Target Information

Target General Information

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Target ID

T30372 (Former ID: TTDR00982)

Target Name

Trypanosoma Cruzipain (Trypano CYSP)

Synonyms

Cruzaine; Major cysteine proteinase

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Gene Name

Trypano CYSP

Target Type

Successful target

[1]

Disease

[+] 1 Target-related Diseases

Parasitic worm infestation [ICD-11: 1F90]

Function

The cysteine protease may play an important role in the development and differentiation of the parasites at several stages of their life cycle.

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BioChemical Class

Peptidase

UniProt ID

CYSP_TRYCR

EC Number

EC 3.4.22.51

Sequence

MSGWARALLLAAVLVVMACLVPAATASLHAEETLTSQFAEFKQKHGRVYESAAEEAFRLS
VFRENLFLARLHAAANPHATFGVTPFSDLTREEFRSRYHNGAAHFAAAQERARVPVKVEV
VGAPAAVDWRARGAVTAVKDQGQCGSCWAFSAIGNVECQWFLAGHPLTNLSEQMLVSCDK
TDSGCSGGLMNNAFEWIVQENNGAVYTEDSYPYASGEGISPPCTTSGHTVGATITGHVEL
PQDEAQIAAWLAVNGPVAVAVDASSWMTYTGGVMTSCVSEQLDHGVLLVGYNDSAAVPYW
IIKNSWTTQWGEEGYIRIAKGSNQCLVKEEASSAVVGGPGPTPEPTTTTTTSAPGPSPSY
FVQMSCTDAACIVGCENVTLPTGQCLLTTSGVSAIVTCGAETLTEEVFLTSTHCSGPSVR
SSVPLNKCNRLLRGSVEFFCGSSSSGRLADVDRQRRHQPYHSRHRRL

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Drugs and Modes of Action

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Approved Drug(s)

[+] 1 Approved Drugs

TRICLABENDAZOLE

Drug Info

Approved

Helminth infection

[2]

Mode of Action

[+] 2 Modes of Action

Inhibitor

[+] 27 Inhibitor drugs

TRICLABENDAZOLE

Drug Info

[1]

MANIDIPINE

Drug Info

[1]

L-755507

Drug Info

[3]

(3Z)-1H-indole-2,3-dione 3-thiosemicarbazone

Drug Info

[4]

1-(1-(3-nitrophenyl)propylidene)thiosemicarbazide

Drug Info

[5]

1-(3,4-dihydronaphthalen-1-yl)ethanone

Drug Info

[5]

1-(3-Methoxy-benzyl)-5-methyl-1H-indole-2,3-dione

Drug Info

[4]

1-(bis(3-bromophenyl)methylene)thiosemicarbazide

Drug Info

[5]

2-(cycloheptylamino)-2-oxoethyl 2-aminonicotinate

Drug Info

[6]

2-(trifluoromethyl)benzaldehyde thiosemicarbazone

Drug Info

[7]

2-methoxy-1-naphthaldehyde thiosemicarbazone

Drug Info

[7]

3'-bromopropiophenonethiosemicarbazone

Drug Info

[8]

3,5-dichlorobenzaldehyde thiosemicarbazone

Drug Info

[7]

3-(trifluoromethyl)benzaldehyde thiosemicarbazone

Drug Info

[7]

3-amino-5-(furan-2-yl)biphenyl-2,4-dicarbonitrile

Drug Info

[3]

3-chloro-N-(4-(phenyldiazenyl)phenyl)benzamide

Drug Info

[3]

5-(3,4-dichlorophenyl)-1H-pyrazol-3-ol

Drug Info

[3]

5-(4-bromophenyl)-2-furaldehyde thiosemicarbazone

Drug Info

[7]

5-Chloro-1-(4-chloro-benzyl)-1H-indole-2,3-dione

Drug Info

[4]

Benzoyl-Arginine-Alanine-Methyl Ketone

Drug Info

[9]

GNF-PF-4478

Drug Info

[10]

K-777

Drug Info

[11]

N1,N4-bis(5-chloro-2-methylphenyl)succinamide

Drug Info

[3]

VITAMIN K2

Drug Info

[1]

WRR-112

Drug Info

[9]

WRR-204

Drug Info

[9]

WRR-99

Drug Info

[9]

Binder

[+] 1 Binder drugs

Vinylsulphones

Drug Info

[12]

Drug Binding Sites of Target

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Ligand Name: WRR-112

Ligand Info

Structure Description

THE CYSTEINE PROTEASE CRUZAIN BOUND TO WRR-112

PDB:1EWM

Method

X-ray diffraction

Resolution

2.00 Å

Mutation

[13]

PDB Sequence

APAAVDWRAR

¹⁰

GAVTAVKDQG

²⁰

QCGSCWAFSA

³⁰

IGNVECQWFL

⁴⁰

AGHPLTNLSE

⁵⁰

QMLVSCDKTD

⁶⁰

SGCSGGLMNN

⁷⁰

AFEWIVQENN

^78B

GAVYTEDSYP

⁸⁷

YASGEGISPP

⁹⁴

CTTSGHTVGA

¹⁰⁵

TITGHVELPQ

¹¹⁵

DEAQIAAWLA

¹²⁵

VNGPVAVAVD

¹³⁵

ASSWMTYTGG

¹⁴⁷

VMTSCVSEQL

¹⁵⁷

DHGVLLVGYN

¹⁶⁷

DSAAVPYWII

¹⁷³

KNSWTTQWGE

¹⁸³

EGYIRIAKGS

¹⁹³

NQCLVKEEAS

²⁰⁷

SAVVG

Residue

Distance (Å)

GLN19

2.961

CYS22

4.011

GLY23

3.180

SER24

3.355

CYS25

1.827

TRP26

3.377

THR59

4.544

ASP60

4.457

SER61

3.497

SER64

4.033

GLY65

3.230

Residue

Distance (Å)

GLY66

3.027

LEU67

3.886

MET68

3.561

ASN70

4.288

ALA133

3.763

LEU157

3.746

ASP158

3.506

HIS159

2.829

GLY160

4.070

GLU205

4.331

Ligand Name: WRR-99

Ligand Info

Structure Description

CRYSTAL STRUCTURE OF CRUZAIN BOUND TO WRR-99

PDB:1EWL

Method

X-ray diffraction

Resolution

2.00 Å

Mutation

[14]

PDB Sequence

APAAVDWRAR

¹⁰

GAVTAVKDQG

²⁰

QCGSCWAFSA

³⁰

IGNVECQWFL

⁴⁰

AGHPLTNLSE

⁵⁰

QMLVSCDKTD

⁶⁰

SGCSGGLMNN

⁷⁰

AFEWIVQENN

^78B

GAVYTEDSYP

⁸⁷

YASGEGISPP

⁹⁴

CTTSGHTVGA

¹⁰⁵

TITGHVELPQ

¹¹⁵

DEAQIAAWLA

¹²⁵

VNGPVAVAVD

¹³⁵

ASSWMTYTGG

¹⁴⁷

VMTSCVSEQL

¹⁵⁷

DHGVLLVGYN

¹⁶⁷

DSAAVPYWII

¹⁷³

KNSWTTQWGE

¹⁸³

EGYIRIAKGS

¹⁹³

NQCLVKEEAS

²⁰⁷

SAVVG

Residue

Distance (Å)

GLN19

2.758

CYS22

4.057

GLY23

3.144

SER24

3.417

CYS25

1.826

TRP26

3.459

SER61

3.992

SER64

3.610

GLY65

3.242

Residue

Distance (Å)

GLY66

3.184

LEU67

3.664

MET68

3.638

ALA133

3.580

LEU157

3.790

ASP158

3.418

HIS159

2.765

GLY160

4.030

GLU205

4.001

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

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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 Similarity Proteins

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

Chemical Structure based Activity Landscape of Target

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Drug Property Profile of Target

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(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

Target Poor or Non Binders

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Target Poor or Non Binders

Target Poor or Non Binders Info

Target-Related Models and Studies

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Target Validation

Target Validation Info

References

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REF 1

Colloid formation by drugs in simulated intestinal fluid. J Med Chem. 2010 May 27;53(10):4259-65.

REF 2

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

REF 3

Quantitative analyses of aggregation, autofluorescence, and reactivity artifacts in a screen for inhibitors of a thiol protease. J Med Chem. 2010 Jan 14;53(1):37-51.

REF 4

Synthesis and evaluation of isatins and thiosemicarbazone derivatives against cruzain, falcipain-2 and rhodesain. Bioorg Med Chem Lett. 2003 Oct 20;13(20):3527-30.

REF 5

Design, synthesis, and biochemical evaluation of novel cruzain inhibitors with potential application in the treatment of Chagas' disease. Bioorg Med Chem Lett. 2006 Aug 15;16(16):4405-9.

REF 6

Divergent modes of enzyme inhibition in a homologous structure-activity series. J Med Chem. 2009 Aug 27;52(16):5005-8.

REF 7

Synthesis and structure-activity relationship study of potent trypanocidal thio semicarbazone inhibitors of the trypanosomal cysteine protease cruz... J Med Chem. 2002 Jun 20;45(13):2695-707.

REF 8

Studies toward the structural optimization of novel thiazolylhydrazone-based potent antitrypanosomal agents. Bioorg Med Chem. 2010 Nov 15;18(22):7826-35.

REF 9

How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.

REF 10

Complementarity between a docking and a high-throughput screen in discovering new cruzain inhibitors. J Med Chem. 2010 Jul 8;53(13):4891-905.

REF 11

Novel non-peptidic vinylsulfones targeting the S2 and S3 subsites of parasite cysteine proteases. Bioorg Med Chem Lett. 2009 Nov 1;19(21):6218-21.

REF 12

Opportunities and challenges in antiparasitic drug discovery. Nat Rev Drug Discov. 2005 Sep;4(9):727-40.

REF 13

THE CYSTEINE PROTEASE CRUZAIN BOUND TO WRR-112

REF 14

CRYSTAL STRUCTURE OF CRUZAIN BOUND TO WRR-99

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