Supplementary Table 1: List of proteins for cardiac remodeling used to focus our analyses on the pathological condition of interest. Motive ID refers to the remodeling condition that the protein is associated with; 1: Cardiomyocyte cell death; 2: Impaired myocyte contractility; 3: Left ventricle extracellular matrix remodeling (including necrosis and apoptosis); 4: Hypertrophy.

MOTIVE ID / Uniprot / Displayed Name / Protein name
1 / O00165 / HAX-1 / HCLS1-associated protein X-1
1 / P30405 / CyP-D / Peptidyl-prolyl cis-trans isomerase F, mitochondrial; Cyclophilin D
1 / P21796 / VDAC1 / Voltage-dependent anion-selective channel protein 1
1 / P45880 / VDAC2 / Voltage-dependent anion-selective channel protein 2
1 / Q9Y277 / VDAC3 / Voltage-dependent anion-selective channel protein 3
1 / P12235 / ANT1 / ADP/ATP translocase 1
1 / P05141 / ANT2 / ADP/ATP translocase 2
1 / P12236 / ANT3 / ADP/ATP translocase 3
1 / Q9H0C2 / ANT4 / ADP/ATP translocase 4
1 / P49841 / GSK3B / Glycogen synthase kinase-3 beta
1 / P25445 / FAS / Tumor necrosis factor receptor superfamily member 6
1 / P48023 / FASLG / Tumor necrosis factor ligand superfamily member 6
1 / P01375 / TNFA / Tumor necrosis factor
1 / P50591 / TRAIL / Tumor necrosis factor ligand superfamily member 10
1 / Q13158 / FADD / FAS-associated death domain protein
1 / Q15628 / TRADD / Tumor necrosis factor receptor type 1-associated DEATH domain protein
1 / Q14790 / CASP8 / Caspase-8
1 / P42574 / CASP3 / Caspase-3
1 / P10415 / BCL2 / Apoptosis regulator Bcl-2
1 / Q07812 / Bax / Apoptosis regulator BAX
1 / Q99683 / MAP3K5 / ASK-1 / Mitogen-activated protein kinase kinase kinase 5
1 / P31152 / MAPK4 / Mitogen-activated protein kinase 4
1 / Q16659 / MAPK6 / Mitogen-activated protein kinase 6
1 / P55957 / BID / BH3-interacting domain death agonist
1 / P98170 / XIAP / E3 ubiquitin-protein ligase XIAP
1 / Q13490 / C-IAP1 / Baculoviral IAP repeat-containing protein 2
1 / O15392 / BIRC5 / Baculoviral IAP repeat-containing protein 5 / survivin
1 / Q9NR28 / DIABLO / SMAC / Diablo homolog, mitochondrial
1 / O43464 / Omi/HtrA2 / Serine protease HTRA2, mitochondrial
1 / Q811U4 / Mfn1 / Mitofusin-1
1 / Q07820 / MCL1 / Induced myeloid leukemia cell differentiation protein Mcl-1
1 / Q92934 / BAD / Bcl2-associated agonist of cell death
1 / P04637 / p53 / Cellular tumor antigen p53
1 / P19634 / NHE1 / Sodium/hydrogen exchanger 1
1 / P29466 / CASP1 / Caspase-1
1 / P13473 / LAMP2 / Lysosome-associated membrane glycoprotein 2
1 / Q9H1Y0 / ATG5 / Autophagy protein 5
1 / O75385 / ULK1 / Serine/threonine-protein kinase ULK1
1 / P42345 / mTORC1 / Serine/threonine-protein kinase mTOR
1 / P49815 / TSC2 / Tuberin
1 / Q8N122 / Raptor / Regulatory-associated protein of mTOR
1 / Q14457 / BECN1 / Beclin-1
1 / Q12983 / BNIP3 / BCL2/adenovirus E1B 19 kDa protein-interacting protein 3
1 / O00429 / Drp1 / Dynamin-1-like protein
1 / P12644 / BMP4 / Bone morphogenetic protein 4
1 / O95140 / Mfn2 / Mitofusin-2
2 / P63098 / PPP3R1 / Calcineurin subunit B type 1
2 / Q96LZ3 / PPP3R2 / Calcineurin subunit B type 2
2 / P17612 / PKACA / cAMP-dependent protein kinase catalytic subunit alpha
2 / P22694 / PKACB / cAMP-dependent protein kinase catalytic subunit beta
2 / P22612 / PKACC / cAMP-dependent protein kinase catalytic subunit gamma
2 / Q13237 / cGK2 / cGMP-dependent protein kinase 2
2 / Q13976 / cGK1 / cGMP-dependent protein kinase 1
2 / P78423 / CX3CL1 / Fractalkine
2 / P33402 / GCSA2 / Guanylate cyclase soluble subunit alpha-2
2 / Q02108 / GCSA3 / Guanylate cyclase soluble subunit alpha-3
2 / Q02153 / GCSB1 / Guanylate cyclase soluble subunit beta-1
2 / O75343 / GCSB2 / Guanylate cyclase soluble subunit beta-2
2 / Q9UQL6 / HDAC5 / Histone deacetylase 5
2 / Q9UKV0 / HDAC9 / Histone deacetylase 9
2 / Q02078 / MEF2A / Myocyte-specific enhancer factor 2A
2 / Q02080 / MEF2B / Myocyte-specific enhancer factor 2B
2 / Q06413 / MEF2C / Myocyte-specific enhancer factor 2C
2 / Q14814 / MEF2D / Myocyte-specific enhancer factor 2D
2 / P13533 / MYH7 / aMHC / Myosin-6 (alternative name: a–myosin heavy chain)
2 / P12883 / MYH6 / bMHC / Myosin-7 (alternative name: b-myosin heavy chain)
2 / P29474 / NOS3 / Nitric oxide synthase, endothelial
2 / O95644 / NFATc1 / Nuclear factor of activated T-cells 1
2 / Q13469 / NFATc2 / Nuclear factor of activated T-cells 2
2 / Q12968 / NFATc3 / Nuclear factor of activated T-cells 3
2 / Q14934 / NFATc4 / Nuclear factor of activated T-cells 4
2 / P26678 / PPLA / phospholamban
2 / O14983 / SERCA1 / Sarcoplasmic/endoplasmic reticulum calcium ATPase 1
2 / P16615 / SERCA2 / Sarcoplasmic/endoplasmic reticulum calcium ATPase 2
2 / Q93084 / SERCA3 / Sarcoplasmic/endoplasmic reticulum calcium ATPase 3
2 / Q08209 / PPP3CA / Serine/threonine-protein phosphatase 2B catalytic subunit alpha isoform
2 / P16298 / PPP3CB / Serine/threonine-protein phosphatase 2B catalytic subunit beta isoform
2 / P48454 / PPP3CC / Serine/threonine-protein phosphatase 2B catalytic subunit gamma isoform
2 / P10827 / THRA / Thyroid hormone receptor alpha
2 / P10828 / THRB / Thyroid hormone receptor beta
2 / Q8WZ42 / TTN / Titin
3 / P01583 / IL1A / Interleukin-1
3 / P08254 / MMP-3 / Stromelysin-1
3 / P14780 / MMP-9 / Matrix metalloproteinase-9
3 / P03956 / MMP-1 / Interstitial collagenase
3 / P16035 / TIMP2 / Metalloproteinase inhibitor 2
3 / P01137 / TGFB1 / Transforming growth factor beta-1
3 / A8TX70 / COL6A5 / Collagen alpha-5(VI) chain
3 / P12109 / COL6A1 / Collagen alpha-1(VI) chain
3 / P12110 / COL6A2 / Collagen alpha-2(VI) chain
3 / P12111 / COL6A3 / Collagen alpha-3(VI) chain
3 / P25391 / LAMA1 / Laminin subunit alpha-1
3 / P24043 / LAMA2 / Laminin subunit alpha-2
3 / Q16787 / LAMA3 / Laminin subunit alpha-3
3 / Q16363 / LAMA4 / Laminin subunit alpha-4
3 / O15230 / LAMA5 / Laminin subunit alpha-5
3 / P07942 / LAMB1 / Laminin subunit beta-1
3 / P55268 / LAMB2 / Laminin subunit beta-2
3 / Q13751 / LAMB3 / Laminin subunit beta-3
3 / A4D0S4 / LAMB4 / Laminin subunit beta-4
3 / P11047 / LAMC1 / Laminin subunit gamma-1
3 / Q13753 / LAMC2 / Laminin subunit gamma-2
3 / Q9Y6N6 / LAMC3 / Laminin subunit gamma-3
3 / P01019 / AGT / Angiotensinogen
3 / P35625 / TIMP3 / Metalloproteinase inhibitor 3
3 / P16035 / TIMP4 / Metalloproteinase inhibitor 4
3 / P02751 / FN1 / Fibronectin
3 / P09486 / SPARC / ON / Secreted protein acidic and rich in cysteine / Osteonectin
3 / P00488 / F13A1 F13 / Transglutaminase A chain
3 / P01033 / TIMP1 / Metalloproteinase inhibitor 1
3 / P09237 / MMP-7 / Matrix metalloproteinase-7
3 / P17302 / GJA1 / Gap junction alpha-1 protein / Connexin-43
3 / P12821 / ACE / Angiotensin-converting enzyme
3 / P05305 / EDN1 / Endothelin-1
3 / P24821 / TN-C / Tenascin-C
3 / P10451 / OPN / Osteopontin
3 / P08253 / MMP-2 / Matrix metalloproteinase-2
3 / P50281 / MMP-14 / Matrix metalloproteinase-14
4 / Q9UBK2 / PPARGC1A // PGC1 / Peroxisome proliferator-activated receptor gamma coactivator 1-alpha
4 / P06396 / GSN / Gelsolin
4 / P49238 / CX3CR1 / CX3C chemokine receptor 1
4 / P78423 / CX3CL1 / Fractalkine
4 / P49116 / NR2C2 TAK1 / Nuclear receptor subfamily 2 group C member 2
4 / P12644 / BMP4 / Bone morphogenetic protein 4
4 / P63098 / PPP3R1 / Calcineurin subunit B type 1
4 / Q96LZ3 / PPP3R2 / Calcineurin subunit B type 2
4 / P00533 / EGFR / epidermal growth factor receptor
4 / P09038 / FGF-2 / bFGF / Fibroblast growth factor 2 / Basic fibroblast growth factor
4 / Q14571 / IP3R2 / Inositol 1,4,5-trisphosphate receptor type 2
4 / P03956 / MMP1 / Matrix metalloproteinase-1
4 / P08235 / MR / Mineralocorticoid receptor
4 / P28482 / ERK2 / Mitogen-activated protein kinase 1
4 / P27361 / ERK1 / Mitogen-activated protein kinase 3
4 / Q99836 / MyD88 / Myeloid differentiation primary response protein MyD88
4 / P29474 / NOS3 / Nitric oxide synthase, endothelial
4 / O95644 / NFATc1 / Nuclear factor of activated T-cells 1
4 / Q13469 / NFATc2 / Nuclear factor of activated T-cells 2
4 / Q12968 / NFATc3 / Nuclear factor of activated T-cells 3
4 / Q14934 / NFATc4 / Nuclear factor of activated T-cells 4
4 / P61296 / HAND2 / Heart- and neural crest derivatives-expressed protein 2
4 / P05121 / PAI / Plasminogen activator inhibitor 1
4 / Q15418 / S6KA1 / Ribosomal protein S6 kinase alpha-1
4 / Q15349 / S6KA2 / Ribosomal protein S6 kinase alpha-2
4 / P51812 / S6KA3 / Ribosomal protein S6 kinase alpha-3
4 / Q08209 / PPP3CA / Serine/threonine-protein phosphatase 2B catalytic subunit alpha isoform
4 / P16298 / PPP3CB / Serine/threonine-protein phosphatase 2B catalytic subunit beta isoform
4 / P48454 / PPP3CC / Serine/threonine-protein phosphatase 2B catalytic subunit gamma isoform
4 / Q9UBN4 / TRPC4 / Short transient receptor potential channel 4
4 / P32418 / NCX / Sodium/calcium exchanger 1
4 / P19634 / NHE1 / sodium-hydrogen antiporter1
4 / P30556 / AT1 / Type-1 angiotensin II receptor

Supplementary Table 2. Manual curation of the literature. List of articles used for molecular characterization of the pathologies under study, and Sacubitril/Valsartan.

Manual curation of the literature: / PMID: 26564789 / PMID: 24080184 / PMID: 19797822
PMID: 26562414 / PMID: 24072174 / PMID: 19679836
PMID: 26553996 / PMID: 23909633 / PMID: 19593942
PMID: 26356605 / PMID: 23806284 / PMID: 19246681
PMID: 25977452 / PMID: 23704873 / PMID: 19179805
PMID: 25752645 / PMID: 23506867 / PMID: 19144865
PMID: 25663976 / PMID: 23429007 / PMID: 18981739
PMID: 25595790 / PMID: 23316962 / PMID: 18585734
PMID: 25520329 / PMID: 23316291 / PMID: 18535174
PMID: 25047165 / PMID: 23176689 / PMID: 18276618
PMID: 24905188 / PMID: 22803959 / PMID: 17928585
PMID: 24859226 / PMID: 22535253 / PMID: 17657164
PMID: 24827991 / PMID: 21799152 / PMID: 17490677
PMID: 24736806 / PMID: 21784127 / PMID: 17379774
PMID: 24615014 / PMID: 21671800 / PMID: 16847152
PMID: 24530674 / PMID: 20888832 / PMID: 15526239
PMID: 24505034 / PMID: 20564207 / PMID: 15364610
PMID: 24415751 / PMID: 20125030 / PMID: 14998631
PMID: 24161931 / PMID: 19919994 / PMID: 14962485
PMID: 24126173 / PMID: 19893013 / PMID: 11120693

Supplementary Table 3: Data sources for generation and training of the mathematical models. List of the different types of information used to generate and train the mathematical models, as well as their quantity.

DATA SOURCES / # ENTRIES
Considered Interactions / 312445
Considered Proteins / 15555
Characterized Drugs / 6605
Drug Targets / 11265
Characterized Clinical Conditions / 222
Clinical Conditions Key Proteins Characterized / 3712

Supplementary Table 4: Molecular restrictions used for generation and training of the mathematical models. Type and quantity of restrictions used to generate the mathematical models. ADR= Adverse Drug Reactions.

MAIN MODEL CONSTRUCTION RESTRICTIONS / DIRECT RESTRICTIONS
CLINICAL CONDITION PREDICTIVE MODELS - ANNs
Curated drug indication/ADRs database / 2500830
SAMPLING METHODS
Curated drug indication/ADRs database / 2500830
Drug indication/ADRs protein correlations / 3970
SPECIFIC POPULATION RESTRICTIONS (High Throughput Differential Expression Restrictions) / Myocardial infarction / Heart failure
4738 / 6074
Uniprot / Displayed Name / Protein name / Remodeling effector
P31749 / AKT1 / RAC-alpha serine/threonine-protein kinase / Cardiomyocyte cell death, Impaired myocyte contractility
Q9Y243 / AKT3 / RAC-gamma serine/threonine-protein kinase / Cardiomyocyte cell death, Impaired myocyte contractility
Q05397 / FAK1 / Focal adhesion kinase 1 / Cardiomyocyte cell death, Hypertrophy,
P49841 / GSK3B / Glycogen synthase kinase-3 beta / Cardiomyocyte cell death
P27986 / P85A / Phosphatidylinositol 3-kinase regulatory subunit alpha / Cardiomyocyte cell death, Impaired myocyte contractility
P42336 / PK3CA / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform / Cardiomyocyte cell death, Impaired myocyte contractility
O00329 / PK3CD / Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform / Cardiomyocyte cell death, Impaired myocyte contractility
P10827 / THRA / Thyroid hormone receptor alpha / Impaired myocyte contractility
Q13490 / BIRC2 / Baculoviral IAP repeat-containing protein 2 / Cardiomyocyte cell death
P09038 / FGF2 / Fibroblast growth factor 2 / Hypertrophy
P02751 / FINC / Fibronectin / Left ventricle extracellular matrix remodeling
P14780 / MMP9 / Matrix metalloproteinase-9 / Left ventricle extracellular matrix remodeling
P42345 / MTOR / Serine/threonine-protein kinase mTOR / Cardiomyocyte cell death
P01137 / TGFB1 / Transforming growth factor beta-1 / Left ventricle extracellular matrix remodeling

Supplementary Table 5: Potential synergistic nodes involved in the downstream effects of sacubitril/valsartan. The first eight proteins of the list scored the best likelihood of occupying synergistic nodes, and so are included in the MoA representation (Fig 2). However, the models predicted 6 additional proteins that could potentially act synergistically, so are included in this table as the six last proteins on the list.

Supplementary Table 6. Specific proteins identified as only associated with the model simulating the efficacy of LCZ696 on MI patients.

Uniprot / Displayed Name
P49238 / CX3C1 (Fractalkine)
Q9BXN2 / CLEC7A (Dectin-1)
P13533 / MYH6
P12883 / MYH7

Supplementary Table 7: Results from pathway and GO enrichment analysis. Sorted by p-value.