Target Information

Target General Information

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Target ID

T02702

Target Name

Bacterial Dihydrofolate reductase (Bact DHFR)

Synonyms

Bact Dihydrofolate reductase

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Gene Name

Bact DHFR

Target Type

Clinical trial target

[1]

Disease

[+] 1 Target-related Diseases

Bacterial infection [ICD-11: 1A00-1C4Z]

Function

Key enzyme in folate metabolism. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis.

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UniProt ID

DYR_ECOLI

EC Number

EC 1.5.1.3

Sequence

MISLIAALAVDRVIGMENAMPWNLPADLAWFKRNTLNKPVIMGRHTWESIGRPLPGRKNI
ILSSQPGTDDRVTWVKSVDEAIAACGDVPEIMVIGGGRVYEQFLPKAQKLYLTHIDAEVE
GDTHFPDYEPDDWESVFSEFHDADAQNSHSYCFEILERR

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3D Structure

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PDB

Drugs and Modes of Action

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Clinical Trial Drug(s)

[+] 1 Clinical Trial Drugs

Iclaprim

Drug Info

Phase 3

Bacterial infection

[2]

Discontinued Drug(s)

[+] 3 Discontinued Drugs

AR-709

Drug Info

Terminated

Bacterial infection

[3]

DIAVERIDINE

Drug Info

Terminated

Bacterial infection

[4]

Epiroprim

Drug Info

Terminated

Bacterial infection

[5]

Mode of Action

[+] 1 Modes of Action

Modulator

[+] 4 Modulator drugs

Iclaprim

Drug Info

[1]

AR-709

Drug Info

[6], [6]

DIAVERIDINE

Drug Info

[7]

Epiroprim

Drug Info

[8]

Drug Binding Sites of Target

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Ligand Name: Folic acid

Ligand Info

Structure Description

Cryogenic WT DHFR

PDB:4KJJ

Method

X-ray diffraction

Resolution

1.15 Å

Mutation

[9]

PDB Sequence

MISLIAALAV

¹⁰

DRVIGMENAM

²⁰

PWNLPADLAW

³⁰

FKRNTLNKPV

⁴⁰

IMGRHTWESI

⁵⁰

GRPLPGRKNI

⁶⁰

ILSSQPGTDD

⁷⁰

RVTWVKSVDE

⁸⁰

AIAACGDVPE

⁹⁰

IMVIGGGRVY

¹⁰⁰

EQFLPKAQKL

¹¹⁰

YLTHIDAEVE

¹²⁰

GDTHFPDYEP

¹³⁰

DDWESVFSEF

¹⁴⁰

HDADAQNSHS

¹⁵⁰

YCFEILERR

Residue

Distance (Å)

ILE5

1.855

ALA6

2.709

ALA7

2.405

MET20

2.590

TRP22

3.992

PRO25

4.529

ASP27

1.977

LEU28

2.004

ALA29

2.740

TRP30

2.851

PHE31

2.458

LYS32

2.122

THR35

4.768

LEU36

4.994

Residue

Distance (Å)

THR46

2.987

SER49

4.703

ILE50

2.251

LEU54

2.723

PRO55

3.366

ARG57

1.858

ILE94

2.256

GLY95

4.366

TYR100

3.362

TYR111

4.369

LEU112

4.598

THR113

2.401

PHE153

4.255

Click to View More Binding Site Information of This Target and Ligand Pair

Ligand Name: Methotrexate

Ligand Info

Structure Description

Crystal structure of the ternary MTX NADPH complex of Escherichia coli dihydrofolate reductase

PDB:3DAU

Method

X-ray diffraction

Resolution

1.50 Å

Mutation

[10]

PDB Sequence

MISLIAALAV

¹⁰

DRVIGMENAM

²⁰

PWNLPADLAW

³⁰

FKRNTLNKPV

⁴⁰

IMGRHTWESI

⁵⁰

GRPLPGRKNI

⁶⁰

ILSSQPGTDD

⁷⁰

RVTWVKSVDE

⁸⁰

AIAACGDVPE

⁹⁰

IMVIGGGRVY

¹⁰⁰

EQFLPKAQKL

¹¹⁰

YLTHIDAEVE

¹²⁰

GDTHFPDYEP

¹³⁰

DDWESVFSEF

¹⁴⁰

HDADAQNSHS

¹⁵⁰

YCFEILERR

Residue

Distance (Å)

ILE5

2.818

ALA6

3.422

ALA7

3.773

MET20

2.890

PRO25

3.409

ASP27

2.659

LEU28

3.449

ALA29

3.530

TRP30

4.141

PHE31

3.416

LYS32

3.324

THR35

4.875

Residue

Distance (Å)

THR46

4.132

SER49

3.927

ILE50

3.543

ARG52

2.941

LEU54

3.665

PRO55

4.211

ARG57

2.754

VAL93

4.982

ILE94

2.915

GLY95

4.713

TYR100

3.235

THR113

3.528

Click to View More Binding Site Information of This Target and Ligand Pair

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

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

Co-Targets

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Co-Targets

Co-Targets Info

Target Poor or Non Binders

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Target Poor or Non Binders

Target Poor or Non Binders Info

References

Top

REF 1

Iclaprim: a novel dihydrofolate reductase inhibitor for skin and soft tissue infections.Future Microbiol.2009 Mar;4(2):131-44.

REF 2

How many modes of action should an antibiotic have Curr Opin Pharmacol. 2008 Oct;8(5):564-73.

REF 3

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800020451)

REF 4

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800002763)

REF 5

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800002670)

REF 6

Activity of the Diaminopyrimidine AR-709 against Recently Collected Multidrug-Resistant Isolates of Invasive Streptococcus pneumoniae from North America

REF 7

Acute and sub-chronic toxicity study of diaveridine in Wistar rats.Regul Toxicol Pharmacol.2015 Oct;73(1):232-40.

REF 8

In vitro activity of epiroprim, a dihydrofolate reductase inhibitor, singly and in combination with brodimoprim and dapsone, against Mycobacterium ... Int J Antimicrob Agents. 1999 Aug;12(4):319-23.

REF 9

Automated identification of functional dynamic contact networks from X-ray crystallography. Nat Methods. 2013 Sep;10(9):896-902.

REF 10

X-ray structure of the ternary MTX.NADPH complex of the anthrax dihydrofolate reductase: a pharmacophore for dual-site inhibitor design. J Struct Biol. 2009 May;166(2):162-71.

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