Target Information

Target General Information

Target ID

T73726 (Former ID: TTDS00359)

Target Name

Candida Cytochrome P450 51 (Candi ERG11)

Synonyms

Sterol 14alpha-demethylase; Sterol 14-alpha demethylase; P450LI; P450L1; P450-14DM; Lanosterol 14 alpha-demethylase; LDM; Erg11p; ERG11; Cytochrome P450-dependent lanosterol 14-demethylase; Cytochrome P-450 lanosterol 14-alpha-demethylase; Cyt P450 14DM; CYPLI; CYPL1

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Gene Name

Candi ERG11

Target Type

Successful target

[1]

Disease

[+] 6 Target-related Diseases

Aspergillosis [ICD-11: 1F20]

Candidosis [ICD-11: 1F23]

Dermatophytosis [ICD-11: 1F28]

Fungal infection [ICD-11: 1F29-1F2F]

Nail/perionychium infection [ICD-11: EE12]

Non-dermatophyte superficial dermatomycose [ICD-11: 1F2D]

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.

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BioChemical Class

Paired donor oxygen oxidoreductase

UniProt ID

CP51_CANAL

Sequence

MAIVETVIDGINYFLSLSVTQQISILLGVPFVYNLVWQYLYSLRKDRAPLVFYWIPWFGS
AASYGQQPYEFFESCRQKYGDVFSFMLLGKIMTVYLGPKGHEFVFNAKLSDVSAEDAYKH
LTTPVFGKGVIYDCPNSRLMEQKKFAKFALTTDSFKRYVPKIREEILNYFVTDESFKLKE
KTHGVANVMKTQPEITIFTASRSLFGDEMRRIFDRSFAQLYSDLDKGFTPINFVFPNLPL
PHYWRRDAAQKKISATYMKEIKSRRERGDIDPNRDLIDSLLIHSTYKDGVKMTDQEIANL
LIGILMGGQHTSASTSAWFLLHLGEKPHLQDVIYQEVVELLKEKGGDLNDLTYEDLQKLP
SVNNTIKETLRMHMPLHSIFRKVTNPLRIPETNYIVPKGHYVLVSPGYAHTSERYFDNPE
DFDPTRWDTAAAKANSVSFNSSDEVDYGFGKVSKGVSSPYLPFGGGRHRCIGEQFAYVQL
GTILTTFVYNLRWTIDGYKVPDPDYSSMVVLPTEPAEIIWEKRETCMF

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3D Structure

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PDB

Drugs and Modes of Action

Top

Approved Drug(s)

[+] 16 Approved Drugs

Bifonazole

Drug Info

Approved

Fungal infection

[2]

Butoconazole

Drug Info

Approved

Candidiasis

[3], [4]

Econazole

Drug Info

Approved

Tinea versicolor

[4]

Efinaconazole

Drug Info

Approved

Fungal infection

[5]

Fluconazole

Drug Info

Approved

Fungal infection

[6]

Itraconazole

Drug Info

Approved

Fungal infection

[7]

Ketoconazole

Drug Info

Approved

Fungal infection

[8], [9]

Luliconazole

Drug Info

Approved

Tinea pedis

[10]

Miconazole

Drug Info

Approved

Fungal infection

[11], [12]

Oteseconazole

Drug Info

Approved

Vulvovaginal Candidiasis

[13]

Oxiconazole

Drug Info

Approved

Tinea pedis

[4], [14]

Posaconazole

Drug Info

Approved

Aspergillosis

[15], [16], [17]

Sertaconazole

Drug Info

Approved

Fungal infection

[18]

Terconazole

Drug Info

Approved

Candidiasis

[19], [4]

Tioconazole

Drug Info

Approved

Onychomycosis

[20], [4]

Voriconazole

Drug Info

Approved

Invasive aspergillosis

[21]

Clinical Trial Drug(s)

[+] 7 Clinical Trial Drugs

CHLORIDE

Drug Info

Phase 3

Solid tumour/cancer

[22], [23]

E-1224

Drug Info

Phase 2

Fungal infection

[24]

EcoNail

Drug Info

Phase 2

Fungal infection

[25]

Pramiconazole

Drug Info

Phase 2

Dermatological disease

[26]

Embeconazole

Drug Info

Phase 1

Fungal infection

[27]

Genaconazole

Drug Info

Phase 1

Fungal infection

[28]

VT-1598

Drug Info

Phase 1

Coccidioidomycosis

[29]

Discontinued Drug(s)

[+] 2 Discontinued Drugs

Abafungin

Drug Info

Discontinued in Phase 3

Fungal infection

[30]

AZALANSTAT

Drug Info

Discontinued in Phase 2

Hyperlipidaemia

[31]

Mode of Action

[+] 3 Modes of Action

Inhibitor

[+] 19 Inhibitor drugs

Bifonazole

Drug Info

[1], [32], [33]

Butoconazole

Drug Info

[34]

Econazole

Drug Info

[35]

Efinaconazole

Drug Info

[5], [4]

Ketoconazole

Drug Info

[37]

Luliconazole

Drug Info

[38], [4]

Oteseconazole

Drug Info

[39]

Oxiconazole

Drug Info

[40], [41]

Posaconazole

Drug Info

[42]

Sertaconazole

Drug Info

[43]

Terconazole

Drug Info

[44]

Tioconazole

Drug Info

[45]

E-1224

Drug Info

[46]

EcoNail

Drug Info

[47]

Embeconazole

Drug Info

[49]

VT-1598

Drug Info

[51]

Abafungin

Drug Info

[52]

ANALOGUE A

Drug Info

[54]

CP-320626

Drug Info

[54]

Modulator

[+] 8 Modulator drugs

Fluconazole

Drug Info

[36]

Itraconazole

Drug Info

[36]

Miconazole

Drug Info

[36]

Voriconazole

Drug Info

[36]

CHLORIDE

Drug Info

[23]

Pramiconazole

Drug Info

[48]

Genaconazole

Drug Info

[50]

AZALANSTAT

Drug Info

[53]

Binder

[+] 1 Binder drugs

citric acid

Drug Info

[55]

Drug Binding Sites of Target

Top

Ligand Name: Posaconazole

Ligand Info

Structure Description

Crystal structure of sterol 14-alpha demethylase (CYP51) from a pathogenic yeast Candida albicans in complex with the antifungal drug posaconazole

PDB:5FSA

Method

X-ray diffraction

Resolution

2.86 Å

Mutation

Yes

[56]

PDB Sequence

KKTPPLVFYW

⁵⁴

IPWFGSAASY

⁶⁴

GQQPYEFFES

⁷⁴

CRQKYGDVFS

⁸⁴

FMLLGKIMTV

⁹⁴

YLGPKGHEFV

¹⁰⁴

FNAKLSDVSA

¹¹⁴

EEAYKHLTTP

¹²⁴

VFGTGVIYDC

¹³⁴

PNSRLMEQKK

¹⁴⁴

FAKFALTTDS

¹⁵⁴

FKRYVPKIRE

¹⁶⁴

EILNYFVTDE

¹⁷⁴

SFKLKEKTHG

¹⁸⁴

VANVMKTQPE

¹⁹⁴

ITIFTASRSL

²⁰⁴

FGDEMRRIFD

²¹⁴

RSFAQLYSDL

²²⁴

DKGFTPINFV

²³⁴

FPNLPLPHYW

²⁴⁴

RRDAAQKKIS

²⁵⁴

ATYMKEIKLR

²⁶⁴

RERGDIDPNR

²⁷⁴

DLIDSLLIHS

²⁸⁴

TYKDGVKMTD

²⁹⁴

QEIANLLIGI

³⁰⁴

LMGGQHTSAS

³¹⁴

TSAWFLLHLG

³²⁴

EKPHLQDVIY

³³⁴

QEVVELLKEK

³⁴⁴

GGDLNDLTYE

³⁵⁴

DLQKLPSVNN

³⁶⁴

TIKETLRMHM

³⁷⁴

PLHSIFRKVT

³⁸⁴

NPLRIPETNY

³⁹⁴

IVPKGHYVLV

⁴⁰⁴

SPGYAHTSER

⁴¹⁴

YFDNPEDFDP

⁴²⁴

TRWDTAAAKA

⁴³⁴

NSVSFNSSDE

⁴⁴⁴

VDYGFGKVSK

⁴⁵⁴

GVSSPYLPFG

⁴⁶⁴

GGRHRCIGEQ

⁴⁷⁴

FAYVQLGTIL

⁴⁸⁴

TTFVYNLRWT

⁴⁹⁴

IDGYKVPDPD

⁵⁰⁴

YSSMVVLPTE

⁵¹⁴

PAEIIWEKRE

⁵²⁴

TCMF

Residue

Distance (Å)

PHE58

3.841

ALA61

3.520

ALA62

4.083

TYR64

3.866

GLY65

4.019

GLN66

4.564

LEU87

4.575

LEU88

4.143

TYR118

3.660

LEU121

3.108

THR122

4.458

PHE126

3.606

ILE131

3.680

TYR132

4.081

PHE228

3.653

PRO230

3.314

Residue

Distance (Å)

PHE233

3.083

GLY303

3.725

ILE304

3.909

GLY307

3.110

GLY308

4.190

THR311

4.112

LEU376

3.340

HIS377

3.293

SER378

4.246

PHE380

3.777

CYS470

4.306

TYR505

3.783

SER506

2.850

SER507

3.090

MET508

3.154

Ligand Name: Otesaconazole

Ligand Info

Structure Description

Crystal structure of sterol 14-alpha demethylase (CYP51) from Candida albicans in complex with the tetrazole-based antifungal drug candidate VT1161 (VT1)

PDB:5TZ1

Method

X-ray diffraction

Resolution

2.00 Å

Mutation

Yes

[56]

PDB Sequence

KKTPPLVFYW

⁵⁴

IPWFGSAASY

⁶⁴

GQQPYEFFES

⁷⁴

CRQKYGDVFS

⁸⁴

FMLLGKIMTV

⁹⁴

YLGPKGHEFV

¹⁰⁴

FNAKLSDVSA

¹¹⁴

EEAYKHLTTP

¹²⁴

VFGTGVIYDC

¹³⁴

PNSRLMEQKK

¹⁴⁴

FAKFALTTDS

¹⁵⁴

FKRYVPKIRE

¹⁶⁴

EILNYFVTDE

¹⁷⁴

SFKLKEKTHG

¹⁸⁴

VANVMKTQPE

¹⁹⁴

ITIFTASRSL

²⁰⁴

FGDEMRRIFD

²¹⁴

RSFAQLYSDL

²²⁴

DKGFTPINFV

²³⁴

FPNLPLPHYW

²⁴⁴

RRDAAQKKIS

²⁵⁴

ATYMKEIKLR

²⁶⁴

RERGDIDPNR

²⁷⁴

DLIDSLLIHS

²⁸⁴

TYKDGVKMTD

²⁹⁴

QEIANLLIGI

³⁰⁴

LMGGQHTSAS

³¹⁴

TSAWFLLHLG

³²⁴

EKPHLQDVIY

³³⁴

QEVVELLKEK

³⁴⁴

GGDLNDLTYE

³⁵⁴

DLQKLPSVNN

³⁶⁴

TIKETLRMHM

³⁷⁴

PLHSIFRKVT

³⁸⁴

NPLRIPETNY

³⁹⁴

IVPKGHYVLV

⁴⁰⁴

SPGYAHTSER

⁴¹⁴

YFDNPEDFDP

⁴²⁴

TRWDTAAAKA

⁴³⁴

NSVSFNSSDE

⁴⁴⁴

VDYGFGKVSK

⁴⁵⁴

GVSSPYLPFG

⁴⁶⁴

GGRHRCIGEQ

⁴⁷⁴

FAYVQLGTIL

⁴⁸⁴

TTFVYNLRWT

⁴⁹⁴

IDGYKVPDPD

⁵⁰⁴

YSSMVVLPTE

⁵¹⁴

PAEIIWEKRE

⁵²⁴

TCMF

Residue

Distance (Å)

TYR64

3.328

TYR118

3.742

LEU121

4.369

THR122

3.845

PHE126

3.684

ILE131

3.735

TYR132

3.576

PHE228

3.377

PRO230

4.093

PHE233

4.281

GLY303

3.468

ILE304

4.193

Residue

Distance (Å)

MET306

4.809

GLY307

3.192

GLY308

4.160

THR311

3.387

LEU376

3.321

HIS377

2.786

SER378

3.146

PHE380

3.404

CYS470

4.592

TYR505

4.267

SER507

4.007

MET508

3.152

Click to View More Binding Site Information of This Target with Different Ligands

Different Human System Profiles of Target	Top
Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target. A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020). Human Similarity Proteins

Different Human System Profiles of Target

Top

Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.

A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020).

Human Similarity Proteins

There is no similarity protein (E value < 0.005) for this target

Drug Property Profile of Target

Top

(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five

Co-Targets

Top

Co-Targets

Co-Targets Info

Target-Related Models and Studies

Top

Target Validation

Target Validation Info

References

Top

REF 1

Investigation of the role of cytochrome P450 2B4 active site residues in substrate metabolism based on crystal structures of the ligand-bound enzyme. Arch Biochem Biophys. 2006 Nov 1;455(1):61-7.

REF 2

Drug information of Bifonazole, 2008. eduDrugs.

REF 3

FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (NDA) 020421.

REF 4

Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015

REF 5

Efinaconazole: Developmental and reproductive toxicity potential of a novel antifungal azole. Reprod Toxicol. 2015 Apr;52:18-25.

REF 6

Fluconazole use as an important risk factor in the emergence of fluconazole-resistant Candida glabrata fungemia. Arch Intern Med. 2009 Aug 10;169(15):1444-5; author reply 1445.

REF 7

FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (ANDA) 076104.

REF 8

URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 2568).

REF 9

FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (ANDA) 075273.

REF 10

Clinical pipeline report, company report or official report of Valeant pharmaceuticals.

REF 11

REF 12

FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (ANDA) 076773.

REF 13

FDA Approved Drug Products from FDA Official Website. 2022. Application Number: 215888.

REF 14

FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (NDA) 019828.

REF 15

FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (NDA) 022003.

REF 16

2006 drug approvals: finding the niche. Nat Rev Drug Discov. 2007 Feb;6(2):99-101.

REF 17

Structural insights into inhibition of sterol 14alpha-demethylase in the human pathogen Trypanosoma cruzi. J Biol Chem. 2010 Aug 13;285(33):25582-90.

REF 18

FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (NDA) 021385.

REF 19

FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (NDA) 021735.

REF 20

FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (ANDA) 075915.

REF 21

Disk diffusion test and E-test with enriched Mueller-Hinton agar for determining susceptibility of Candida species to voriconazole and fluconazole. J Microbiol Immunol Infect. 2009 Apr;42(2):148-53.

REF 22

REF 23

Isavuconazonium: first global approval. Drugs. 2015 May;75(7):817-22.

REF 24

ClinicalTrials.gov (NCT01489228) Proof-of-Concept Study of E1224 to Treat Adult Patients With Chagas Disease. U.S. National Institutes of Health.

REF 25

ClinicalTrials.gov (NCT00385502) A Trial of the Safety and Efficacy of EcoNail in the Treatment of Fungus Infections of the Great Toenail. U.S. National Institutes of Health.

REF 26

The efficacy of oral treatment with pramiconazole in pityriasis versicolor: a phase II a trial. Br J Dermatol. 2007 Jun;156(6):1385-8.

REF 27

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800014655)

REF 28

In vivo efficacy of SM-8668 (Sch 39304), a new oral triazole antifungal agent. Antimicrob Agents Chemother. 1990 Jun;34(6):980-4.

REF 29

ClinicalTrials.gov (NCT04208321) A Phase 1, First-In-Human, Randomized, Double-Blind, Placebo-Controlled, Single Dose-Escalation Study to Evaluate the Safety and Pharmacokinetics of Single Oral Doses of VT-1598 in Healthy Adult Subjects. U.S.National Institutes of Health.

REF 30

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800022887)

REF 31

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800002302)

REF 32

Bifonazole, a biochemist's view. Dermatologica. 1984;169 Suppl 1:3-9.

REF 33

Bifonazole and clotrimazole. Their mode of action and the possible reason for the fungicidal behaviour of bifonazole. Arzneimittelforschung. 1984;34(2):139-46.

REF 34

Effects of terconazole and other azole antifungal agents on the sterol and carbohydrate composition of Candida albicans. Diagn Microbiol Infect Dis. 1990 Jan-Feb;13(1):31-5.

REF 35

Differential azole antifungal efficacies contrasted using a Saccharomyces cerevisiae strain humanized for sterol 14 alpha-demethylase at the homolo... Antimicrob Agents Chemother. 2008 Oct;52(10):3597-603.

REF 36

Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.

REF 37

Clinical pharmacokinetics and pharmacodynamics of solifenacin. Clin Pharmacokinet. 2009;48(5):281-302.

REF 38

Radium 223 dichloride for prostate cancer treatment. Drug Des Devel Ther. 2017 Sep 6;11:2643-2651.

REF 39

Efficacy of the clinical agent VT-1161 against fluconazole-sensitive and -resistant Candida albicans in a murine model of vaginal candidiasis. Antimicrob Agents Chemother. 2015 Sep;59(9):5567-73.

REF 40

Antifungal agents: mechanisms of action. Trends Microbiol. 2003 Jun;11(6):272-9.

REF 41

Antifungal agents: mode of action in yeast cells. Rev Esp Quimioter. 2006 Jun;19(2):130-9.

REF 42

A new, broad-spectrum azole antifungal: posaconazole--mechanisms of action and resistance, spectrum of activity. Mycoses. 2006;49 Suppl 1:2-6.

REF 43

Sertaconazole: a review of its use in the management of superficial mycoses in dermatology and gynaecology. Drugs. 2009;69(3):339-59.

REF 44

Mode of action of anti-Candida drugs: focus on terconazole and other ergosterol biosynthesis inhibitors. Am J Obstet Gynecol. 1991 Oct;165(4 Pt 2):1193-9.

REF 45

Biological spectra analysis: Linking biological activity profiles to molecular structure. Proc Natl Acad Sci U S A. 2005 Jan 11;102(2):261-6.

REF 46

Recent Developments in Sterol 14-demethylase Inhibitors for Chagas Disease. Int J Parasitol Drugs Drug Resist. 2012 Dec;2:236-242.

REF 47

Azole binding properties of Candida albicans sterol 14-alpha demethylase (CaCYP51). Antimicrob Agents Chemother. 2010 Oct;54(10):4235-45.

REF 48

Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.

REF 49

CS-758. Antifungal lanosterol 14alpha-demethylase inhibitor, 003, vol28, no3, 217-223.

REF 50

New targets and delivery systems for antifungal therapy. Med Mycol. 2000;38 Suppl 1:335-47.

REF 51

The novel fungal CYP51 inhibitor VT-1598 displays classic dose-dependent antifungal activity in murine models of invasive aspergillosis. Med Mycol. 2020 Jun 1;58(4):505-513.

REF 52

Upregulation of sterol C14-demethylase expression in Trypanosoma cruzi treated with sterol biosynthesis inhibitors. Mol Biochem Parasitol. 2005 Nov;144(1):68-75.

REF 53

Azalanstat (RS-21607), a lanosterol 14 alpha-demethylase inhibitor with cholesterol-lowering activity. Biochem Pharmacol. 1995 Aug 8;50(4):529-44.

REF 54

Three-dimensional quantitative structure-activity relationship analysis of human CYP51 inhibitors. Drug Metab Dispos. 2007 Mar;35(3):493-500.

REF 55

Chemosensitization of fluconazole resistance in Saccharomyces cerevisiae and pathogenic fungi by a D-octapeptide derivative. Antimicrob Agents Chemother. 2004 Apr;48(4):1256-71.

REF 56

Structural analyses of Candida albicans sterol 14Alpha-demethylase complexed with azole drugs address the molecular basis of azole-mediated inhibition of fungal sterol biosynthesis. J Biol Chem. 2017 Apr 21;292(16):6728-6743.

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