Target Information

Target General Information

Top

Target ID

T71390 (Former ID: TTDR01183)

Target Name

Steroid 5-alpha-reductase 2 (SRD5A2)

Synonyms

Type 2 steroid 5alpha-reductase (5alpha-R); SRD5A2; SR type 2; 5-alpha reductase 2; 5 alpha-SR2

Click to Show/Hide

Gene Name

SRD5A2

Target Type

Successful target

[1]

Disease

[+] 1 Target-related Diseases

Prostate hyperplasia [ICD-11: GA90]

Function

Converts testosterone (T) into 5-alpha- dihydrotestosterone (DHT) and progesterone or corticosterone into their corresponding 5-alpha-3-oxosteroids. It plays a central role in sexual differentiation and androgen physiology.

Click to Show/Hide

BioChemical Class

CH-CH donor oxidoreductase

UniProt ID

S5A2_HUMAN

EC Number

EC 1.3.1.22

Sequence

MQVQCQQSPVLAGSATLVALGALALYVAKPSGYGKHTESLKPAATRLPARAAWFLQELPS
FAVPAGILARQPLSLFGPPGTVLLGLFCVHYFHRTFVYSLLNRGRPYPAILILRGTAFCT
GNGVLQGYYLIYCAEYPDGWYTDIRFSLGVFLFILGMGINIHSDYILRQLRKPGEISYRI
PQGGLFTYVSGANFLGEIIEWIGYALATWSLPALAFAFFSLCFLGLRAFHHHRFYLKMFE
DYPKSRKALIPFIF

Click to Show/Hide

3D Structure

Click to Show 3D Structure of This Target

PDB

HIT2.0 ID

T66JU3

Drugs and Modes of Action

Top

Approved Drug(s)

[+] 1 Approved Drugs

Finasteride

Drug Info

Approved

Benign prostatic hyperplasia

[2], [3]

Mode of Action

[+] 1 Modes of Action

Inhibitor

[+] 16 Inhibitor drugs

Finasteride

Drug Info

[1]

(3-fluoro-4-(4-phenoxybenzoyl)phenyl)acetic acid

Drug Info

[4]

(3-methyl-4-(4-phenoxybenzoyl)phenyl)acetic acid

Drug Info

[4]

(E)-3-(4-(4-phenoxybenzoyl)phenyl)acrylic acid

Drug Info

[4]

2,3,5,6-Tetrafluoro-4-pentafluorophenylazo-phenol

Drug Info

[5]

3-[4-(4-phenoxybenzoyl)phenyl]propanoic acid

Drug Info

[4]

4,4'-dihydroxyoctafluoroazobenzene

Drug Info

[5]

4-(4-phenoxybenzoyl)benzoic acid

Drug Info

[4]

4-(4-phenoxybenzoyl)phenylacetic acid

Drug Info

[4]

4-[3-(benzyloxy)benzoyl]benzoic acid

Drug Info

[4]

4-[4-(benzhydryloxy)benzoyl]benzoic acid

Drug Info

[4]

4-[4-(benzoylamino)benzoyl]benzoic acid

Drug Info

[4]

4-[4-(benzylamino)benzoyl]benzoic acid

Drug Info

[4]

4-[4-benzyloxy)benzoyl]benzoic acid

Drug Info

[4]

GP515

Drug Info

[6]

{4-[4-(4-bromophenoxy)benzoyl]phenyl}acetic acid

Drug Info

[4]

Cell-based Target Expression Variations

Top

Cell-based Target Expression Variations

Cell-based Target Expression Variations Info

Drug Binding Sites of Target

Top

Ligand Name: [[(2~{R},3~{S},4~{R},5~{R})-5-[4-[(1~{S},3~{a}~{S},3~{b}~{S},5~{a}~{R},8~{S},9~{a}~{R},9~{b}~{S},11~{a}~{S})-1-(~{tert}-butylcarbamoyl)-9~{a},11~{a}-dimethyl-7-oxidanylidene-1,2,3,3~{a},3~{b},4,5,5~{a},6,8,9,9~{b},10,11-tetradecahydroindeno[5,4-f]quinolin-8-yl]-3-aminocarbonyl-4~{H}-pyridin-1-yl]-3,4-bis(oxidanyl)oxolan-2-yl]methoxy-oxidanyl-phosphoryl] [(2~{R},3~{R},4~{R},5~{R})-5-(6-aminopurin-9-yl)-3-oxidanyl-4-phosphonooxy-oxolan-2-yl]methyl hydrogen phosphate

Ligand Info

Structure Description

Crystal structure of Steroid 5-alpha-reductase 2 in complex with Finasteride

PDB:7BW1

Method

X-ray diffraction

Resolution

2.80 Å

Mutation

[7]

PDB Sequence

CQQSPVLAGS

¹⁴

ATLVALGALA

²⁴

LYVAKPSGYG

³⁴

KHTEATRLPA

⁴⁹

RAAWFLQELP

⁵⁹

SFAVPAGILA

⁶⁹

RQPLSLFGPP

⁷⁹

GTVLLGLFCV

⁸⁹

HYFHRTFVYS

⁹⁹

LLNRGRPYPA

¹⁰⁹

ILILRGTAFC

¹¹⁹

TGNGVLQGYY

¹²⁹

LIYCAEYPDG

¹³⁹

WYTDIRFSLG

¹⁴⁹

VFLFILGMGI

¹⁵⁹

NIHSDYILRQ

¹⁶⁹

LRKPGEISYR

¹⁷⁹

IPQGGLFTYV

¹⁸⁹

SGANFLGEII

¹⁹⁹

EWIGYALATW

²⁰⁹

SLPALAFAFF

²¹⁹

SLCFLGLRAF

²²⁹

HHHRFYLKMF

²³⁹

EDYPKSRKAL

²⁴⁹

IPFIF

Residue

Distance (Å)

LEU20

4.076

LEU23

3.946

ALA24

3.663

VAL27

4.792

SER31

3.364

TYR33

2.934

GLY34

3.380

LYS35

2.853

TRP53

3.433

GLN56

3.813

GLU57

2.866

TYR91

4.479

ARG94

2.866

TYR98

3.074

ASN102

2.812

ARG103

3.959

GLY104

3.289

ARG105

3.079

TYR107

3.743

LEU111

3.862

ARG114

3.007

GLY115

3.849

PHE118

3.352

Residue

Distance (Å)

CYS119

4.690

ASN160

2.767

ASP164

2.730

LEU167

3.629

LEU170

3.738

ARG171

3.021

SER177

3.593

TYR178

2.804

ARG179

2.870

PRO181

4.176

ASN193

2.952

PHE194

3.472

GLU197

2.815

TRP201

3.195

PHE216

3.944

PHE219

3.687

SER220

3.126

PHE223

3.389

LEU224

3.795

ARG227

2.520

HIS231

2.768

TYR235

3.122

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 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 Pathway Affiliation Biological Network Descriptors

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 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 Pathway Affiliation

Biological Network Descriptors

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

KEGG Pathway	Pathway ID	Affiliated Target	Pathway Map
Steroid hormone biosynthesis	hsa00140	Affiliated Target
Class: Metabolism => Lipid metabolism	Pathway Hierarchy

Degree	13	Degree centrality	1.40E-03	Betweenness centrality	1.53E-04
Closeness centrality	1.48E-01	Radiality	1.19E+01	Clustering coefficient	3.97E-01
Neighborhood connectivity	9.38E+00	Topological coefficient	2.91E-01	Eccentricity	11
Download	Click to Download the Full PPI Network of This Target

Chemical Structure based Activity Landscape of Target

Top

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 Poor or Non Binders

Top

Target Poor or Non Binders

Target Poor or Non Binders Info

Target Affiliated Biological Pathways

Top

BioCyc

[+] 3 BioCyc Pathways

Superpathway of steroid hormone biosynthesis

Allopregnanolone biosynthesis

Androgen biosynthesis

KEGG Pathway

[+] 2 KEGG Pathways

Steroid hormone biosynthesis

Prostate cancer

Reactome

[+] 1 Reactome Pathways

Androgen biosynthesis

Target-Related Models and Studies

Top

Target Validation

Target Validation Info

References

Top

REF 1

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

REF 2

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: 6818).

REF 3

Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007 Mar;70(3):461-77.

REF 4

Novel 5alpha-reductase inhibitors: synthesis, structure-activity studies, and pharmacokinetic profile of phenoxybenzoylphenyl acetic acids. J Med Chem. 2006 Jan 26;49(2):748-59.

REF 5

Hydroxyperfluoroazobenzenes: novel inhibitors of enzymes of androgen biosynthesis. J Med Chem. 1990 Sep;33(9):2452-5.

REF 6

19-nor-10-azasteroids: a novel class of inhibitors for human steroid 5alpha-reductases 1 and 2. J Med Chem. 1997 Mar 28;40(7):1112-29.

REF 7

Structure of human steroid 5Alpha-reductase 2 with anti-androgen drug finasteride. Res Sq. 2020 Jul 15:rs.3.rs-40159.

If You Find Any Error in Data or Bug in Web Service, Please Kindly Report It to Dr. Zhou and Dr. Zhang.

Prof. Feng ZHU

Prof. Yuzong CHEN