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Center for Computational Systems Medicine
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Dataset summary

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Drug summary

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Umap of single cell types and conditions (resistant and sensitive)

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Comparison of cell composition between the resistant and sensitive groups (This dataset does not contain this module)

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Comparison of intra-tumor heterogeneity (ITH) and epithelial-mesenchymal transition (EMT) scores of malignant cells between the resistant and sensitive groups

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Difference of cell-cell interactions between the resistant and sensitive groups (This dataset does not contain this module)

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Differentially expressed genes (DEGs) between the resistant and sensitive groups for each cell type

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Mechanism analysis of drug resistance-related DEGs for each cell type in the pre-treatment samples (This dataset does not contain this module)

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Mechanism analysis of drug resistance-related DEGs for each cell type in the post-treatment samples (This dataset does not contain this module)

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Mechanism analysis of drug resistance-related DEGs for each cell type in one patient or cell lines

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MicroRNAs (miRNAs) regulating drug resistance-related DEGs for Malignant cells

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Motifs and transcription factors (TFs) regulating drug resistance-related DEGs for each cell type

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Differentially expressed genes act as transcription factors

Dataset: GSE168668

Dataset summary for GSE168668

Datast informationDatasetGSE168668
PMID34489465
Raw data ID/linkPRJNA713356
OrganismHomo sapiens
SourceLNCaP cell line
TissueCell line
Cancer type level1Prostate cancer
Cancer type level2Prostate cancer
Regimenenzalutamide
Drug typeTargeted therapy
Sample sizeresistant 2, sensitive 1
Cell number10698
Extract protocol10x genomics
Data processingCellRanger 3.0.2
Public datePublic on Aug 17, 2021
DescriptionThis dataset has 1 cell line with 1 sensitive pre-treatment sample and 2 resistant post-treatment samples.

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Drug summary for GSE168668

Drug nameDrugBank IDDrug typeTargets nameTargets uniprot ID
"Enzalutamide"

DB08899

small moleculeARP10275

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Umap of single cell types and conditions (resistant and sensitive)

check buttonUmap of cell types and conditions (resistant and sensitive). If this dataset has both pre-treatment and post-treatment samples, the cell types were annotated together. If this dataset is a cell line dataset, the UMAP of cell clusters and the cell ratio of drug-resistant and sensitive groups within each cluster will also be shown. (If the image exists, the user can click on it to enlarge it in a new window.)
Umap of cell typesboxplotUmap of conditionsboxplot
Umap of cell clustersboxplotCell ratio of drug-resistant and sensitive groups within each clusterboxplot

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Comparison of cell composition between the resistant and sensitive groups

check buttonIn the pre-treatment samples, the cell composition of the resistant and sensitive groups were compared.
* represents significant difference.
(If the image exists, the user can click on it to enlarge it in a new window.)

check buttonIn the post-treatment samples, the cell composition of the resistant and sensitive groups were compared.
* represents significant difference.
(If the image exists, the user can click on it to enlarge it in a new window.)

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Comparison of ITH and EMT scores of malignant cells between the resistant and sensitive groups

check buttonComparison of ITH (intra-tumoral heterogeneity) and EMT (epithelial-mesenchymal transition) scores of malignant cells between the resistant and sensitive groups. ITH represents intratumoral heterogeneity, EMT represents epithelial mesenchymal transition, pre represents pre-treatment, post represents post-treatment, post2 represents longer post-treatment. (If the image exists, the user can click on it to enlarge it in a new window.)
Comparison of ITH scoresboxplotComparison of EMT scoresboxplot

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Difference of cell-cell interactions between the resistant and sensitive groups

check buttonIn the pre-treatment samples, the difference in cell-cell interactions between the resistant and sensitive groups was compared. The numbers indicate the count of cell-cell interactions that were either higher or lower in the resistant group compared to the sensitive group. The dot plots of significant ligand-receptor pairs in the resistant group and sensitive group are subsequently displayed. (If the image exists, the user can click on it to enlarge it in a new window. Complete files can be downloaded from the download section.)

check buttonIn the post-treatment samples, the difference in cell-cell interactions between the resistant and sensitive groups was compared. The numbers indicate the count of cell-cell interactions that were either higher or lower in the resistant group compared to the sensitive group. The dot plots of significant ligand-receptor pairs in the resistant group and sensitive group are subsequently displayed. (If the image exists, the user can click on it to enlarge it in a new window. Complete files can be downloaded from the download section.)

check buttonThis dataset only has one patient or is a cell line dataset, the resistant sample is the post-treatment sample and the sensitive sample is the pre-treatment sample. The difference in cell-cell interactions between the resistant and sensitive groups was compared. The numbers indicate the count of cell-cell interactions that were either higher or lower in the resistant group compared to the sensitive group. The dot plots of significant ligand-receptor pairs in the resistant group and sensitive group are subsequently displayed. (If the image exists, the user can click on it to enlarge it in a new window. Complete files can be downloaded from the download section.)

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Differentially expressed genes (DEGs) between the resistant and sensitive groups for each cell type

check buttonIn the pre-treatment samples, the differentially expressed genes (|avg_log2FC|>0.25 & p_val_adj<0.05) between the resistant and sensitive groups for each cell type.

check buttonIn the post-treatment samples, the differentially expressed genes (|avg_log2FC|>0.25 & p_val_adj<0.05) between the resistant and sensitive groups for each cell type.

check buttonThis dataset only has one patient or is a cell line dataset, the resistant sample is the post-treatment sample and the sensitive sample is the pre-treatment sample. The following are differentially expressed genes (|avg_log2FC|>0.25 & p_val_adj<0.05) between the resistant and sensitive groups for each cell type.
Gene symbolGene idavg_log2FCp_valp_val_adjpct.1pct.2Cell typeTimepoint

IGFBP5

ENSG000001154611.895990.00e+000.00e+000.4460.032Malignant cellsNA

CHPT1

ENSG000001116661.892750.00e+000.00e+000.9850.715Malignant cellsNA

ASPH

ENSG000001983631.883890.00e+000.00e+000.6550.346Malignant cellsNA

EPHX1

ENSG000001438191.853010.00e+000.00e+000.9570.384Malignant cellsNA

LMO4

ENSG000001430131.795580.00e+000.00e+000.8190.521Malignant cellsNA

SNHG25

ENSG000002664021.719090.00e+000.00e+000.9820.494Malignant cellsNA

PAGE1

ENSG000000689851.697340.00e+000.00e+000.6520.14Malignant cellsNA

HSP90AA1

ENSG000000808241.581920.00e+000.00e+0010.99Malignant cellsNA

TMSB4X

ENSG000002055421.510560.00e+000.00e+000.8140.168Malignant cellsNA

ATG3

ENSG000001448481.500620.00e+000.00e+000.8930.358Malignant cellsNA

BAMBI

ENSG000000957391.493230.00e+000.00e+000.8460.293Malignant cellsNA

SQSTM1

ENSG000002840991.473420.00e+000.00e+000.9860.667Malignant cellsNA

VIM

ENSG000000260251.457890.00e+000.00e+000.5540.051Malignant cellsNA

ATP1B1

ENSG000001431531.407940.00e+000.00e+000.9880.74Malignant cellsNA

EIF1B

ENSG000001147841.327260.00e+000.00e+000.8120.545Malignant cellsNA

CAMK2N1

ENSG000001625451.323910.00e+000.00e+000.4210.159Malignant cellsNA

SELENBP1

ENSG000001434161.322840.00e+000.00e+000.9380.628Malignant cellsNA

LDHB

ENSG000001117161.27840.00e+000.00e+000.9990.895Malignant cellsNA

AIDA

ENSG000001860631.260.00e+000.00e+000.9270.588Malignant cellsNA

MARCKSL1

ENSG000001751301.259650.00e+000.00e+000.9970.914Malignant cellsNA

ATP2B1

ENSG000000709611.181450.00e+000.00e+000.720.333Malignant cellsNA

GTF3C6

ENSG000001551151.1780.00e+000.00e+000.9980.902Malignant cellsNA

CSTB

ENSG000001602131.155070.00e+000.00e+000.990.803Malignant cellsNA

MYL6

ENSG000000928411.153540.00e+000.00e+0010.974Malignant cellsNA

HSPA5

ENSG000000445741.138350.00e+000.00e+000.9460.861Malignant cellsNA

TMSB10

ENSG000000345101.04770.00e+000.00e+000.9650.854Malignant cellsNA

TUBA1A

ENSG000001675521.042920.00e+000.00e+000.4390.022Malignant cellsNA

ARL1

ENSG000001208051.031780.00e+000.00e+000.8960.565Malignant cellsNA

SOD1

ENSG000001421681.021220.00e+000.00e+000.9990.956Malignant cellsNA

SLC9A3R1

ENSG000001090621.012780.00e+000.00e+000.8570.472Malignant cellsNA

BZW1

ENSG000000821530.9985360.00e+000.00e+000.8960.552Malignant cellsNA

CALR

ENSG000001792180.9678420.00e+000.00e+000.9950.959Malignant cellsNA

XBP1

ENSG000001002190.965530.00e+000.00e+000.9320.71Malignant cellsNA

HSP90AB1

ENSG000000963840.9629080.00e+000.00e+0010.997Malignant cellsNA

HSPA8

ENSG000001099710.9488480.00e+000.00e+0010.971Malignant cellsNA

POMP

ENSG000001329630.9429520.00e+000.00e+000.9860.818Malignant cellsNA

TAX1BP1

ENSG000001060520.9277510.00e+000.00e+000.9560.765Malignant cellsNA

HSP90B1

ENSG000001665980.9231180.00e+000.00e+000.9980.976Malignant cellsNA

AP1S1

ENSG000001063670.906540.00e+000.00e+000.9290.655Malignant cellsNA

HNRNPM

ENSG000000997830.8798410.00e+000.00e+000.9260.642Malignant cellsNA

GSTA1

ENSG000002439550.866150.00e+000.00e+000.4310.1Malignant cellsNA

TOX3

ENSG000001034600.8638830.00e+000.00e+000.4230.028Malignant cellsNA

UGT2B11

ENSG000002137590.8604840.00e+000.00e+000.3740.03Malignant cellsNA

BROX

ENSG000001628190.8459140.00e+000.00e+000.7230.385Malignant cellsNA

GNG5

ENSG000001740210.8448470.00e+000.00e+000.9990.973Malignant cellsNA

ARPC5

ENSG000001627040.8395170.00e+000.00e+000.9310.746Malignant cellsNA

KLHL35

ENSG000001492430.8368240.00e+000.00e+000.6490.218Malignant cellsNA

GNAI1

ENSG000001279550.8285270.00e+000.00e+000.370.06Malignant cellsNA

CALM1

ENSG000001986680.8270680.00e+000.00e+000.9970.936Malignant cellsNA

ADD3

ENSG000001487000.8136160.00e+000.00e+000.3840.18Malignant cellsNA
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Mechanism analysis of drug resistance-related DEGs for each cell type in the pre-treatment samples

check buttonEnrichment results for 5 known drug-resistant mechanisms in malignant cells and 1 known mechanism in TME cells.The "Signature" column represents the differentially expressed genes (DEGs) used for enrichment. The "Geneset" column represents the genes included in this mechanism. The "Overlap" column represents the number of genes in the "Geneset" that are enriched in the "Signature". The "Enriched Genes" column represents the genes in the "Geneset" that are enriched in the "Signature". (If the image exists, the user can click on it to enlarge it in a new window.)

check buttonHallmark, KEGG and GOBP enrichment results for up-regulated genes in resistant group of pre-treatment samples. Only show the top 50 pathways with fdr<0.05. If certain cell types are not displayed, it means that there are no significant pathways based on DEGs in those cell types. (If the image exists, the user can click on it to enlarge it in a new window. Complete files can be downloaded from the download section.)

check buttonHallmark, KEGG and GOBP enrichment results for down-regulated genes in resistant group of pre-treatment samples. Only show the top 50 pathways with fdr<0.05. If certain cell types are not displayed, it means that there are no significant pathways based on DEGs in those cell types. (If the image exists, the user can click on it to enlarge it in a new window.Complete files can be downloaded from the download section.)

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Mechanism analysis of drug resistance-related DEGs for each cell type in the post-treatment samples

check buttonEnrichment results for 5 known drug resistance mechanisms in malignant cells and 1 known mechanism in TME cells.The "Signature" column represents the differentially expressed genes (DEGs) used for enrichment. The "Geneset" column represents the genes included in this mechanism. The "Overlap" column represents the number of genes in the "Geneset" that are enriched in the "Signature". The "Enriched Genes" column represents the genes in the "Geneset" that are enriched in the "Signature". (If the image exists, the user can click on it to enlarge it in a new window.)

check buttonHallmark, KEGG and GOBP enrichment results for up-regulated genes in resistant group of post-treatment samples. Only show the top 50 pathways with fdr<0.05. If certain cell types are not displayed, it means that there are no significant pathways based on DEGs in those cell types. (If the image exists, the user can click on it to enlarge it in a new window. Complete files can be downloaded from the download section.)

check buttonHallmark, KEGG and GOBP enrichment results for down-regulated genes in resistant group of post-treatment samples. Only show the top 50 pathways with fdr<0.05. If certain cell types are not displayed, it means that there are no significant pathways based on DEGs in those cell types. (If the image exists, the user can click on it to enlarge it in a new window. Complete files can be downloaded from the download section.)

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Mechanism analysis of drug resistance-related DEGs for each cell type in one patient or cell lines

check buttonThis dataset only has one patient or is a cell line dataset, the resistant sample is the post-treatment sample and the sensitive sample is the pre-treatment sample. Enrichment results for 5 known drug resistance mechanisms in malignant cells and 1 known mechanism in TME cells are shown here.The "Signature" column represents the differentially expressed genes (DEGs) used for enrichment. The "Geneset" column represents the genes included in this mechanism. The "Overlap" column represents the number of genes in the "Geneset" that are enriched in the "Signature". The "Enriched Genes" column represents the genes in the "Geneset" that are enriched in the "Signature". (If the image exists, the user can click on it to enlarge it in a new window.)
Enrichment results for 5 known drug resistance mechanisms in malignant cells
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MechnismPvalFDRSignatureGenesetOverlapBackgroundCell typeEnriched Genes
Unusual Activation of Pro-survival Pathway3.30e-131.70e-1212567819323467Malignant cellsPPP2R5A,ADAM10,ADAM9,ADGRV1,BBC3,BRAF,CDK4,CDKN1A,DNMT1,EGFR,FUBP1,HMOX1,JUN,PKM,MAP1LC3B,MYC,PARP1,RALBP1,RPS6,SELENOW,ST3GAL4,SOX4,STMN1,TPD52,TRIM16,ALDH1A3,AR,ATG3,HSPA5,BNIP2,BTG1,CDK1,CCND1,CCNG1,ALCAM,HSPD1,SLC31A1,EHF,EIF3A,HSP90B1,FN1,FOXA1,FTL,FUS,GAPDH,GCLM,GSR,HAX1,HMGN5,HNRNPU,HSPA8,IDH1,EIF4A3,IKBKB,ITGB1,KAT6A,KDM5B,PRKCD,LAMP2,LASP1,LRIG1,MAP1LC3A,NFATC3,NQO1,POMP,PRKDC,PURA,RAP1B,ERBB3,SFPQ,SMC4,SRSF2,TPT1,TMED3,TOP1,TOP2B,USP14,ENO1,FASN,PFKL,SLC16A1,GNAS,CALR,CEBPD,EIF4EBP1,PPP3CA,SQLE,TM7SF2,TNFAIP8,NUPR1,TRIB3,CERS6,ACAT2
Irregularity in Drug Uptake and Drug Efflux4.60e-021.10e-01125637523467Malignant cellsSLC3A2,ABCC1,ABCC4,SLC4A4,SLC7A11
Aberration of the Drug's Therapeutic Target3.50e-015.80e-01125690623467Malignant cellsBRAF,CDK4,EGFR,AR,IDH1,MAOA
Drug Inactivation by Structure Modification7.70e-019.70e-01125627123467Malignant cellsNME1
Epigenetic Alteration of DNA, RNA or Protein1.00e+001.00e+0012564551123467Malignant cellsBRAF,DNMT1,EGFR,PMAIP1,GAPDH,IDH1,SMC4,MALAT1,GDI2,MT-CO2,GABPB1-AS1


check buttonHallmark, KEGG and GOBP enrichment results for up-regulated genes in resistant group. Only show the top 50 pathways with fdr<0.05. If certain cell types are not displayed, it means that there are no significant pathways based on DEGs in those cell types. (If the image exists, the user can click on it to enlarge it in a new window. Complete files can be downloaded from the download section.)
Up-regulated HallmarkUp-regulated KEGGUp-regulated GO BP

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check buttonHallmark, KEGG and GOBP enrichment results for down-regulated genes in resistant group. Only show the top 50 pathways with fdr<0.05. If certain cell types are not displayed, it means that there are no significant pathways based on DEGs in those cell types. (If the image exists, the user can click on it to enlarge it in a new window. Complete files can be downloaded from the download section.)
Down-regulated HallmarkDown-regulated KEGGDown-regulated GO BP

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MicroRNAs (miRNAs) regulating drug resistance-related DEGs for malignant cells

check buttonIn the pre-treatment samples, the miRNAs with a score greater than 80 that regulate the top10 abs(avg_log2FC) drug resistance-related DEGs for malignant cells are shown here. If the gene does not have any miRNAs with a score greater than 80, it will not be shown. Here only the names of miRNAs with a score greater than 90 are shown, but some names will not be shown because of too many overlaps. (Complete files containing all datasets and cell types can be downloaded from the download section.)

check buttonIn the post-treatment samples, the miRNAs with a score greater than 80 that regulate the top10 abs(avg_log2FC) drug resistance-related DEGs for Malignant cells are shown here. If the gene does not have any miRNAs with a score greater than 80, it will not be shown. Here only the names of miRNAs with a score greater than 90 are shown, but some names will not be shown because of too many overlaps. (Complete files containing all datasets and cell types can be downloaded from the download section.)

check buttonThis dataset only has one patient or is a cell line dataset, the resistant sample is the post-treatment sample and the sensitive sample is the pre-treatment sample. The miRNAs with a score greater than 80 that regulate the top10 abs(avg_log2FC) drug resistance-related DEGs for Malignant cells are shown here. Here only the names of miRNAs with a score greater than 80 are shown, but some names will not be shown because of too many overlaps. If the gene does not have any miRNAs with a score greater than 90, it will not be shown. (Complete files containing all datasets and cell types can be downloaded from the download section.)
Regulating up-regulated DEGs in resistant groupRegulating down-regulated DEGs in resistant group
boxplotboxplot

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Motifs and transcription factors (TFs) regulating drug resistance-related DEGs for each cell type

check buttonIn the pre-treatment samples, the motifs and TFs that regulate drug resistance-related DEGs for each cell type are shown here. (Complete files can be downloaded from the download section.)

check buttonIn the post-treatment samples, the motifs and TFs that regulate drug resistance-related DEGs for each cell type are shown here. (Complete files can be downloaded from the download section.)

check buttonThis dataset only has one patient or is a cell line dataset, the resistant sample is the post-treatment sample and the sensitive sample is the pre-treatment sample. Motifs and TFs that regulate drug resistance-related DEGs for each cell type are shown here. (Complete files can be downloaded from the download section.)
Motifs and TFs regulating up-regulated DEGs in resistant group
motifmotifNESAUCTF_highConfCell_type
motifmetacluster_174.34.490.054MBD2; NFYA; NFYB; NFYC; PBX3 (directAnnotation). Malignant cells
motiftransfac_pro__M059814.260.0525ZNF233 (directAnnotation). Malignant cells
motifmetacluster_57.34.250.0525ARNT; ATF3; ATF3; ATF3; ATF3; BHLHE40; BHLHE40; BHLHE40; BHLHE41; BHLHE41; BHLHE41; MITF; MITF; MITF; MLX; MLXIPL; SREBF1; SREBF1; SREBF1; SREBF1; SREBF2; SREBF2; SREBF2; TFE3; TFEC; USF1; USF1; USF1; USF1; USF1; USF1; USF1; USF1; USF1; USF2; USF2; USF2; USF2; USF2; USF2; USF2; USF2; USF2; USF2; USF2; USF2; USF2; ZNF507 (directAnnotation). ARNTL; BHLHE40; BHLHE40; BHLHE41; HELT; HES1; HES2; HES3; HES5; HES6; HES7; HEY1; HEY2; HEYL; MLX; MLX; SREBF1; SREBF2; TFE3; USF1; USF1; USF2; USF2 (inferredBy_Orthology). Malignant cells
motifjaspar__MA0502.24.070.0513NFYB (directAnnotation). Malignant cells
motiftaipale_tf_pairs__E2F1_ELK1_SGCGCNNNNNCGGAAGN_CAP_repr4.040.0512E2F1; ELK1 (directAnnotation). Malignant cells
motifdbtfbs__E4F1_K562_ENCSR731LHZ_merged_N13.910.0504E4F1 (directAnnotation). Malignant cells
motifmetacluster_174.23.80.0497CEBPZ; CEBPZ; DRAP1; FOS; FOXI1; FOXI1; HMGXB3; IRF3; NFYA; NFYA; NFYA; NFYA; NFYA; NFYA; NFYA; NFYA; NFYA; NFYB; NFYB; NFYB; NFYB; NFYB; NFYC; NFYC; NFYC; NFYC; NFYC; NFYC; NFYC; PBX3; PBX3; SP2 (directAnnotation). NFYA; NFYA; NFYC; PBX1; PBX3 (inferredBy_Orthology). Malignant cells
motiftransfac_pro__M049503.770.0495EGR1 (directAnnotation). Malignant cells
motiftaipale_tf_pairs__ETV2_HES7_RSCGGAANNNNNNNCACGTGNN_CAP_repr3.760.0494ETV2; HES7 (directAnnotation). Malignant cells
motiftaipale_tf_pairs__GCM1_ETV4_RTGCGGGCGGAAGTR_CAP3.730.0492ETV4; GCM1 (directAnnotation). Malignant cells
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Motifs and TFs regulating down-regulated DEGs in resistant group
motifmotifNESAUCTF_highConfCell_type
motifkznf__ZBTB14_Schmitges2016_RCADE3.730.0664ZBTB14 (directAnnotation). Malignant cells
motiftaipale_tf_pairs__E2F3_HES7_NNNNGCGCSNNNNNCACGTGNN_CAP3.640.0656E2F3; HES7 (directAnnotation). Malignant cells
motiftransfac_pro__M020893.510.0644E2F3 (directAnnotation). Malignant cells
motiftaipale_cyt_meth__E2F2_NCGCGCGCGCM_eDBD_meth3.480.0642E2F2 (directAnnotation). Malignant cells
motiftransfac_pro__M008033.470.0641E2F1; E2F3; E2F4; TFDP1 (directAnnotation). Malignant cells
motiftransfac_pro__M048173.250.0621ZBTB33 (directAnnotation). Malignant cells
motifmetacluster_143.133.190.0615ZBTB7A (directAnnotation). Malignant cells
motiftransfac_pro__M028613.170.0614GATA6 (inferredBy_Orthology). Malignant cells
motiftfdimers__MD004833.170.0614ZBTB14 (directAnnotation). Malignant cells
motifcisbp__M079383.160.0613E2F1 (directAnnotation). Malignant cells
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Differentially expressed genes act as transcription factors

check buttonThis table shows the differentially expressed genes that act as transcription factors. (Complete files can be downloaded from the download section.)
TFmotifExpressionCell typeTimepoint

HES1

metacluster_57.3upMalignant cellsNA

TFDP1

transfac_pro__M00803downMalignant cellsNA

SMAD9

jaspar__MA0535.1downMalignant cellsNA

TFDP1

metacluster_15.2downMalignant cellsNA

TFDP1

jaspar__MA1122.1downMalignant cellsNA

ATF3

metacluster_57.3downMalignant cellsNA

HES6

metacluster_57.3downMalignant cellsNA

ZNF814

transfac_pro__M06071downMalignant cellsNA

ELK4

metacluster_166.2downMalignant cellsNA

ETV1

metacluster_166.2downMalignant cellsNA
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1"Sun X, Zhang Y, Li H, Zhou Y, Shi S, Chen Z, He X, Zhang H, Li F, Yin J, Mou M, Wang Y, Qiu Y, Zhu F. DRESIS: the first comprehensive landscape of drug resistance information. Nucleic Acids Res. 2023 Jan 6;51(D1):D1263-D1275. doi: 10.1093/nar/gkac812. PMID: 36243960; PMCID: PMC9825618."
2"Wishart DS, Feunang YD, Guo AC, Lo EJ, Marcu A, Grant JR, Sajed T, Johnson D, Li C, Sayeeda Z, Assempour N, Iynkkaran I, Liu Y, Maciejewski A, Gale N, Wilson A, Chin L, Cummings R, Le D, Pon A, Knox C, Wilson M. DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 2018 Jan 4;46(D1):D1074-D1082. doi: 10.1093/nar/gkx1037. PMID: 29126136; PMCID: PMC5753335."