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Table 2 Drug target inhibitors

From: In silico work flow for scaffold hopping in Leishmania

No.

PROTEIN

Inhibitor name

IC50 /Ki

i1

Pteridine Reductase 1

methotrexate (nature structural biology, volume 8, number 6, june 2001)

1.1 μM

i2

Pteridine Reductase 1

Trimethoprim (Experimental Parasitology 87, 157–169 (1997))

12 μM

i3

Pteridine Reductase 1

10 – propargyl-5,8-dideazafolic acid (J. Mol. Biol. (2005) 352, 105–116)

> 10 μM

i4

Trypanothione Reductase

methyl [(4S) - 6 - bromo - 2 - methyl - 4 - phenylquinazolin - 3(4H)-YL] acetate (J. Med. Chem. 2011, 54, 6514–6530)

6.8 μM

i5

Trypanothione Reductase

(4 s) - 3 - benzyl - 6 - chloro - 2 - methyl - 4 - phenyl - 3,4 – dihydroquinazoline (J. Med. Chem. 2011, 54, 6514–6530)

0.93 μM

i6

Trypanothione Reductase

n - {2 - [(4 s) - 6 - chloro - 2 - methyl - 4 - phenylquinazolin - 3(4 h) - yl] ethyl}furan - 2 – carboxamide (J. Med. Chem. 2011, 54, 6514–6530)

0.86 μM

i7

Trypanothione Reductase

(4 s) - 6 - chloro - 3 - {2 - [4 - (furan - 2 - ylcarbonyl)piperazin - 1 - yl]ethyl} -2 - methyl - 4 - phenyl - 3,4 –dihydroquinazoline (J. Med. Chem. 2011, 54, 6514–6530)

0.42 μM

i8

Trypanothione Reductase

3 - [(4 s) - 6 - chloro - 2 - methyl - 4 - (4 - methylphenyl) quinazolin - 3(4 h) -yl] - n,n - dimethylpropan - 1 – amine (J. Med. Chem. 2011, 54, 6514–6530)

0.23 μM

i9

Trypanothione Reductase

a C6 - substituted and C8 - substituted 3,4 - dihydroquinazoline analogue (J. Med. Chem. 2011, 54, 6514–6530)

0.35 μM

i10

Pteridine Reductase 1

a quinazoline derivative (Experimental Parasitology 1997, 87, 157–169 )

0.4 μM

i11

Pteridine Reductase 1

a 2,4-Diaminopyrimidine derivative (Experimental Parasitology 1997 ,87, 157–169 )

0.4 μM

iTb4 to iTb8

Trypanothione Reductase crystal complex from T. brucei

Above inhibitor i1 to i5. (J. Med. Chem. 2011, 54, 6514–6530)

Same as above

i12

ATP dependent Phospho Fructo Kinase

a N, N0 - substituted - 1-amino - 2, 5 - anhydro - 1 - deoxy - 1 - D -mannonamide derivatives (Bioorg. Med. Chem. 2008, 16 , 5050–5061)

49 μM

i13

ATP dependent Phospho Fructo Kinase

2, 5 - anhydro - 1 - deoxy - 1 - (3, 4 - dichlorobenzylamino) - D – mannitol (Bioorg. Med. Chem. 2008, 16 , 5050–5061)

0.4 μM

i14

ATP dependent Phospho Fructo Kinase

2, 5 - Anhydro - 1 - deoxy - 1 - (3, 4 - dichlorobenzylamino) - D - 3, 4 - dichlorobenzylmannonamide (Bioorg. Med. Chem. 2008, 16 , 5050–5061)

23 μM

i15

Deoxyuridine Triphosphate Nucleotidohydrolase

a 5′ - tert - butyldiphenylsilyloxy derivative (J. Med. Chem. 2005, 48, 5942–5954)

3.0 μM

i16

Deoxyuridine Triphosphate Nucleotidohydrolase

a 5′ - Ph3CNH derivative (J. Med. Chem. 2005, 48, 5942–5954)

NA; substrate analog

i17

Deoxyuridine Triphosphate Nucleotidohydrolase

5′ - tritylamino - 3′ - fluoro - 2′, 3′, 5′ – trideoxyuridine (J. Med. Chem. 2005, 48, 5942–5954)

3.6 μM

i18

Deoxyuridine Triphosphate Nucleotidohydrolase

5′ - O - triphenylsilyl - 2′, 3′ - didehydro - 2′, 3′ – dideoxyuridine (J. Med. Chem. 2005, 48, 5942–5954)

12 μM

i19

Nonspecific Nucleoside Hydrolase

immucillin A (J. Biol. Chem. 1999,274(30, 21114–21120)

15 nM

i20

Nonspecific Nucleoside Hydrolase

immucilin ACAP (J. Biol. Chem.1999, 274(30), 21114–21120)

6.5 nM

i21

Nonspecific Nucleoside Hydrolase

N - (9 - deaza - adenin - 9 - yl) methyl - 1, 4 - dideoxy - 1, 4 - imino - D - ribitol (Antimicrobial Agents and Chemotherapy, 2010, 1900–1908)

0.49 μM

i22

Nonspecific Nucleoside Hydrolase

immucillin-H (1, 4 - dideoxy - 4 - aza - 1 - (s) - (9 - deazahypoxanthin - 9 - yl) - d - ribitol) (Biochem Biophys. Acta.2009, 1794, 953–960)

Ki = 6.2 nM

i23

Nonspecific Nucleoside Hydrolase

7 - (((2R, 3R, 4S) - 3, 4 - dihydroxy - 2 - (hydroxymethyl) pyrrolidin - 1 - yl) methyl) - 3H - pyrrolo [3, 2-d] pyrimidin - 4 (5H) - one (Biochem Biophys. Acta. 2009, 1794 , 953–960)

Ki = 4.4 nM

i24

Nonspecific Nucleoside Hydrolase

(2R, 3R, 4S) - 2 - (hydroxymethyl) - 1 - (quinolin - 8 - ylmethyl) pyrrolidine - 3, 4 – diol (Biochem Biophys. Acta. 2009, 1794, 953–960)

Ki = 10.8 μM

i25

Trypanothione Synthetase

1-[3-(3-fluorophenyl)indazol-1-yl]-3,3-dimethylbutan-2-one (J.Biol.Chem., 2009, 284( 52), pp. 36137–36145)

0.095 μM

i26

Putative-UDP-glc-4′-epimerase

ebselen (Bioorg. & Med. Chem. Lett. 2006, 16 , 5744–5747)

0.62 μM

i27

GLO1

S-4-bromobenzylglutathionylspermidine (Molecular Microbiology,2006, 59, 1239–1248)

Ki = 0.54 μM

  1. Inhibitors identified for eight of the proteins from Table 1 along with their respective IC50’s or Ki values with respect to their corresponding target proteins. The inhibitors will be referred to by the numbers assigned in the first column.