Drugbank Logo

Showing drug card for Miconazole (DB01110)

Legend: drug field target field enzyme field

for drugs
Version 2.5
Creation Date 2005-06-13 13:24:05
Update Date 2009-06-23 18:06:00
Primary Accession Number DB01110
Secondary Accession Number
  • APRD01115
Name Miconazole
Drug Type
  • Approved
  • Investigational
  • Small Molecule
Description An imidazole antifungal agent that is used topically and by intravenous infusion. [PubChem]
Synonyms
  1. MCZ
  2. miconazole
Brand Names
  1. Daktarin
  2. Femizol-M
  3. M-zole 3 Combination Pack
  4. M-zole 7 Dual Pack
  5. Micatin
  6. Miconazole 3
  7. Miconazole 3 Combination Pack
  8. Miconazole 7
  9. Miconazole 7 Combination Pack
  10. Miconazole Nitrate
  11. Miconazole Nitrate Combination Pack
  12. Miconazole-7
  13. Micozole
  14. Minostate
  15. Monazole 7
  16. Monistat
  17. Monistat 1 Combination Pack
  18. Monistat 3
  19. Monistat 3 Combination Pack
  20. Monistat 3 Dual-Pak
  21. Monistat 3 Vaginal Ovules
  22. Monistat 5
  23. Monistat 5 Tampon
  24. Monistat 7
  25. Monistat 7 Combination Pack
  26. Monistat 7 Dual-Pak
  27. Monistat 7 Vaginal Suppositories
  28. Monistat Dual- PAK
  29. Monistat IV
  30. Monistat-3 Combination Pack
  31. Monistat-Derm
  32. Novo-Miconazole Vaginal Ovules
  33. Vusion
  34. Zimycan
Brand Mixtures Not Available
Chemical IUPAC Name 1-[2-(2,4-dichlorophenyl)-2-[(2,4-dichlorophenyl)methoxy]ethyl]imidazole
Chemical Formula C18H14Cl4N2O
Chemical Structure Structure
CAS Registry Number 22916-47-8
InChI Identifier InChI=1/C18H14Cl4N2O/c19-13-2-1-12(16(21)7-13)10-25-18(9-24-6-5-23-11-24)15-4-3-14(20)8-17(15)22/h1-8,11,18H,9-10H2
InChI Key BYBLEWFAAKGYCD-UHFFFAOYAA
KEGG Drug D00882 Link Image
KEGG Compound C08070 Link Image
PubChem Compound 4189 Link Image
PubChem Substance 602748 Link Image
ChEBI ID Not Available
PharmGKB ID PA450494 Link Image
HET ID Not Available
GenBank ID Not Available
Drug ID Number [DIN] 02245546 Link Image
RxList Link http://www.rxlist.com/cgi/generic2/micon.htm Link Image
PDRhealth Link http://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/mon1273.shtml Link Image
Wikipedia Link http://en.wikipedia.org/wiki/Miconazole Link Image
FDA Label
Material Safety Data Sheet (MSDS)
Synthesis Reference Not Available
Average Molecular Weight 416.1290
Monoisotopic Molecular Weight 413.9860
State Solid
Melting Point 159 - 163 oC
Experimental Water Solubility 1g/100mL (20°C) Source: PhysProp
Predicted Water Solubility 7.63e-04 mg/mL Calculated using ALOGPS
Experimental LogP/Hydrophobicity 6.1 Source: PhysProp
Predicted LogP 5.86 Calculated using ALOGPS
Experimental LogS Not Available
Predicted LogS -5.74 Calculated using ALOGPS
Experimental Caco2 Permeability Not Available
pKa/Isoelectric Point Not Available
Mass Spectrum Not Available
MOL File Show Link Image | Download Link Image
SDF File Show Link Image | Download Link Image
PDB File Show Link Image | Download Link Image
2D Structure
3D Structure
Experimental PDB ID Not Available
Isomeric SMILES ClC1=CC(Cl)=C(CO[C@@H](CN2C=CN=C2)C2=C(Cl)C=C(Cl)C=C2)C=C1
Canonical SMILES ClC1=CC(Cl)=C(COC(CN2C=CN=C2)C2=C(Cl)C=C(Cl)C=C2)C=C1
Drug Category
  • Antifungal Agents
ATC Codes
AHFS Codes
  • 84:04.08.08
Indication For topical application in the treatment of tinea pedis (athlete’s foot), tinea cruris, and tinea corporis caused by Trichophyton rubrum, Trichophyton mentagrophytes, and Epidermophyton floccosum, in the treatment of cutaneous candidiasis (moniliasis), and in the treatment of tinea versicolor.
Pharmacology Miconazole is an anti-fungal medication related to fluconazole (Diflucan), ketoconazole (Nizoral), itraconazole (Sporanox), and clotrimazole (Lotrimin, Mycelex). It is used either on the skin or in the vagina for fungal infections. Miconazole was approved by the FDA in 1974. Miconazole prevents fungal organisms from producing vital substances required for growth and function. This medication is effective only for infections caused by fungal organisms. It will not work for bacterial or viral infections.
Mechanism of Action Miconazole interacts with 14-α demethylase, a cytochrome P-450 enzyme necessary to convert lanosterol to ergosterol. As ergosterol is an essential component of the fungal cell membrane, inhibition of its synthesis results in increased cellular permeability causing leakage of cellular contents. Miconazole may also inhibit endogenous respiration, interact with membrane phospholipids, inhibit the transformation of yeasts to mycelial forms, inhibit purine uptake, and impair triglyceride and/or phospholipid biosynthesis.
Absorption Not Available
Toxicity Oral, mouse: LD50 = 3800 mg/kg; Oral, rat: LD50 = 3 gm/kg. Ingestion of the amounts of the components contained in a tube of cream are unlikely to produce overdosage and toxic effects.
Protein Binding Not Available
Biotransformation Not Available
Half Life Not Available
Dosage Forms
Form Route
Aerosol Topical
Cream Intravaginal
Cream Topical
Suppository Intravaginal
Patient Information Not Available
Contraindications Show Link Image
Interactions Not Available
Drug Interactions
Drug Interaction
Acenocoumarol Vaginal miconazole increases the anticoagulant effect
Anisindione Vaginal miconazole increases the anticoagulant effect
Dicumarol Vaginal miconazole increases the anticoagulant effect
Warfarin Vaginal miconazole increases the anticoagulant effect
Food Interactions Not Available
Pathways Not Available
General References
  1. Wikipedia Link Image
  2. RxList Link Image
  3. PDRhealth Link Image
Organisms Affected
  • Fungi, yeast and protozoans
Phase 1 Metabolizing Enzymes
  1. Cytochrome P450 2C9 (CYP2C9)
  2. Cytochrome P450 2D6 (CYP2D6)
Targets
  1. Calcium-transporting ATPase type 2C member 1
  2. Calmodulin
  3. Cytochrome P450 51
  4. Cytochrome P450 51A1
Phase 1 Metabolizing Enzyme 1 [top]
Enzyme 1 Name Cytochrome P450 2C9 (CYP2C9)
Enzyme 1 Gene Name CYP2C9
Enzyme 1 SwissProt ID P11712 Link Image
Enzyme 1 SNPs SNPJam Report Link Image
Enzyme 1 Protein Sequence >sp|P11712|CP2C9_HUMAN Cytochrome P450 2C9 (EC 1.14.13.80) 
MDSLVVLVLCLSCLLLLSLWRQSSGRGKLPPGPTPLPVIGNILQIGIKDISKSLTNLSKV
YGPVFTLYFGLKPIVVLHGYEAVKEALIDLGEEFSGRGIFPLAERANRGFGIVFSNGKKW
KEIRRFSLMTLRNFGMGKRSIEDRVQEEARCLVEELRKTKASPCDPTFILGCAPCNVICS
IIFHKRFDYKDQQFLNLMEKLNENIKILSSPWIQICNNFSPIIDYFPGTHNKLLKNVAFM
KSYILEKVKEHQESMDMNNPQDFIDCFLMKMEKEKHNQPSEFTIESLENTAVDLFGAGTE
TTSTTLRYALLLLLKHPEVTAKVQEEIERVIGRNRSPCMQDRSHMPYTDAVVHEVQRYID
LLPTSLPHAVTCDIKFRNYLIPKGTTILISLTSVLHDNKEFPNPEMFDPHHFLDEGGNFK
KSKYFMPFSAGKRICVGEALAGMELFLFLTSILQNFNLKSLVDPKNLDTTPVVNGFASVP
PFYQLCFIPV
Phase 1 Metabolizing Enzyme 2 [top]
Enzyme 2 Name Cytochrome P450 2D6 (CYP2D6)
Enzyme 2 Gene Name CYP2D6
Enzyme 2 SwissProt ID P10635 Link Image
Enzyme 2 SNPs SNPJam Report Link Image
Enzyme 2 Protein Sequence >sp|P10635|CP2D6_HUMAN Cytochrome P450 2D6 (EC 1.14.14.1) 
MGLEALVPLAVIVAIFLLLVDLMHRRQRWAARYPPGPLPLPGLGNLLHVDFQNTPYCFDQ
LRRRFGDVFSLQLAWTPVVVLNGLAAVREALVTHGEDTADRPPVPITQILGFGPRSQGVF
LARYGPAWREQRRFSVSTLRNLGLGKKSLEQWVTEEAACLCAAFANHSGRPFRPNGLLDK
AVSNVIASLTCGRRFEYDDPRFLRLLDLAQEGLKEESGFLREVLNAVPVLLHIPALAGKV
LRFQKAFLTQLDELLTEHRMTWDPAQPPRDLTEAFLAEMEKAKGNPESSFNDENLRIVVA
DLFSAGMVTTSTTLAWGLLLMILHPDVQRRVQQEIDDVIGQVRRPEMGDQAHMPYTTAVI
HEVQRFGDIVPLGMTHMTSRDIEVQGFRIPKGTTLITNLSSVLKDEAVWEKPFRFHPEHF
LDAQGHFVKPEAFLPFSAGRRACLGEPLARMELFLFFTSLLQHFSFSVPTGQPRPSHHGV
FAFLVSPSPYELCAVPR
Drug Target 1 [top]
Target 1 ID 241
Target 1 Name Calcium-transporting ATPase type 2C member 1
Target 1 Synonyms
  1. ATP-dependent Ca(2+
  2. ATPase 2C1
  3. EC 3.6.3.8
Target 1 Gene Name ATP2C1
Target 1 Protein Sequence >Calcium-transporting ATPase type 2C member 1 
MKVARFQKIPNGENETMIPVLTSKKASELPVSEVASILQADLQNGLNKCEVSHRRAFHGW
NEFDISEDEPLWKKYISQFKNPLIMLLLASAVISVLMHQFDDAVSITVAILIVVTVAFVQ
EYRSEKSLEELSKLVPPECHCVREGKLEHTLARDLVPGDTVCLSVGDRVPADLRLFEAVD
LSIDESSLTGETTPCSKVTAPQPAATNGDLASRSNIAFMGTLVRCGKAKGVVIGTGENSE
FGEVFKMMQAEEAPKTPLQKSMDLLGKQLSFYSFGIIGIIMLVGWLLGKDILEMFTISVS
LAVAAIPEGLPIVVTVTLALGVMRMVKKRAIVKKLPIVETLGCCNVICSDKTGTLTKNEM
TVTHIFTSDGLHAEVTGVGYNQFGEVIVDGDVVHGFYNPAVSRIVEAGCVCNDAVIRNNT
LMGKPTEGALIALAMKMGLDGLQQDYIRKAEYPFSSEQKWMAVKCVHRTQQDRPEICFMK
GAYEQVIKYCTTYQSKGQTLTLTQQQRDVYQQEKARMGSAGLRVLALASGPELGQLTFLG
LVGIIDPPRTGVKEAVTTLIASGVSIKMITGDSQETAVAIASRLGLYSKTSQSVSGEEID
AMDVQQLSQIVPKVAVFYRASPRHKMKIIKSLQKNGSVVAMTGDGVNDAVALKAADIGVA
MGQTGTDVCKEAADMILVDDDFQTIMSAIEEGKGIYNNIKNFVRFQLSTSIAALTLISLA
TLMNFPNPLNAMQILWINIIMDGPPAQSLGVEPVDKDVIRKPPRNWKDSILTKNLILKIL
VSSIIIVCGTLFVFWRELRDNVITPRDTTMTFTCFVFFDMFNALSSRSQTKSVFEIGLCS
NRMFCYAVLGSIMGQLLVIYFPPLQKVFQTESLSILDLLFLLGLTSSVCIVAEIIKKVER
SREKIQKHVSSTSSSFLEV
Target 1 Number of Residues 934
Target 1 Molecular Weight 100579
Target 1 Theoretical pI 6.72
Target 1 GO Classification
Function
hydrolase activity
hydrolase activity, acting on acid anhydrides
hydrolase activity, acting on acid anhydrides, catalyzing transmembrane movement of substances
catalytic activity
ATPase activity, coupled to transmembrane movement of ions, phosphorylative mechanism
binding
nucleotide binding
purine nucleotide binding
adenyl nucleotide binding
ATP binding
transporter activity
ion transporter activity
cation transporter activity
di-, tri-valent inorganic cation transporter activity
calcium ion transporter activity
calcium-transporting ATPase activity
Process
metabolism
physiological process
cellular physiological process
transport
ion transport
cation transport
di-, tri-valent inorganic cation transport
calcium ion transport
Component
cell
membrane
intrinsic to membrane
integral to membrane
Target 1 General Function Inorganic ion transport and metabolism
Target 1 Specific Function This magnesium-dependent enzyme catalyzes the hydrolysis of ATP coupled with the transport of the calcium
Target 1 Pathways Not Available
Target 1 Reactions
  • ATP + H2O + Ca2+cis = ADP + phosphate + Ca2+trans
Target 1 Pfam Domain Function
Target 1 Signals
  • None
Target 1 Transmembrane Regions
  • 71-91
  • 105-123
  • 263-282
  • 295-312
  • 700-719
  • 730-750
  • 771-793
  • 809-828
  • 842-860
  • 876-896
Target 1 Essentiality Non-Essential
Target 1 GenBank ID Protein 6715131 Link Image
Target 1 UniProtKB/Swiss-Prot ID P98194 Link Image
Target 1 UniProtKB/Swiss-Prot Entry Name AT2C1_HUMAN Link Image
Target 1 PDB ID Not Available
Target 1 Cellular Location
  • Golgi apparatus
  • Golgi apparatus membrane
  • multi-pass membrane protein
Target 1 Gene Sequence >2760 bp 
ATGAAGGTTGCACGTTTTCAAAAAATACCTAATGGTGAAAATGAGACAATGATTCCTGTA
TTGACATCAAAAAAAGCAAGTGAATTACCAGTCAGTGAAGTTGCAAGCATTCTCCAAGCT
GATCTTCAGAATGGTCTAAACAAATGTGAAGTTAGTCATAGGCGAGCCTTTCATGGCTGG
AATAAGTTTGATATTAGTGAAGATGAGCCACTGTGGAAGAAGTATATTTCTCAGTTTAAA
AATCCCCTTATTATGCTGCTTCTGGCTTCTGCAGTCATCAGTGTTTTAATGCATCAGTTT
GATGATGCCGTCAGTATCACTGTGGCAATACTTATCGTTGTTACAGTTGCCTTTGTTCAG
GAATATCGTTCAGAAAAATCTCTTGAAGAATTGAGTAAACTTGTGCCACCAGAATGCCAT
TGTGTGCGTGAAGGAAAATTGGAGCATACACTTGCCCGAGACTTGGTTCCAGGTGATACA
GTTTGCCTTTCTGTTGGGGATAGAGTTCCTGCTGACTTACGCTTGTTTGAGGCTGTGGAT
CTTTCCATTGATGAGTCCAGCTTGACAGGTGAGACAACGCCTTGTTCTAAGGTGACAGCT
CCTCAGCCAGCTGCAACTAATGGAGATCTTGCATCGAGAAGTAACATTGCCTTTATGGGA
ACACTGGTCAGATGTGGCAAAGCAAAGGGTGTTGTCATTGGAACAGGAGAAAATTCTGAA
TTTGGGGAGGTTTTTAAAATGATGCAAGCAGAAGAGGCACCAAAAACCCCTCTGCAGAAG
AGCATGGACCTCTTAGGAAAACAACTTTCCTTTTACTCCTTTGGTATAATAGGAATCATC
ATGTTGGTTGGCTGGTTACTGGGAAAAGATATCCTGGAAATGTTTACTATTAGTGTAAGT
TTGGCTGTAGCAGCAATTCCTGAAGGTCTCCCCATTGTGGTCACAGTGACGCTAGCTCTT
GGTGTTATGAGAATGGTGAAGAAAAGGGCCATTGTGAAAAAGCTGCCTATTGTTGAAACT
CTGGGCTGCTGTAATGTGATTTGTTCAGATAAAACTGGAACACTGACGAAGAATGAAATG
ACTGTTACTCACATATTTACTTCAGATGGTCTGCATACTGAGGTTACTGGAGTTGGCTAT
AATCAATTTGGGGAAGTGATTGTTGATGGTGATGTTGTTCATGGATTCTATAACCCAGCT
GTTAGCAGAATTGTTGAGGCGGGCTGTGTGTGCAATGATGCTGTAATTAGAAACAATACT
CTAATGGGGAAGCCAACAGAAGGGGCCTTAATTGCTCTTGCAATGAAGATGGGTCTTGAT
GGACTTCAACAAGACTACATCAGAAAAGCTGAATACCCTTTTAGCTCTGAGCAAAAGTGG
ATGGCTGTTAAGTGTGTACACCGAACACAGCAGGACAGACCAGAGATTTGTTTTATGAAA
GGTGCTTACGAACAAGTAATTAAGTACTGTACTACATACCAGAGCAAAGGGCAGACCTTG
ACACTTACTCAGCAGCAGAGAGATGTGTACCAACAAGAGAAGGCACGCATGGGCTCAGCG
GGACTCAGAGTTCTTGCTTTGGCTTCTGGTCCTGAACTGGGACAGCTGACATTTCTTGGC
TTGGTGGGAATCATTGATCCACCTAGAACTGGTGTGAAAGAAGCTGTTACAACACTCATT
GCCTCAGGAGTATCAATAAAAATGATTACTGGAGATTCACAGGAGACTGCAGTTGCAATC
GCCAGTCGTCTGGGATTGTATTCCAAAACTTCCCAGTCAGTCTCAGGAGAAGAAATAGAT
GCAATGGATGTTCAGCAGCTTTCACAAATAGTACCAAAGGTTGCAGTATTTTACAGAGCT
AGCCCAAGGCACAAGATGAAAATTATTAAGTCGCTACAGAAGAACGGTTCAGTTGTAGCC
ATGACAGGAGATGGAGTAAATGATGCAGTTGCTCTGAAGGCTGCAGACATTGGAGTTGCG
ATGGGCCAGACTGGTACAGATGTTTGCAAAGAGGCAGCAGACATGATCCTAGTGGATGAT
GATTTTCAAACCATAATGTCTGCAATCGAAGAGGGTAAAGGGATTTATAATAACATTAAA
AATTTCGTTAGATTCCAGCTGAGCACGAGTATAGCAGCATTAACTTTAATCTCATTGGCT
ACATTAATGAACTTTCCTAATCCTCTCAATGCCATGCAGATTTTGTGGATCAATATTATT
ATGGATGGACCCCCAGCTCAGAGCCTTGGAGTAGAACCAGTGGATAAAGATGTCATTCGT
AAACCTCCTCGCAACTGGAAAGACAGCATTTTGACTAAAAACTTGATACTTAAAATACTT
GTTTCATCAATAATCATTGTTTGTGGGACTTTGTTTGTCTTCTGGCGTGAGCTACGAGAC
AATGTGATTACACCTCGAGACACAACAATGACCTTCACATGCTTTGTGTTTTTTGACATG
TTCAATGCACTAAGTTCCAGATCCCAGACCAAGTCTGTGTTTGAGATTGGACTCTGCAGT
AATAGAATGTTTTGCTATGCAGTTCTTGGATCCATCATGGGACAATTACTAGTTATTTAC
TTTCCTCCGCTTCAGAAGGTTTTTCAGACTGAGAGCCTAAGCATACTGGATCTGTTGTTT
CTTTTGGGTCTCACCTCATCAGTGTGCATAGTGGCAGAAATTATAAAGAAGGTTGAAAGG
AGCAGGGAAAAGATCCAGAAGCATGTTAGTTCGACATCATCATCTTTTCTTGAAGTATGA
Target 1 GenBank Gene ID
Target 1 GeneCard ID ATP2C1 Link Image
Target 1 GenAtlas ID ATP2C1 Link Image
Target 1 HGNC ID HGNC:13211 Link Image
Target 1 Chromosome Location 3
Target 1 Locus 3q22.1
Target 1 SNPs SNPJam Report Link Image
Target 1 General References
  1. Hu Z, Bonifas JM, Beech J, Bench G, Shigihara T, Ogawa H, Ikeda S, Mauro T, Epstein EH Jr: Mutations in ATP2C1, encoding a calcium pump, cause Hailey-Hailey disease. Nat Genet. 2000 Jan;24(1):61-5. [PubMed Link Image]
  2. Nagase T, Kikuno R, Ishikawa KI, Hirosawa M, Ohara O: Prediction of the coding sequences of unidentified human genes. XVI. The complete sequences of 150 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 2000 Feb 28;7(1):65-73. [PubMed Link Image]
  3. Sudbrak R, Brown J, Dobson-Stone C, Carter S, Ramser J, White J, Healy E, Dissanayake M, Larregue M, Perrussel M, Lehrach H, Munro CS, Strachan T, Burge S, Hovnanian A, Monaco AP: Hailey-Hailey disease is caused by mutations in ATP2C1 encoding a novel Ca(2+) pump. Hum Mol Genet. 2000 Apr 12;9(7):1131-40. [PubMed Link Image]
  4. Stanchi F, Bertocco E, Toppo S, Dioguardi R, Simionati B, Cannata N, Zimbello R, Lanfranchi G, Valle G: Characterization of 16 novel human genes showing high similarity to yeast sequences. Yeast. 2001 Jan 15;18(1):69-80. [PubMed Link Image]
  5. Fairclough RJ, Dode L, Vanoevelen J, Andersen JP, Missiaen L, Raeymaekers L, Wuytack F, Hovnanian A: Effect of Hailey-Hailey Disease mutations on the function of a new variant of human secretory pathway Ca2+/Mn2+-ATPase (hSPCA1). J Biol Chem. 2003 Jul 4;278(27):24721-30. Epub 2003 Apr 21. [PubMed Link Image]
Target 1 Drug References
  1. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [PubMed Link Image]
  2. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed Link Image]
Drug Target 2 [top]
Target 2 ID 465
Target 2 Name Calmodulin
Target 2 Synonyms
  1. CaM
Target 2 Gene Name CALM1
Target 2 Protein Sequence >Calmodulin 
ADQLTEEQIAEFKEAFSLFDKDGDGTITTKELGTVMRSLGQNPTEAELQDMINEVDADGN
GTIDFPEFLTMMARKMKDTDSEEEIREAFRVFDKDGNGYISAAELRHVMTNLGEKLTDEE
VDEMIREADIDGDGQVNYEEFVQMMTAK
Target 2 Number of Residues 150
Target 2 Molecular Weight 16707
Target 2 Theoretical pI 3.84
Target 2 GO Classification
Function
binding
ion binding
cation binding
calcium ion binding
Process
Not Available
Component
Not Available
Target 2 General Function Involved in calcium ion binding
Target 2 Specific Function Calmodulin mediates the control of a large number of enzymes and other proteins by Ca(2+). Among the enzymes to be stimulated by the calmodulin-Ca(2+) complex are a number of protein kinases and phosphatases
Target 2 Pathways Not Available
Target 2 Reactions Not Available
Target 2 Pfam Domain Function
Target 2 Signals
  • None
Target 2 Transmembrane Regions
  • None
Target 2 Essentiality Non-Essential
Target 2 GenBank ID Protein 179888 Link Image
Target 2 UniProtKB/Swiss-Prot ID P62158 Link Image
Target 2 UniProtKB/Swiss-Prot Entry Name CALM_HUMAN Link Image
Target 2 PDB ID 1IQ5 Link Image
Target 2 PDB File Show
Target 2 3D Structure
Target 2 Cellular Location Not Available
Target 2 Gene Sequence >450 bp 
ATGGCTGACCAGCTGACTGAGGAGCAGATTGCAGAGTTCAAGGAGGCCTTCTCCCTCTTT
GACAAGGATGGAGATGGCACTATCACCACCAAGGAGTTGGGGACAGTGATGAGATCCCTG
GGACAGAACCCCACTGAAGCAGAGCTGCAGGATATGATCAATGAGGTGGATGCAGATGGG
AACGGGACCATTGACTTCCCGGAGTTCCTGACCATGATGGCCAGAAAGATGAAGGACACA
GACAGTGAGGAGGAGATCCGAGAGGCGTTCCGTGTCTTTGACAAGGATGGGAATGGCTAC
ATCAGCGCCGCAGAGCTGCGTCACGTAATGACGAACCTGGGGGAGAAGCTGACCGATGAG
GAGGTGGATGAGATGATCAGGGAGGCTGACATCGATGGAGATGGCCAGGTCAATTATGAA
GAGTTTGTACAGATGATGACTGCAAAGTGA
Target 2 GenBank Gene ID
Target 2 GeneCard ID CALM1 Link Image
Target 2 GenAtlas ID CALM1 Link Image
Target 2 HGNC ID HGNC:1442 Link Image
Target 2 Chromosome Location 14
Target 2 Locus 14q24-q31
Target 2 SNPs SNPJam Report Link Image
Target 2 General References
  1. Drum CL, Yan SZ, Bard J, Shen YQ, Lu D, Soelaiman S, Grabarek Z, Bohm A, Tang WJ: Structural basis for the activation of anthrax adenylyl cyclase exotoxin by calmodulin. Nature. 2002 Jan 24;415(6870):396-402. [PubMed Link Image]
  2. Heilig R, Eckenberg R, Petit JL, Fonknechten N, Da Silva C, Cattolico L, Levy M, Barbe V, de Berardinis V, Ureta-Vidal A, Pelletier E, Vico V, Anthouard V, Rowen L, Madan A, Qin S, Sun H, Du H, Pepin K, Artiguenave F, Robert C, Cruaud C, Bruls T, Jaillon O, Friedlander L, Samson G, Brottier P, Cure S, Segurens B, Aniere F, Samain S, Crespeau H, Abbasi N, Aiach N, Boscus D, Dickhoff R, Dors M, Dubois I, Friedman C, Gouyvenoux M, James R, Madan A, Mairey-Estrada B, Mangenot S, Martins N, Menard M, Oztas S, Ratcliffe A, Shaffer T, Trask B, Vacherie B, Bellemere C, Belser C, Besnard-Gonnet M, Bartol-Mavel D, Boutard M, Briez-Silla S, Combette S, Dufosse-Laurent V, Ferron C, Lechaplais C, Louesse C, Muselet D, Magdelenat G, Pateau E, Petit E, Sirvain-Trukniewicz P, Trybou A, Vega-Czarny N, Bataille E, Bluet E, Bordelais I, Dubois M, Dumont C, Guerin T, Haffray S, Hammadi R, Muanga J, Pellouin V, Robert D, Wunderle E, Gauguet G, Roy A, Sainte-Marthe L, Verdier J, Verdier-Discala C, Hillier L, Fulton L, McPherson J, Matsuda F, Wilson R, Scarpelli C, Gyapay G, Wincker P, Saurin W, Quetier F, Waterston R, Hood L, Weissenbach J: The DNA sequence and analysis of human chromosome 14. Nature. 2003 Feb 6;421(6923):601-7. Epub 2003 Jan 1. [PubMed Link Image]
  3. Koller M, Schnyder B, Strehler EE: Structural organization of the human CaMIII calmodulin gene. Biochim Biophys Acta. 1990 Oct 23;1087(2):180-9. [PubMed Link Image]
  4. SenGupta B, Friedberg F, Detera-Wadleigh SD: Molecular analysis of human and rat calmodulin complementary DNA clones. Evidence for additional active genes in these species. J Biol Chem. 1987 Dec 5;262(34):16663-70. [PubMed Link Image]
  5. Fischer R, Koller M, Flura M, Mathews S, Strehler-Page MA, Krebs J, Penniston JT, Carafoli E, Strehler EE: Multiple divergent mRNAs code for a single human calmodulin. J Biol Chem. 1988 Nov 15;263(32):17055-62. [PubMed Link Image]
  6. Wawrzynczak EJ, Perham RN: Isolation and nucleotide sequence of a cDNA encoding human calmodulin. Biochem Int. 1984 Aug;9(2):177-85. [PubMed Link Image]
  7. Sasagawa T, Ericsson LH, Walsh KA, Schreiber WE, Fischer EH, Titani K: Complete amino acid sequence of human brain calmodulin. Biochemistry. 1982 May 11;21(10):2565-9. [PubMed Link Image]
  8. Rhyner JA, Ottiger M, Wicki R, Greenwood TM, Strehler EE: Structure of the human CALM1 calmodulin gene and identification of two CALM1-related pseudogenes CALM1P1 and CALM1P2. Eur J Biochem. 1994 Oct 1;225(1):71-82. [PubMed Link Image]
  9. Toutenhoofd SL, Foletti D, Wicki R, Rhyner JA, Garcia F, Tolon R, Strehler EE: Characterization of the human CALM2 calmodulin gene and comparison of the transcriptional activity of CALM1, CALM2 and CALM3. Cell Calcium. 1998 May;23(5):323-38. [PubMed Link Image]
Target 2 Drug References
  1. Louis CF, Turnquist J, Jarvis B: Inhibition of calmodulin-dependent and independent cardiac sarcoplasmic reticulum activities by R24571. Cell Calcium. 1983 Apr;4(2):107-16. [PubMed Link Image]
  2. Wolff DJ, Datto GA, Samatovicz RA: The dual mode of inhibition of calmodulin-dependent nitric-oxide synthase by antifungal imidazole agents. J Biol Chem. 1993 May 5;268(13):9430-6. [PubMed Link Image]
Drug Target 3 [top]
Target 3 ID 761
Target 3 Name Cytochrome P450 51
Target 3 Synonyms
  1. CYPLI
  2. EC 1.14.13.70
  3. Lanosterol 14-alpha demethylase
  4. P450-14DM
  5. P450-LIA1
  6. Sterol 14- alpha-demethylase
Target 3 Gene Name ERG11
Target 3 Protein Sequence >Cytochrome P450 51 
MSTENTSLVVELLEYVKLGLSYFQALPLAQRVSIMVALPFVYTITWQLLYSLRKDRPPLV
FYWIPWVGSAIPYGTKPYEFFEDCQKKYGDIFSFMLLGRIMTVYLGPKGHEFIFNAKLAD
VSAEAAYSHLTTPVFGKGVIYDCPNHRLMEQKKFVKGALTKEAFVRYVPLIAEEIYKYFR
NSKNFKINENNSGIVDVMVSQPEMTIFTASRSLLGKEMRDKLDTDFAYLYSDLDKGFTPI
NFVFPNLPLEHYRKRDHAQQAISGTYMSLIKERREKNDIQNRDLIDELMKNSTYKDGTKM
TDQEIANLLIGVLMGGQHTSAATSAWCLLHLAERPDVQEELYQEQMRVLNNDTKELTYDD
LQNMPLLNQMIKETLRLHHPLHSLFRKVMRDVAIPNTSYVVPRDYHVLVSPGYTHLQEEF
FPKPNEFNIHRWDGDAASSSAAGGDEVDYGFGAISKGVSSPYLPFGGGRHRCIGELFAYC
QLGVLMSIFIRTMKWRYPTEGETVPPSDFTSMVTLPTAPAKIYWEKRHPEQKY
Target 3 Number of Residues 541
Target 3 Molecular Weight 61306
Target 3 Theoretical pI 7.07
Target 3 GO Classification
Function
tetrapyrrole binding
heme binding
binding
ion binding
cation binding
transition metal ion binding
iron ion binding
catalytic activity
oxidoreductase activity
monooxygenase activity
Process
physiological process
metabolism
cellular metabolism
generation of precursor metabolites and energy
electron transport
Component
Not Available
Target 3 General Function Secondary metabolites biosynthesis, transport and catabolism
Target 3 Specific Function Catalyzes C14-demethylation of lanosterol which is critical for ergosterol biosynthesis. It transforms lanosterol into 4,4'-dimethyl cholesta-8,14,24-triene-3-beta-ol
Target 3 Pathways Not Available
Target 3 Reactions
  • obtusifoliol + 3 O2 + 3 NADPH + 3 H+ = 4alpha-methyl-5alpha-ergosta-8,14,24(28)-trien-3beta-ol + formate + 3 NADP+ + 4 H2O
Target 3 Pfam Domain Function
Target 3 Signals
  • None
Target 3 Transmembrane Regions
  • None
Target 3 Essentiality Essential
Target 3 GenBank ID Protein 755693 Link Image
Target 3 UniProtKB/Swiss-Prot ID P50859 Link Image
Target 3 UniProtKB/Swiss-Prot Entry Name CP51_CANGA Link Image
Target 3 PDB ID Not Available
Target 3 Cellular Location Not Available
Target 3 Gene Sequence >1602 bp 
ATGTCCACTGAAAACACTTCTTTGGTCGTTGAACTATTGGAGTACGTGAAGCTTGGTCTT
TCGTACTTCCAAGCTCTGCCATTGGCGCAGAGAGTGTCTATTATGGTCGCCTTGCCATTT
GTGTACACCATCACATGGCAATTGCTTTACTCCTTGAGAAAGGACAGACCACCACTTGTG
TTCTACTGGATCCCATGGGTCGGCTCTGCTATCCCATACGGTACCAAGCCATACGAGTTC
TTCGAAGACTGCCAAAAGAAATACGGTGATATCTTCTCTTTCATGCTATTGGGTAGAATT
ATGACTGTCTACTTGGGTCCAAAGGGTCACGAATTCATCTTCAACGCCAAGTTGGCCGAT
GTTTCCGCTGAAGCTGCTTACTCCCACTTGACCACCCCAGTGTTCGGTAAAGGTGTTATC
TACGATTGTCCAAACCACAGACTAATGGAACAAAAGAAGTTTGTCAAGGGTGCTTTGACT
AAGGAAGCCTTTGTCAGATACGTTCCATTGATCGCTGAGGAAATCTACAAGTACTTCAGA
AACTCCAAGAACTTCAAGATCAACGAAAACAACTCCGGTATCGTCGACGTTATGGTCTCC
CAACCTGAAATGACTATCTTCACTGCTTCCAGATCCTTGCTAGGTAAGGAAATGAGAGAC
AAGTTGGACACCGACTTCGCTTACTTGTACAGTGACTTGGACAAGGGTTTCACCCCAATT
AACTTCGTCTTCCCTAACTTGCCTCTAGAACACTACAGAAAGAGAGATCATGCCCAACAA
GCTATCTCTGGTACTTACATGTCCTTGATTAAGGAAAGACGTGAGAAGAACGATATCCAA
AACCGTGACTTGATTGATGAATTGATGAAGAACTCCACTTACAAGGATGGTACTAAGATG
ACCGACCAAGAAATTGCCAACCTATTGATTGGTGTCTTGATGGGTGGTCAACATACTTCC
GCTGCTACCTCCGCTTGGTGTCTATTGCATTTGGCTGAAAGACCAGATGTCCAAGAAGAA
TTATACCAAGAACAAATGCGCGTCTTGAACAACGATACCAAGGAATTGACTTACGATGAC
CTACAAAACATGCCTCTATTGAACCAAATGATCAAGGAAACTTTGAGATTGCACCACCCA
TTGCACTCTTTGTTCCGTAAAGTCATGAGAGATGTCGCTATTCCAAACACTTCCTACGTT
GTCCCAAGGGACTACCACGTTCTAGTCTCCCCAGGTTACACTCACTTGCAAGAAGAATTC
TTCCCTAAGCCAAATGAATTCAACATCCACCGTTGGGACGGTGATGCTGCTTCTTCCAGT
GCTGCTGGTGGTGACGAAGTTGATTACGGTTTCGGTGCTATCTCCAAGGGTGTTTCCTCT
CCATACTTGCCATTCGGTGGTGGTAGACACAGATGTATCGGTGAATTGTTCGCTTACTGT
CAATTGGGTGTGTTGATGTCCATTTTCATCAGAACCATGAAATGGCGTTACCCAACTGAA
GGTGAAACTGTCCCACCATCTGACTTCACCTCCATGGTCACCCTACCAACTGCCCCTGCT
AAGATCTACTGGGAAAAGAGACATCCAGAACAAAAGTACTAG
Target 3 GenBank Gene ID
Target 3 GeneCard ID Not Available
Target 3 GenAtlas ID Not Available
Target 3 HGNC ID Not Available
Target 3 Chromosome Location Not Available
Target 3 Locus Not Available
Target 3 SNPs SNPJam Report Link Image
Target 3 General References
  1. Burgener-Kairuz P, Zuber JP, Jaunin P, Buchman TG, Bille J, Rossier M: Rapid detection and identification of Candida albicans and Torulopsis (Candida) glabrata in clinical specimens by species-specific nested PCR amplification of a cytochrome P-450 lanosterol-alpha-demethylase (L1A1) gene fragment. J Clin Microbiol. 1994 Aug;32(8):1902-7. [PubMed Link Image]
  2. Geber A, Hitchcock CA, Swartz JE, Pullen FS, Marsden KE, Kwon-Chung KJ, Bennett JE: Deletion of the Candida glabrata ERG3 and ERG11 genes: effect on cell viability, cell growth, sterol composition, and antifungal susceptibility. Antimicrob Agents Chemother. 1995 Dec;39(12):2708-17. [PubMed Link Image]
Target 3 Drug References
  1. Henry KW, Nickels JT, Edlind TD: Upregulation of ERG genes in Candida species by azoles and other sterol biosynthesis inhibitors. Antimicrob Agents Chemother. 2000 Oct;44(10):2693-700. [PubMed Link Image]
  2. Edlind T, Smith L, Henry K, Katiyar S, Nickels J: Antifungal activity in Saccharomyces cerevisiae is modulated by calcium signalling. Mol Microbiol. 2002 Oct;46(1):257-68. [PubMed Link Image]
  3. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [PubMed Link Image]
  4. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed Link Image]
  5. Raucy JL, Carpenter SJ, Trzaskos JM: Identification of lanosterol 14 alpha-methyl demethylase in human tissues. Biochem Biophys Res Commun. 1991 May 31;177(1):497-503. [PubMed Link Image]
Drug Target 4 [top]
Target 4 ID 1010
Target 4 Name Cytochrome P450 51A1
Target 4 Synonyms
  1. CYPLI
  2. EC 1.14.13.70
  3. LDM
  4. Lanosterol 14-alpha demethylase
  5. P450-14DM
  6. P45014DM
  7. P450LI
  8. Sterol 14-alpha demethylase
Target 4 Gene Name CYP51A1
Target 4 Protein Sequence >Cytochrome P450 51A1 
MLLLGLLQAGGSVLGQAMEKVTGGNLLSMLLIACAFTLSLVYLIRLAAGHLVQLPAGVKS
PPYIFSPIPFLGHAIAFGKSPIEFLENAYEKYGPVFSFTMVGKTFTYLLGSDAAALLFNS
KNEDLNAEDVYSRLTTPVFGKGVAYDVPNPVFLEQKKMLKSGLNIAHFKQHVSIIEKETK
EYFESWGESGEKNVFEALSELIILTASHCLHGKEIRSQLNEKVAQLYADLDGGFSHAAWL
LPGWLPLPSFRRRDRAHREIKDIFYKAIQKRRQSQEKIDDILQTLLDATYKDGRPLTDDE
VAGMLIGLLLAGQHTSSTTSAWMGFFLARDKTLQKKCYLEQKTVCGENLPPLTYDQLKDL
NLLDRCIKETLRLRPPIMIMMRMARTPQTVAGYTIPPGHQVCVSPTVNQRLKDSWVERLD
FNPDRYLQDNPASGEKFAYVPFGAGRHRCIGENFAYVQIKTIWSTMLRLYEFDLIDGYFP
TVNYTTMIHTPENPVIRYKRRSK
Target 4 Number of Residues 511
Target 4 Molecular Weight 56807
Target 4 Theoretical pI 8.72
Target 4 GO Classification
Function
tetrapyrrole binding
heme binding
binding
ion binding
cation binding
transition metal ion binding
iron ion binding
catalytic activity
oxidoreductase activity
monooxygenase activity
Process
physiological process
metabolism
cellular metabolism
generation of precursor metabolites and energy
electron transport
Component
Not Available
Target 4 General Function Secondary metabolites biosynthesis, transport and catabolism
Target 4 Specific Function Catalyzes C14-demethylation of lanosterol; it transforms lanosterol into 4,4'-dimethyl cholesta-8,14,24-triene-3-beta-ol
Target 4 Pathways Not Available
Target 4 Reactions
  • obtusifoliol + 3 O2 + 3 NADPH + 3 H+ = 4alpha-methyl-5alpha-ergosta-8,14,24(28)-trien-3beta-ol + formate + 3 NADP+ + 4 H2O
Target 4 Pfam Domain Function
Target 4 Signals
  • None
Target 4 Transmembrane Regions
  • 24-44
Target 4 Essentiality Non-Essential
Target 4 GenBank ID Protein 1698396 Link Image
Target 4 UniProtKB/Swiss-Prot ID Q16850 Link Image
Target 4 UniProtKB/Swiss-Prot Entry Name CP51A_HUMAN Link Image
Target 4 PDB ID Not Available
Target 4 Cellular Location
  • Microsome (Potential)
Target 4 Gene Sequence >1530 bp 
ATGGCGGCGGCGGCTGGGATGCTGCTGCTGGGCTTGCTGCAGGCGGGTGGGTCGGTGCTG
GGCCAGGCGATGGAGAAGGTGACAGGCGGCAACCTCTTGTCCATGCTGCTGATCGCCTGC
GCCTTCACCCTCAGCCTGGTCTACCTGATCCGTCTGGCCGCCGGCCACCTGGTCCAGCTG
CCCGCAGGGGTGAAAAGTCCTCCATACATTTTCTCCCCAATTCCATTCCTTGGGCATGCC
ATAGCATTTGGGAAAAGTCCAATTGAATTTCTAGAAAATGCATATGAGAAGTATGGACCT
GTATTTAGTTTTACCATGGTAGGCAAGACATTTACTTACCTTCTGGGGAGTGATGCTGCT
GCACTGCTTTTTAATAGTAAAAATGAAGACCTGAATGCAGAAGATGTCTACAGTCGCCTG
ACAACACCTGTGTTTGGGAAGGGAGTTGCATACGATGTGCCTAATCCAGTTTTCTTGGAG
CAGAAGAAAATGTTAAAAAGTGGCCTTAACATAGCCCACTTTAAACAGCATGTTTCTATA
ATTGAAAAAGAAACAAAGGAATACTTTGAGAGTTGGGGAGAAAGTGGAGAAAAAAATGTG
TTTGAAGCTCTTTCTGAGCTCATAATTTTAACAGCTAGCCATTGTTTGCATGGAAAGGAA
ATCAGAAGTCAACTCAATGAAAAGGTAGCACAGCTGTATGCAGATTTGGATGGAGGTTTC
AGCCATGCAGCCTGGCTCTTACCAGGTTGGCTGCCTTTGCCTAGTTTCAGACGCAGGGAC
AGAGCTCATCGGGAAATCAAGGATATTTTCTATAAGGCAATCCAGAAACGCAGACAGTCT
CAAGAAAAAATTGATGACATTCTCCAAACTTTACTAGATGCTACATACAAGGATGGGCGT
CCTTTGACTGATGATGAAGTAGCAGGGATGCTTATTGGATTACTCTTGGCAGGGCAGCAT
ACATCCTCAACTACTAGTGCTTGGATGGGCTTCTTTTTGGCCAGAGACAAAACACTTCAA
AAAAAATGTTATTTAGAACAGAAAACAGTCTGTGGAGAGAATCTGCCTCCTTTAACTTAT
GACCAGCTCAAGGATCTAAATTTACTTGATCGCTGTATAAAAGAAACATTAAGACTTAGA
CCTCCTATAATGATCATGATGAGAATGGCCAGAACTCCTCAGACTGTGGCAGGGTATACC
ATTCCTCCAGGACATCAGGTGTGTGTTTCTCCCACTGTCAATCAAAGACTTAAAGACTCA
TGGGTAGAACGCCTGGACTTTAATCCTGATCGCTACTTACAGGATAACCCAGCATCAGGG
GAAAAGTTTGCCTATGTGCCATTTGGAGCTGGGCGTCATCGTTGTATTGGGGAAAATTTT
GCCTATGTTCAAATTAAGACAATTTGGTCCACTATGCTTCGTTTATATGAATTTGATCTC
ATTGATGGATACTTTCCCACTGTGAATTATACAACTATGATTCACACCCCTGAGAACCCA
GTTATCCGTTACAAACGAAGATCAAAATGA
Target 4 GenBank Gene ID
Target 4 GeneCard ID CYP51A1 Link Image
Target 4 GenAtlas ID CYP51A1 Link Image
Target 4 HGNC ID HGNC:2649 Link Image
Target 4 Chromosome Location 7
Target 4 Locus 7q21.2-q21.3
Target 4 SNPs SNPJam Report Link Image
Target 4 General References
  1. Hillier LW, Fulton RS, Fulton LA, Graves TA, Pepin KH, Wagner-McPherson C, Layman D, Maas J, Jaeger S, Walker R, Wylie K, Sekhon M, Becker MC, O'Laughlin MD, Schaller ME, Fewell GA, Delehaunty KD, Miner TL, Nash WE, Cordes M, Du H, Sun H, Edwards J, Bradshaw-Cordum H, Ali J, Andrews S, Isak A, Vanbrunt A, Nguyen C, Du F, Lamar B, Courtney L, Kalicki J, Ozersky P, Bielicki L, Scott K, Holmes A, Harkins R, Harris A, Strong CM, Hou S, Tomlinson C, Dauphin-Kohlberg S, Kozlowicz-Reilly A, Leonard S, Rohlfing T, Rock SM, Tin-Wollam AM, Abbott A, Minx P, Maupin R, Strowmatt C, Latreille P, Miller N, Johnson D, Murray J, Woessner JP, Wendl MC, Yang SP, Schultz BR, Wallis JW, Spieth J, Bieri TA, Nelson JO, Berkowicz N, Wohldmann PE, Cook LL, Hickenbotham MT, Eldred J, Williams D, Bedell JA, Mardis ER, Clifton SW, Chissoe SL, Marra MA, Raymond C, Haugen E, Gillett W, Zhou Y, James R, Phelps K, Iadanoto S, Bubb K, Simms E, Levy R, Clendenning J, Kaul R, Kent WJ, Furey TS, Baertsch RA, Brent MR, Keibler E, Flicek P, Bork P, Suyama M, Bailey JA, Portnoy ME, Torrents D, Chinwalla AT, Gish WR, Eddy SR, McPherson JD, Olson MV, Eichler EE, Green ED, Waterston RH, Wilson RK: The DNA sequence of human chromosome 7. Nature. 2003 Jul 10;424(6945):157-64. [PubMed Link Image]
  2. Stromstedt M, Rozman D, Waterman MR: The ubiquitously expressed human CYP51 encodes lanosterol 14 alpha-demethylase, a cytochrome P450 whose expression is regulated by oxysterols. Arch Biochem Biophys. 1996 May 1;329(1):73-81. [PubMed Link Image]
  3. Rozman D, Stromstedt M, Waterman MR: The three human cytochrome P450 lanosterol 14 alpha-demethylase (CYP51) genes reside on chromosomes 3, 7, and 13: structure of the two retrotransposed pseudogenes, association with a line-1 element, and evolution of the human CYP51 family. Arch Biochem Biophys. 1996 Sep 15;333(2):466-74. [PubMed Link Image]
  4. Rozman D, Stromstedt M, Tsui LC, Scherer SW, Waterman MR: Structure and mapping of the human lanosterol 14alpha-demethylase gene (CYP51) encoding the cytochrome P450 involved in cholesterol biosynthesis; comparison of exon/intron organization with other mammalian and fungal CYP genes. Genomics. 1996 Dec 15;38(3):371-81. [PubMed Link Image]
Target 4 Drug References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed Link Image]

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.