Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT10H1AB)

• DOT Name: DNA mismatch repair protein Msh2 (MSH2)
• Synonyms: hMSH2; MutS protein homolog 2
• Gene Name: MSH2
• Related Disease:
  Lynch syndrome
  Lynch syndrome 1
  Mismatch repair cancer syndrome 1
  Muir-Torre syndrome
  Mismatch repair cancer syndrome 2
  Ovarian cancer
  Malignant pancreatic neoplasm
  Prostate cancer
  Rhabdomyosarcoma
  Breast cancer
  Hereditary breast carcinoma
• UniProt ID: MSH2_HUMAN
• PDB ID: 2O8B; 2O8C; 2O8D; 2O8E; 2O8F; 3THW; 3THX; 3THY; 3THZ; 8AG6; 8OLX; 8OM5; 8OM9; 8OMA; 8OMO; 8OMQ
• Pfam ID: PF01624 ; PF05188 ; PF05192 ; PF05190 ; PF00488
• Sequence:
  MAVQPKETLQLESAAEVGFVRFFQGMPEKPTTTVRLFDRGDFYTAHGEDALLAAREVFKT
  QGVIKYMGPAGAKNLQSVVLSKMNFESFVKDLLLVRQYRVEVYKNRAGNKASKENDWYLA
  YKASPGNLSQFEDILFGNNDMSASIGVVGVKMSAVDGQRQVGVGYVDSIQRKLGLCEFPD
  NDQFSNLEALLIQIGPKECVLPGGETAGDMGKLRQIIQRGGILITERKKADFSTKDIYQD
  LNRLLKGKKGEQMNSAVLPEMENQVAVSSLSAVIKFLELLSDDSNFGQFELTTFDFSQYM
  KLDIAAVRALNLFQGSVEDTTGSQSLAALLNKCKTPQGQRLVNQWIKQPLMDKNRIEERL
  NLVEAFVEDAELRQTLQEDLLRRFPDLNRLAKKFQRQAANLQDCYRLYQGINQLPNVIQA
  LEKHEGKHQKLLLAVFVTPLTDLRSDFSKFQEMIETTLDMDQVENHEFLVKPSFDPNLSE
  LREIMNDLEKKMQSTLISAARDLGLDPGKQIKLDSSAQFGYYFRVTCKEEKVLRNNKNFS
  TVDIQKNGVKFTNSKLTSLNEEYTKNKTEYEEAQDAIVKEIVNISSGYVEPMQTLNDVLA
  QLDAVVSFAHVSNGAPVPYVRPAILEKGQGRIILKASRHACVEVQDEIAFIPNDVYFEKD
  KQMFHIITGPNMGGKSTYIRQTGVIVLMAQIGCFVPCESAEVSIVDCILARVGAGDSQLK
  GVSTFMAEMLETASILRSATKDSLIIIDELGRGTSTYDGFGLAWAISEYIATKIGAFCMF
  ATHFHELTALANQIPTVNNLHVTALTTEETLTMLYQVKKGVCDQSFGIHVAELANFPKHV
  IECAKQKALELEEFQYIGESQGYDIMEPAAKKCYLEREQGEKIIQEFLSKVKQMPFTEMS
  EENITIKLKQLKAEVIAKNNSFVNEIISRIKVTT
• Function: Component of the post-replicative DNA mismatch repair system (MMR). Forms two different heterodimers: MutS alpha (MSH2-MSH6 heterodimer) and MutS beta (MSH2-MSH3 heterodimer) which binds to DNA mismatches thereby initiating DNA repair. When bound, heterodimers bend the DNA helix and shields approximately 20 base pairs. MutS alpha recognizes single base mismatches and dinucleotide insertion-deletion loops (IDL) in the DNA. MutS beta recognizes larger insertion-deletion loops up to 13 nucleotides long. After mismatch binding, MutS alpha or beta forms a ternary complex with the MutL alpha heterodimer, which is thought to be responsible for directing the downstream MMR events, including strand discrimination, excision, and resynthesis. Recruits DNA helicase MCM9 to chromatin which unwinds the mismatch containing DNA strand. ATP binding and hydrolysis play a pivotal role in mismatch repair functions. The ATPase activity associated with MutS alpha regulates binding similar to a molecular switch: mismatched DNA provokes ADP-->ATP exchange, resulting in a discernible conformational transition that converts MutS alpha into a sliding clamp capable of hydrolysis-independent diffusion along the DNA backbone. This transition is crucial for mismatch repair. MutS alpha may also play a role in DNA homologous recombination repair. In melanocytes may modulate both UV-B-induced cell cycle regulation and apoptosis.
• Tissue Specificity: Ubiquitously expressed.
• KEGG Pathway:
  Platinum drug resistance (hsa01524)
  Mismatch repair (hsa03430)
  Pathways in cancer (hsa05200)
  Colorectal cancer (hsa05210)
• Reactome Pathway:
  Mismatch repair (MMR) directed by MSH2 (R-HSA-5358606)
  Defective Mismatch Repair Associated With MSH3 (R-HSA-5632927)
  Defective Mismatch Repair Associated With MSH2 (R-HSA-5632928)
  Defective Mismatch Repair Associated With MSH6 (R-HSA-5632968)
  TP53 Regulates Transcription of DNA Repair Genes (R-HSA-6796648)
  Mismatch repair (MMR) directed by MSH2 (R-HSA-5358565)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Lynch syndrome	DIS3IW5F	Definitive	Autosomal dominant	[1]
Lynch syndrome 1	DISSABLZ	Definitive	Autosomal dominant	[2]
Mismatch repair cancer syndrome 1	DISB7J1A	Definitive	Autosomal recessive	[1]
Muir-Torre syndrome	DISKFFSW	Definitive	Autosomal dominant	[2]
Mismatch repair cancer syndrome 2	DISE81BQ	Strong	Autosomal recessive	[3]
Ovarian cancer	DISZJHAP	Strong	Autosomal dominant	[4]
Malignant pancreatic neoplasm	DISH4FJX	Moderate	Autosomal dominant	[5]
Prostate cancer	DISF190Y	Moderate	Autosomal dominant	[6]
Rhabdomyosarcoma	DISNR7MS	Moderate	Autosomal recessive	[4]
Breast cancer	DIS7DPX1	Disputed	Autosomal dominant	[6]
Hereditary breast carcinoma	DISAEZT5	Refuted	Autosomal dominant	[1]

This DOT Affected the Drug Response of 4 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Temozolomide	DMKECZD	Approved	DNA mismatch repair protein Msh2 (MSH2) decreases the response to substance of Temozolomide.	[43]
DTI-015	DMXZRW0	Approved	DNA mismatch repair protein Msh2 (MSH2) affects the response to substance of DTI-015.	[44]
Floxuridine	DM04LR2	Approved	DNA mismatch repair protein Msh2 (MSH2) decreases the response to substance of Floxuridine.	[45]
Thioguanine	DM7NKEV	Approved	DNA mismatch repair protein Msh2 (MSH2) increases the response to substance of Thioguanine.	[43]

32 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of DNA mismatch repair protein Msh2 (MSH2).	[7]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of DNA mismatch repair protein Msh2 (MSH2).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of DNA mismatch repair protein Msh2 (MSH2).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of DNA mismatch repair protein Msh2 (MSH2).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of DNA mismatch repair protein Msh2 (MSH2).	[11]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of DNA mismatch repair protein Msh2 (MSH2).	[12]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of DNA mismatch repair protein Msh2 (MSH2).	[13]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of DNA mismatch repair protein Msh2 (MSH2).	[14]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of DNA mismatch repair protein Msh2 (MSH2).	[15]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of DNA mismatch repair protein Msh2 (MSH2).	[17]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of DNA mismatch repair protein Msh2 (MSH2).	[18]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of DNA mismatch repair protein Msh2 (MSH2).	[19]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of DNA mismatch repair protein Msh2 (MSH2).	[20]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of DNA mismatch repair protein Msh2 (MSH2).	[21]
Menadione	DMSJDTY	Approved	Menadione affects the expression of DNA mismatch repair protein Msh2 (MSH2).	[22]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of DNA mismatch repair protein Msh2 (MSH2).	[23]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of DNA mismatch repair protein Msh2 (MSH2).	[24]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of DNA mismatch repair protein Msh2 (MSH2).	[25]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of DNA mismatch repair protein Msh2 (MSH2).	[26]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of DNA mismatch repair protein Msh2 (MSH2).	[27]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of DNA mismatch repair protein Msh2 (MSH2).	[28]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of DNA mismatch repair protein Msh2 (MSH2).	[29]
Chlorpromazine	DMBGZI3	Phase 3 Trial	Chlorpromazine decreases the expression of DNA mismatch repair protein Msh2 (MSH2).	[30]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene increases the expression of DNA mismatch repair protein Msh2 (MSH2).	[32]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of DNA mismatch repair protein Msh2 (MSH2).	[33]
Arecoline	DMFJZK3	Phase 1	Arecoline decreases the expression of DNA mismatch repair protein Msh2 (MSH2).	[35]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of DNA mismatch repair protein Msh2 (MSH2).	[36]
Piperazinyl methyl quinazolinone derivative 2	DM913KS	Patented	Piperazinyl methyl quinazolinone derivative 2 increases the expression of DNA mismatch repair protein Msh2 (MSH2).	[37]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of DNA mismatch repair protein Msh2 (MSH2).	[39]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of DNA mismatch repair protein Msh2 (MSH2).	[40]
BRN-3548355	DM4KXT0	Investigative	BRN-3548355 decreases the expression of DNA mismatch repair protein Msh2 (MSH2).	[41]
OXYBENZONE	DMMZYX6	Investigative	OXYBENZONE increases the expression of DNA mismatch repair protein Msh2 (MSH2).	[42]

3 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of DNA mismatch repair protein Msh2 (MSH2).	[16]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of DNA mismatch repair protein Msh2 (MSH2).	[34]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of DNA mismatch repair protein Msh2 (MSH2).	[38]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of DNA mismatch repair protein Msh2 (MSH2).	[31]

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