", "\tBCB000039 & 0 & 1\\\\\n", "\t11-deoxy-16,16-dimethylprostaglandin E2 & 0 & 1\\\\\n", "\\end{tabular}\n" ], "text/markdown": [ "\n", "A matrix: 1288 × 2 of type dbl\n", "\n", "| | Connectivity | P_value |\n", "|---|---|---|\n", "| valproic acid | -0.376625 | 0.003243431 |\n", "| rifabutin | -0.340380 | 0.003249652 |\n", "| levomepromazine | -0.329905 | 0.003363063 |\n", "| promazine | -0.338460 | 0.003408985 |\n", "| Prestwick-559 | -0.332285 | 0.003453743 |\n", "| maprotiline | -0.345995 | 0.003483930 |\n", "| nicergoline | -0.297975 | 0.003540995 |\n", "| GW-8510 | -0.365775 | 0.003643482 |\n", "| lasalocid | -0.287965 | 0.003653011 |\n", "| pyrvinium | -0.312920 | 0.003692544 |\n", "| nortriptyline | -0.346990 | 0.003785772 |\n", "| prochlorperazine | -0.360245 | 0.003809080 |\n", "| norcyclobenzaprine | -0.319960 | 0.003935323 |\n", "| fluphenazine | -0.351740 | 0.004089757 |\n", "| LY-294002 | -0.358135 | 0.004118938 |\n", "| raloxifene | -0.301795 | 0.004218595 |\n", "| 4,5-dianilinophthalimide | -0.809330 | 0.006282675 |\n", "| trichostatin A | -0.330245 | 0.006335983 |\n", "| eucatropine | -0.288555 | 0.006421429 |\n", "| syrosingopine | -0.318895 | 0.006459413 |\n", "| mebendazole | -0.300325 | 0.006618701 |\n", "| lycorine | 0.319895 | 0.006644780 |\n", "| rescinnamine | -0.323295 | 0.006987249 |\n", "| reserpine | -0.285080 | 0.007184183 |\n", "| sirolimus | -0.361685 | 0.007393165 |\n", "| trifluoperazine | -0.375195 | 0.007405285 |\n", "| vorinostat | -0.378310 | 0.008683363 |\n", "| methotrexate | -0.336405 | 0.008864197 |\n", "| fulvestrant | -0.281245 | 0.009065718 |\n", "| phenazopyridine | -0.321425 | 0.009136916 |\n", "| ... | ... | ... |\n", "| PF-00562151-00 | 0 | 1 |\n", "| pioglitazone | 0 | 1 |\n", "| PF-00539745-00 | 0 | 1 |\n", "| valdecoxib | 0 | 1 |\n", "| PF-00539758-00 | 0 | 1 |\n", "| orlistat | 0 | 1 |\n", "| 5707885 | 0 | 1 |\n", "| C-75 | 0 | 1 |\n", "| 5155877 | 0 | 1 |\n", "| dinoprostone | 0 | 1 |\n", "| 5194442 | 0 | 1 |\n", "| AG-028671 | 0 | 1 |\n", "| 6-bromoindirubin-3'-oxime | 0 | 1 |\n", "| Gly-His-Lys | 0 | 1 |\n", "| STOCK1N-35696 | 0 | 1 |\n", "| STOCK1N-28457 | 0 | 1 |\n", "| H-89 | 0 | 1 |\n", "| SB-202190 | 0 | 1 |\n", "| NS-398 | 0 | 1 |\n", "| SB-203580 | 0 | 1 |\n", "| AH-6809 | 0 | 1 |\n", "| alsterpaullone | 0 | 1 |\n", "| SC-19220 | 0 | 1 |\n", "| 0198306-0000 | 0 | 1 |\n", "| AR-A014418 | 0 | 1 |\n", "| semustine | 0 | 1 |\n", "| CP-944629 | 0 | 1 |\n", "| irinotecan | 0 | 1 |\n", "| BCB000039 | 0 | 1 |\n", "| 11-deoxy-16,16-dimethylprostaglandin E2 | 0 | 1 |\n", "\n" ], "text/plain": [ " Connectivity P_value \n", "valproic acid -0.376625 0.003243431\n", "rifabutin -0.340380 0.003249652\n", "levomepromazine -0.329905 0.003363063\n", "promazine -0.338460 0.003408985\n", "Prestwick-559 -0.332285 0.003453743\n", "maprotiline -0.345995 0.003483930\n", "nicergoline -0.297975 0.003540995\n", "GW-8510 -0.365775 0.003643482\n", "lasalocid -0.287965 0.003653011\n", "pyrvinium -0.312920 0.003692544\n", "nortriptyline -0.346990 0.003785772\n", "prochlorperazine -0.360245 0.003809080\n", "norcyclobenzaprine -0.319960 0.003935323\n", "fluphenazine -0.351740 0.004089757\n", "LY-294002 -0.358135 0.004118938\n", "raloxifene -0.301795 0.004218595\n", "4,5-dianilinophthalimide -0.809330 0.006282675\n", "trichostatin A -0.330245 0.006335983\n", "eucatropine -0.288555 0.006421429\n", "syrosingopine -0.318895 0.006459413\n", "mebendazole -0.300325 0.006618701\n", "lycorine 0.319895 0.006644780\n", "rescinnamine -0.323295 0.006987249\n", "reserpine -0.285080 0.007184183\n", "sirolimus -0.361685 0.007393165\n", "trifluoperazine -0.375195 0.007405285\n", "vorinostat -0.378310 0.008683363\n", "methotrexate -0.336405 0.008864197\n", "fulvestrant -0.281245 0.009065718\n", "phenazopyridine -0.321425 0.009136916\n", "... ... ... \n", "PF-00562151-00 0 1 \n", "pioglitazone 0 1 \n", "PF-00539745-00 0 1 \n", "valdecoxib 0 1 \n", "PF-00539758-00 0 1 \n", "orlistat 0 1 \n", "5707885 0 1 \n", "C-75 0 1 \n", "5155877 0 1 \n", "dinoprostone 0 1 \n", "5194442 0 1 \n", "AG-028671 0 1 \n", "6-bromoindirubin-3'-oxime 0 1 \n", "Gly-His-Lys 0 1 \n", "STOCK1N-35696 0 1 \n", "STOCK1N-28457 0 1 \n", "H-89 0 1 \n", "SB-202190 0 1 \n", "NS-398 0 1 \n", "SB-203580 0 1 \n", "AH-6809 0 1 \n", "alsterpaullone 0 1 \n", "SC-19220 0 1 \n", "0198306-0000 0 1 \n", "AR-A014418 0 1 \n", "semustine 0 1 \n", "CP-944629 0 1 \n", "irinotecan 0 1 \n", "BCB000039 0 1 \n", "11-deoxy-16,16-dimethylprostaglandin E2 0 1 " ] }, "metadata": {}, "output_type": "display_data" } ], "source": [ "p_value_sars\n" ] }, { "cell_type": "code", "execution_count": 87, "metadata": {}, "outputs": [], "source": [ "mers_up_and_down_genes <-read.csv(\"HCoV_EMC2012_24Hour_23631916_GSE45042.csv\",stringsAsFactors = F, header = T, sep=\";\")\n", "rownames(mers_up_and_down_genes) <- mers_up_and_down_genes$Feature\n", "mers<- mers_up_and_down_genes$Direction\n", "names(mers) <- rownames(mers_up_and_down_genes)\n" ] }, { "cell_type": "code", "execution_count": 88, "metadata": {}, "outputs": [], "source": [ "res_mers <- apply(drug.perturbation[,,c(\"tstat\", \"fdr\")], \n", " 2,function(x, mers){\n", " return(connectivityScore(x=x, \n", " y=mers,\n", " method=\"fgsea\", nperm=100))\n", " },mers = mers)" ] }, { "cell_type": "code", "execution_count": 89, "metadata": {}, "outputs": [], "source": [ "rownames(res_mers) <- c(\"Connectivity\", \"P_value\")\n", "res_mers <- t(res_mers)\n" ] }, { "cell_type": "code", "execution_count": 98, "metadata": {}, "outputs": [], "source": [ "con_score <-res_mers[order((res_mers[,1]),decreasing = F),]\n", "p_value <- res_mers[order((res_mers[,2]),decreasing = F),]\n" ] }, { "cell_type": "code", "execution_count": 99, "metadata": {}, "outputs": [ { "data": { "text/html": [ "\n", "\n", "\n", "\t\n", "\n", "\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\t\n", "\n", "
A matrix: 1288 × 2 of type dbl
ConnectivityP_value
valproic acid-0.3766250.003319676
flupentixol-0.2690900.003383565
syrosingopine-0.3188950.003397262
levomepromazine-0.3299050.003426580
eucatropine-0.2885550.003468201
vorinostat-0.3783100.003530871
prochlorperazine-0.3602450.003554838
rescinnamine-0.3232950.003575237
maprotiline-0.3459950.003584323
promazine-0.3384600.003632854
phenazopyridine-0.3214250.003734297
nortriptyline-0.3469900.003890230
norcyclobenzaprine-0.3199600.003968853
lasalocid-0.2879650.004218595
trifluoperazine-0.3751950.004504136
fluphenazine-0.3517400.004867912
sirolimus-0.3616850.005503567
methotrexate-0.3364050.006284774
resveratrol-0.3504650.006437040
nicergoline-0.2979750.006459316
GW-8510-0.3657750.006644780
LY-294002-0.3581350.006971206
antimycin A-0.2829150.006971206
chlorpromazine-0.3125500.006971420
ampyrone-0.3020000.007577828
trichostatin A-0.3302450.008959310
bromocriptine-0.2983800.009140214
cefadroxil-0.3024600.009152568
HC toxin-0.3711250.009495673
fluspirilene-0.2714450.009801250
.........
PF-00562151-0001
pioglitazone01
PF-00539745-0001
valdecoxib01
PF-00539758-0001
orlistat01
570788501
C-7501
515587701
dinoprostone01
519444201
AG-02867101
6-bromoindirubin-3'-oxime01
Gly-His-Lys01
STOCK1N-3569601
STOCK1N-2845701
H-8901
SB-20219001
NS-39801
SB-20358001
AH-680901
alsterpaullone01
SC-1922001
0198306-000001
AR-A01441801
semustine01
CP-94462901
irinotecan01
BCB00003901
11-deoxy-16,16-dimethylprostaglandin E201
\n" ], "text/latex": [ "A matrix: 1288 × 2 of type dbl\n", "\\begin{tabular}{r|ll}\n", " & Connectivity & P\\_value\\\\\n", "\\hline\n", "\tvalproic acid & -0.376625 & 0.003319676\\\\\n", "\tflupentixol & -0.269090 & 0.003383565\\\\\n", "\tsyrosingopine & -0.318895 & 0.003397262\\\\\n", "\tlevomepromazine & -0.329905 & 0.003426580\\\\\n", "\teucatropine & -0.288555 & 0.003468201\\\\\n", "\tvorinostat & -0.378310 & 0.003530871\\\\\n", "\tprochlorperazine & -0.360245 & 0.003554838\\\\\n", "\trescinnamine & -0.323295 & 0.003575237\\\\\n", "\tmaprotiline & -0.345995 & 0.003584323\\\\\n", "\tpromazine & -0.338460 & 0.003632854\\\\\n", "\tphenazopyridine & -0.321425 & 0.003734297\\\\\n", "\tnortriptyline & -0.346990 & 0.003890230\\\\\n", "\tnorcyclobenzaprine & -0.319960 & 0.003968853\\\\\n", "\tlasalocid & -0.287965 & 0.004218595\\\\\n", "\ttrifluoperazine & -0.375195 & 0.004504136\\\\\n", "\tfluphenazine & -0.351740 & 0.004867912\\\\\n", "\tsirolimus & -0.361685 & 0.005503567\\\\\n", "\tmethotrexate & -0.336405 & 0.006284774\\\\\n", "\tresveratrol & -0.350465 & 0.006437040\\\\\n", "\tnicergoline & -0.297975 & 0.006459316\\\\\n", "\tGW-8510 & -0.365775 & 0.006644780\\\\\n", "\tLY-294002 & -0.358135 & 0.006971206\\\\\n", "\tantimycin A & -0.282915 & 0.006971206\\\\\n", "\tchlorpromazine & -0.312550 & 0.006971420\\\\\n", "\tampyrone & -0.302000 & 0.007577828\\\\\n", "\ttrichostatin A & -0.330245 & 0.008959310\\\\\n", "\tbromocriptine & -0.298380 & 0.009140214\\\\\n", "\tcefadroxil & -0.302460 & 0.009152568\\\\\n", "\tHC toxin & -0.371125 & 0.009495673\\\\\n", "\tfluspirilene & -0.271445 & 0.009801250\\\\\n", "\t... & ... & ...\\\\\n", "\tPF-00562151-00 & 0 & 1\\\\\n", "\tpioglitazone & 0 & 1\\\\\n", "\tPF-00539745-00 & 0 & 1\\\\\n", "\tvaldecoxib & 0 & 1\\\\\n", "\tPF-00539758-00 & 0 & 1\\\\\n", "\torlistat & 0 & 1\\\\\n", "\t5707885 & 0 & 1\\\\\n", "\tC-75 & 0 & 1\\\\\n", "\t5155877 & 0 & 1\\\\\n", "\tdinoprostone & 0 & 1\\\\\n", "\t5194442 & 0 & 1\\\\\n", "\tAG-028671 & 0 & 1\\\\\n", "\t6-bromoindirubin-3'-oxime & 0 & 1\\\\\n", "\tGly-His-Lys & 0 & 1\\\\\n", "\tSTOCK1N-35696 & 0 & 1\\\\\n", "\tSTOCK1N-28457 & 0 & 1\\\\\n", "\tH-89 & 0 & 1\\\\\n", "\tSB-202190 & 0 & 1\\\\\n", "\tNS-398 & 0 & 1\\\\\n", "\tSB-203580 & 0 & 1\\\\\n", "\tAH-6809 & 0 & 1\\\\\n", "\talsterpaullone & 0 & 1\\\\\n", "\tSC-19220 & 0 & 1\\\\\n", "\t0198306-0000 & 0 & 1\\\\\n", "\tAR-A014418 & 0 & 1\\\\\n", "\tsemustine & 0 & 1\\\\\n", "\tCP-944629 & 0 & 1\\\\\n", "\tirinotecan & 0 & 1\\\\\n", "\tBCB000039 & 0 & 1\\\\\n", "\t11-deoxy-16,16-dimethylprostaglandin E2 & 0 & 1\\\\\n", "\\end{tabular}\n" ], "text/markdown": [ "\n", "A matrix: 1288 × 2 of type dbl\n", "\n", "| | Connectivity | P_value |\n", "|---|---|---|\n", "| valproic acid | -0.376625 | 0.003319676 |\n", "| flupentixol | -0.269090 | 0.003383565 |\n", "| syrosingopine | -0.318895 | 0.003397262 |\n", "| levomepromazine | -0.329905 | 0.003426580 |\n", "| eucatropine | -0.288555 | 0.003468201 |\n", "| vorinostat | -0.378310 | 0.003530871 |\n", "| prochlorperazine | -0.360245 | 0.003554838 |\n", "| rescinnamine | -0.323295 | 0.003575237 |\n", "| maprotiline | -0.345995 | 0.003584323 |\n", "| promazine | -0.338460 | 0.003632854 |\n", "| phenazopyridine | -0.321425 | 0.003734297 |\n", "| nortriptyline | -0.346990 | 0.003890230 |\n", "| norcyclobenzaprine | -0.319960 | 0.003968853 |\n", "| lasalocid | -0.287965 | 0.004218595 |\n", "| trifluoperazine | -0.375195 | 0.004504136 |\n", "| fluphenazine | -0.351740 | 0.004867912 |\n", "| sirolimus | -0.361685 | 0.005503567 |\n", "| methotrexate | -0.336405 | 0.006284774 |\n", "| resveratrol | -0.350465 | 0.006437040 |\n", "| nicergoline | -0.297975 | 0.006459316 |\n", "| GW-8510 | -0.365775 | 0.006644780 |\n", "| LY-294002 | -0.358135 | 0.006971206 |\n", "| antimycin A | -0.282915 | 0.006971206 |\n", "| chlorpromazine | -0.312550 | 0.006971420 |\n", "| ampyrone | -0.302000 | 0.007577828 |\n", "| trichostatin A | -0.330245 | 0.008959310 |\n", "| bromocriptine | -0.298380 | 0.009140214 |\n", "| cefadroxil | -0.302460 | 0.009152568 |\n", "| HC toxin | -0.371125 | 0.009495673 |\n", "| fluspirilene | -0.271445 | 0.009801250 |\n", "| ... | ... | ... |\n", "| PF-00562151-00 | 0 | 1 |\n", "| pioglitazone | 0 | 1 |\n", "| PF-00539745-00 | 0 | 1 |\n", "| valdecoxib | 0 | 1 |\n", "| PF-00539758-00 | 0 | 1 |\n", "| orlistat | 0 | 1 |\n", "| 5707885 | 0 | 1 |\n", "| C-75 | 0 | 1 |\n", "| 5155877 | 0 | 1 |\n", "| dinoprostone | 0 | 1 |\n", "| 5194442 | 0 | 1 |\n", "| AG-028671 | 0 | 1 |\n", "| 6-bromoindirubin-3'-oxime | 0 | 1 |\n", "| Gly-His-Lys | 0 | 1 |\n", "| STOCK1N-35696 | 0 | 1 |\n", "| STOCK1N-28457 | 0 | 1 |\n", "| H-89 | 0 | 1 |\n", "| SB-202190 | 0 | 1 |\n", "| NS-398 | 0 | 1 |\n", "| SB-203580 | 0 | 1 |\n", "| AH-6809 | 0 | 1 |\n", "| alsterpaullone | 0 | 1 |\n", "| SC-19220 | 0 | 1 |\n", "| 0198306-0000 | 0 | 1 |\n", "| AR-A014418 | 0 | 1 |\n", "| semustine | 0 | 1 |\n", "| CP-944629 | 0 | 1 |\n", "| irinotecan | 0 | 1 |\n", "| BCB000039 | 0 | 1 |\n", "| 11-deoxy-16,16-dimethylprostaglandin E2 | 0 | 1 |\n", "\n" ], "text/plain": [ " Connectivity P_value \n", "valproic acid -0.376625 0.003319676\n", "flupentixol -0.269090 0.003383565\n", "syrosingopine -0.318895 0.003397262\n", "levomepromazine -0.329905 0.003426580\n", "eucatropine -0.288555 0.003468201\n", "vorinostat -0.378310 0.003530871\n", "prochlorperazine -0.360245 0.003554838\n", "rescinnamine -0.323295 0.003575237\n", "maprotiline -0.345995 0.003584323\n", "promazine -0.338460 0.003632854\n", "phenazopyridine -0.321425 0.003734297\n", "nortriptyline -0.346990 0.003890230\n", "norcyclobenzaprine -0.319960 0.003968853\n", "lasalocid -0.287965 0.004218595\n", "trifluoperazine -0.375195 0.004504136\n", "fluphenazine -0.351740 0.004867912\n", "sirolimus -0.361685 0.005503567\n", "methotrexate -0.336405 0.006284774\n", "resveratrol -0.350465 0.006437040\n", "nicergoline -0.297975 0.006459316\n", "GW-8510 -0.365775 0.006644780\n", "LY-294002 -0.358135 0.006971206\n", "antimycin A -0.282915 0.006971206\n", "chlorpromazine -0.312550 0.006971420\n", "ampyrone -0.302000 0.007577828\n", "trichostatin A -0.330245 0.008959310\n", "bromocriptine -0.298380 0.009140214\n", "cefadroxil -0.302460 0.009152568\n", "HC toxin -0.371125 0.009495673\n", "fluspirilene -0.271445 0.009801250\n", "... ... ... \n", "PF-00562151-00 0 1 \n", "pioglitazone 0 1 \n", "PF-00539745-00 0 1 \n", "valdecoxib 0 1 \n", "PF-00539758-00 0 1 \n", "orlistat 0 1 \n", "5707885 0 1 \n", "C-75 0 1 \n", "5155877 0 1 \n", "dinoprostone 0 1 \n", "5194442 0 1 \n", "AG-028671 0 1 \n", "6-bromoindirubin-3'-oxime 0 1 \n", "Gly-His-Lys 0 1 \n", "STOCK1N-35696 0 1 \n", "STOCK1N-28457 0 1 \n", "H-89 0 1 \n", "SB-202190 0 1 \n", "NS-398 0 1 \n", "SB-203580 0 1 \n", "AH-6809 0 1 \n", "alsterpaullone 0 1 \n", "SC-19220 0 1 \n", "0198306-0000 0 1 \n", "AR-A014418 0 1 \n", "semustine 0 1 \n", "CP-944629 0 1 \n", "irinotecan 0 1 \n", "BCB000039 0 1 \n", "11-deoxy-16,16-dimethylprostaglandin E2 0 1 " ] }, "metadata": {}, "output_type": "display_data" } ], "source": [ "p_value" ] }, { "cell_type": "code", "execution_count": 92, "metadata": {}, "outputs": [], "source": [ "write.csv(p_value,\"mers_results.csv\", row.names = T)" ] }, { "cell_type": "code", "execution_count": 93, "metadata": {}, "outputs": [], "source": [ "write.csv(p_value_sars,\"sars_results.csv\", row.names = T)" ] }, { "cell_type": "code", "execution_count": null, "metadata": {}, "outputs": [], "source": [ "Based on p value and connectivity score (negative score means that drug reverses the disease signature) I have decided to do \n", "docking on rescinnamine. This drug is FDA-approved angiotensin-converting enzyme inhibitor used as an antihypertensive drug.\n", "It is already known that Angiotensin-converting Enzyme is functional receptor for SARS coronavirues.\n", "Virtual screening results of small-molecule compounds against Spike structural protein of coronaviruses showed that rescinnamine \n", "has a high binding affinity against coronavirus.\n", "I also in my results get that sirolimus can be used against coronaviruses, and study by Zhou et al get the similar results.\n", "Based on my analysis valproic acid could also be used against coronaviruses, and there are currently clinical trial of valproic\n", "acid against HIV-viruses, but I get better binding affinity energy using PyRx with rescinnamine.\n", "\n", "Kuhn JH, Li W, Choe H, Farzan M. Angiotensin-converting enzyme 2: a functional receptor for SARS coronavirus.\n", "Cell Mol Life Sci. 2004;61(21):2738–2743. doi:10.1007/s00018-004-4242-5\n", "\n", "Yushun Wan, Jian Shang, Rachel Graham, Ralph S. Baric, Fang Li. Receptor recognition by novel coronavirus from Wuhan: \n", "An analysis based on decade-long structural studies of SARS. \n", "Journal of Virology, 2020; DOI: 10.1128/JVI.00127-20\n", "\n", "Canrong Wu, Yang Liu, Yueying Yang, Peng Zhang, Wu Zhong, Yali Wang, Qiqi Wang, Yang Xu, Mingxue Li, Xingzhou Li, Mengzhu Zheng, Lixia Chen, Hua Li,\n", "Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods,\n", "Acta Pharmaceutica Sinica B,2020,\n", "\n", "Yadi Zhou, Yuan Hou, Jiayu Shen, Yin Huang, William Martin, Feixiong Cheng.Network-based Drug Repurposing for Human Coronavirus\n", "doi: https://doi.org/10.1101/2020.02.03.20020263\n", "\n", " \n", "O. Trott, A. J. Olson,AutoDock Vina: improving the speed and accuracy of dockingwith a new scoring function,\n", "efficient optimization and multithreading, Journal of Computational Chemistry 31 (2010); 455-461; DOI 10.1002/jcc.21334 \n", "\n", "Study of Valproic Acid to Treat HIV Infected Adults https://clinicaltrials.gov/ct2/show/NCT00312546" ] } ], "metadata": { "kernelspec": { "display_name": "R", "language": "R", "name": "ir" }, "language_info": { "codemirror_mode": "r", "file_extension": ".r", "mimetype": "text/x-r-source", "name": "R", "pygments_lexer": "r", "version": "3.6.1" } }, "nbformat": 4, "nbformat_minor": 2 }