Target Information

Target General Information

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Target ID

T32972

Target Name

Lanosterol 14-alpha demethylase (CYP51A1)

Synonyms

Cytochrome P450LI; Cytochrome P45014DM; Cytochrome P450-14DM; Cytochrome P450 51A1

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Gene Name

CYP51A1

Target Type

Clinical trial target

[1]

Disease

[+] 3 Target-related Diseases

Nail/perionychium infection [ICD-11: EE12]

Onchocerciasis [ICD-11: 1F6A]

Infectious meningitis [ICD-11: 1D01]

Function

Catalyzes C14-demethylation of lanosterol; it transforms lanosterol into 4,4'-dimethyl cholesta-8,14,24-triene-3-beta-ol.

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BioChemical Class

Cytochrome P450 family

UniProt ID

CP51A_HUMAN

EC Number

EC 1.14.14.154

Sequence

MLLLGLLQAGGSVLGQAMEKVTGGNLLSMLLIACAFTLSLVYLIRLAAGHLVQLPAGVKS
PPYIFSPIPFLGHAIAFGKSPIEFLENAYEKYGPVFSFTMVGKTFTYLLGSDAAALLFNS
KNEDLNAEDVYSRLTTPVFGKGVAYDVPNPVFLEQKKMLKSGLNIAHFKQHVSIIEKETK
EYFESWGESGEKNVFEALSELIILTASHCLHGKEIRSQLNEKVAQLYADLDGGFSHAAWL
LPGWLPLPSFRRRDRAHREIKDIFYKAIQKRRQSQEKIDDILQTLLDATYKDGRPLTDDE
VAGMLIGLLLAGQHTSSTTSAWMGFFLARDKTLQKKCYLEQKTVCGENLPPLTYDQLKDL
NLLDRCIKETLRLRPPIMIMMRMARTPQTVAGYTIPPGHQVCVSPTVNQRLKDSWVERLD
FNPDRYLQDNPASGEKFAYVPFGAGRHRCIGENFAYVQIKTIWSTMLRLYEFDLIDGYFP
TVNYTTMIHTPENPVIRYKRRSK

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3D Structure

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PDB

HIT2.0 ID

T74XTP

Drugs and Modes of Action

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Clinical Trial Drug(s)

[+] 1 Clinical Trial Drugs

VT-1129

Drug Info

Phase 2

Onchocerciasis

[2]

Mode of Action

[+] 1 Modes of Action

Inhibitor

[+] 1 Inhibitor drugs

VT-1129

Drug Info

[1]

Cell-based Target Expression Variations

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Cell-based Target Expression Variations

Cell-based Target Expression Variations Info

Drug Binding Sites of Target

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Ligand Name: Ketoconazole

Ligand Info

Structure Description

Crystal structure of human lanosterol 14alpha-demethylase (CYP51) in complex with ketoconazole

PDB:3LD6

Method

X-ray diffraction

Resolution

2.80 Å

Mutation

[3]

PDB Sequence

VKSPPYIFSP

⁶⁷

IPFLGHAIAF

⁷⁷

GKSPIEFLEN

⁸⁷

AYEKYGPVFS

⁹⁷

FTMVGKTFTY

¹⁰⁷

LLGSDAAALL

¹¹⁷

FNSKNEDLNA

¹²⁷

EDVYSRLTTP

¹³⁷

VFGKGVAYDV

¹⁴⁷

PNPVFLEQKK

¹⁵⁷

MLKSGLNIAH

¹⁶⁷

FKQHVSIIEK

¹⁷⁷

ETKEYFESWG

¹⁸⁷

ESGEKNVFEA

¹⁹⁷

LSELIILTAS

²⁰⁷

HCLHGKEIRS

²¹⁷

QLNEKVAQLY

²²⁷

ADLDGGFSHA

²³⁷

AWLLPGWLPL

²⁴⁷

PSFRRRDRAH

²⁵⁷

REIKDIFYKA

²⁶⁷

IQKRRQSQEK

²⁷⁷

IDDILQTLLD

²⁸⁷

ATYKDGRPLT

²⁹⁷

DDEVAGMLIG

³⁰⁷

LLLAGQHTSS

³¹⁷

TTSAWMGFFL

³²⁷

ARDKTLQKKC

³³⁷

YLEQKTVCGE

³⁴⁷

NLPPLTYDQL

³⁵⁷

KDLNLLDRCI

³⁶⁷

KETLRLRPPI

³⁷⁷

MIMMRMARTP

³⁸⁷

QTVAGYTIPP

³⁹⁷

GHQVCVSPTV

⁴⁰⁷

NQRLKDSWVE

⁴¹⁷

RLDFNPDRYL

⁴²⁷

QDNPASGEKF

⁴³⁷

AYVPFGAGRH

⁴⁴⁷

RCIGENFAYV

⁴⁵⁷

QIKTIWSTML

⁴⁶⁷

RLYEFDLIDG

⁴⁷⁷

YFPTVNYTTM

⁴⁸⁷

IHTPENPVIR

⁴⁹⁷

YKRRS

Residue

Distance (Å)

PHE77

3.869

PHE105

4.011

TYR107

4.544

TYR131

3.240

LEU134

3.757

THR135

4.338

PHE139

3.424

TYR145

3.494

PHE152

4.639

PHE234

3.669

HIS236

4.319

TRP239

3.564

Residue

Distance (Å)

GLY307

3.639

LEU308

4.739

LEU310

4.729

ALA311

3.296

GLY312

4.986

THR315

3.431

ILE377

3.264

ILE379

2.995

MET380

4.758

MET381

3.893

CYS449

4.724

MET487

3.682

Ligand Name: ATX-101

Ligand Info

Structure Description

Human sterol 14a-demethylase (CYP51) in complex with the functionally irreversible inhibitor (R)-N-(1-(3-chloro-4'-fluoro-[1,1'-biphenyl]-4-yl)-2-(1H-imidazol-1-yl)ethyl)-4-(5-(3-fluoro-5-(5-fluoropyrimidin-4-yl)phenyl)-1,3,4-oxadiazol-2-yl)benzamide

PDB:6Q2T

Method

X-ray diffraction

Resolution

2.80 Å

Mutation

[4]

PDB Sequence

GKLPPYIFSP

⁶⁷

IPFLGHAIAF

⁷⁷

GKSPIEFLEN

⁸⁷

AYEKYGPVFS

⁹⁷

FTMVGKTFTY

¹⁰⁷

LLGSDAAALL

¹¹⁷

FNSKNEDLNA

¹²⁷

EDVYSRLTTP

¹³⁷

VFGKGVAYDV

¹⁴⁷

PNPVFLEQKK

¹⁵⁷

MLKSGLNIAH

¹⁶⁷

FKQHVSIIEK

¹⁷⁷

ETKEYFESWG

¹⁸⁷

ESGEKNVFEA

¹⁹⁷

LSELIILTAS

²⁰⁷

HCLHGKEIRS

²¹⁷

QLNEKVAQLY

²²⁷

ADLDGGFSHA

²³⁷

AWLLPGWLPL

²⁴⁷

PSFRRRDRAH

²⁵⁷

REIKDIFYKA

²⁶⁷

IQKRRQSQEK

²⁷⁷

IDDILQTLLD

²⁸⁷

ATYKDGRPLT

²⁹⁷

DDEVAGMLIG

³⁰⁷

LLLAGQHTSS

³¹⁷

TTSAWMGFFL

³²⁷

ARDKTLQKKC

³³⁷

YLEQKTVCGE

³⁴⁷

NLPPLTYDQL

³⁵⁷

KDLNLLDRCI

³⁶⁷

KETLRLRPPI

³⁷⁷

MIMMRMARTP

³⁸⁷

QTVAGYTIPP

³⁹⁷

GHQVCVSPTV

⁴⁰⁷

NQRLKDSWVE

⁴¹⁷

RLDFNPDRYL

⁴²⁷

QDNPASGEKF

⁴³⁷

AYVPFGAGRH

⁴⁴⁷

RCIGENFAYV

⁴⁵⁷

QIKTIWSTML

⁴⁶⁷

RLYEFDLIDG

⁴⁷⁷

YFPTVNYTTM

⁴⁸⁷

IHTPENPVIR

⁴⁹⁷

YKRRS

Residue

Distance (Å)

PHE70

3.345

LEU71

3.843

ALA74

3.478

ILE75

4.362

PHE77

4.054

GLY78

3.986

PRO81

4.317

MET100

4.483

VAL101

3.772

HIS236

3.231

Residue

Distance (Å)

TRP239

4.057

LEU240

3.906

LEU241

3.812

PRO242

4.380

TRP244

3.310

LEU245

4.141

PRO246

2.856

TYR484

4.357

HIS489

4.934

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 Tissue Distribution of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues. The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects (Nat Rev Drug Discov, 20: 64-81, 2021). Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function. Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006). Biological Network Descriptors of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database. The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information (Front Pharmacol, 9, 1245, 2018; Curr Opin Struct Biol. 44:134-142, 2017). Human Similarity Proteins Human Tissue Distribution Human Pathway Affiliation Biological Network Descriptors

Different Human System Profiles of Target

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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 Tissue Distribution of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.

The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects (Nat Rev Drug Discov, 20: 64-81, 2021).

Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.

Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006).

Biological Network Descriptors of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.

The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information (Front Pharmacol, 9, 1245, 2018; Curr Opin Struct Biol. 44:134-142, 2017).

Human Similarity Proteins

Human Tissue Distribution

Human Pathway Affiliation

Biological Network Descriptors

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


Note: If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.

KEGG Pathway	Pathway ID	Affiliated Target	Pathway Map
Steroid biosynthesis	hsa00100	Affiliated Target
Class: Metabolism => Lipid metabolism	Pathway Hierarchy

Degree	19	Degree centrality	2.04E-03	Betweenness centrality	5.20E-04
Closeness centrality	2.04E-01	Radiality	1.36E+01	Clustering coefficient	3.80E-01
Neighborhood connectivity	1.22E+01	Topological coefficient	1.63E-01	Eccentricity	11
Download	Click to Download the Full PPI Network of This Target

Chemical Structure based Activity Landscape of Target

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Target Poor or Non Binders

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Target Poor or Non Binders

Target Poor or Non Binders Info

Target Affiliated Biological Pathways

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KEGG Pathway

[+] 2 KEGG Pathways

Steroid biosynthesis

Metabolic pathways

References

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REF 1

Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)

REF 2

ClinicalTrials.gov (NCT01891305) A Study to Evaluate the Efficacy and Safety of Oral VT-1161 in Patients With Moderate - Severe Interdigital Tinea Pedis. U.S. National Institutes of Health.

REF 3

Structural basis of human CYP51 inhibition by antifungal azoles. J Mol Biol. 2010 Apr 9;397(4):1067-78.

REF 4

Validation of Human Sterol 14Alpha-Demethylase (CYP51) Druggability: Structure-Guided Design, Synthesis, and Evaluation of Stoichiometric, Functionally Irreversible Inhibitors. J Med Chem. 2019 Nov 27;62(22):10391-10401.

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