Limits...
Diphenyl urea derivatives as inhibitors of transketolase: a structure-based virtual screening.

Obiol-Pardo C, Alcarraz-Vizán G, Cascante M, Rubio-Martinez J - PLoS ONE (2012)

Bottom Line: Transketolase is an enzyme involved in a critical step of the non-oxidative branch of the pentose phosphate pathway whose inhibition could lead to new anticancer drugs.Here, we report new human transketolase inhibitors, based on the phenyl urea scaffold, found by applying structure-based virtual screening.These inhibitors are designed to cover a hot spot in the dimerization interface of the homodimer of the enzyme, providing for the first time compounds with a suggested novel binding mode not based on mimicking the thiamine pyrophosphate cofactor.

View Article: PubMed Central - PubMed

Affiliation: Departamento de Química Física, Facultat de Química, Universitat de Barcelona and Institut de Recerca en Química Teòrica i Computacional, Barcelona, Spain.

ABSTRACT
Transketolase is an enzyme involved in a critical step of the non-oxidative branch of the pentose phosphate pathway whose inhibition could lead to new anticancer drugs. Here, we report new human transketolase inhibitors, based on the phenyl urea scaffold, found by applying structure-based virtual screening. These inhibitors are designed to cover a hot spot in the dimerization interface of the homodimer of the enzyme, providing for the first time compounds with a suggested novel binding mode not based on mimicking the thiamine pyrophosphate cofactor.

Show MeSH

Related in: MedlinePlus

Comparison of transketolase model with crystal structure.A) Superimposition of the homology model of human transketolase (in pink) with the recently released crystal structure (in white). B) Close view of the residues used for pharmacophore definition, in the homology model (in pink and thin residues) and in the crystal structure (in white and thick residues).
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3293897&req=5

pone-0032276-g004: Comparison of transketolase model with crystal structure.A) Superimposition of the homology model of human transketolase (in pink) with the recently released crystal structure (in white). B) Close view of the residues used for pharmacophore definition, in the homology model (in pink and thin residues) and in the crystal structure (in white and thick residues).

Mentions: During the course of this research, the crystal structure of human transketolase was made public (pdb code 3MOS) [8] allowing its comparison with our previously reported homology model [15] that was used in the virtual screening protocol. Figure 4A shows a superimposition of our initial homology model and the crystal structure of transketolase highlighting a high similarity with a backbone RMSd of only 1.1 Å (for modeled monomer 1 and 331 atom pairs) and 1.2 Å (for modeled monomer 2 and 330 atom pairs). Overall our model predicted correctly the main structural parts of the protein, although the uncommon long loop of transketolase found in K282-A320 was not well predicted (Figure 4A between arrows). Nonetheless, this sequence is solvent exposed not participating in dimer stabilization nor catalytical activity. It is worth mentioning that the proposed pharmacophore used in this study (formed by Q203, K204 and E207) can be also extracted, with minor distances differences (all atom RMSd of 1.77 Å and 1.82 Å for modeled monomer 1 and 2, respectively), from the crystal structure of human transketolase (Figure 4B). Thereby, either our model or the crystal structure should be considered equally representative for the alpha helix fragment used in our virtual screening protocol.


Diphenyl urea derivatives as inhibitors of transketolase: a structure-based virtual screening.

Obiol-Pardo C, Alcarraz-Vizán G, Cascante M, Rubio-Martinez J - PLoS ONE (2012)

Comparison of transketolase model with crystal structure.A) Superimposition of the homology model of human transketolase (in pink) with the recently released crystal structure (in white). B) Close view of the residues used for pharmacophore definition, in the homology model (in pink and thin residues) and in the crystal structure (in white and thick residues).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3293897&req=5

pone-0032276-g004: Comparison of transketolase model with crystal structure.A) Superimposition of the homology model of human transketolase (in pink) with the recently released crystal structure (in white). B) Close view of the residues used for pharmacophore definition, in the homology model (in pink and thin residues) and in the crystal structure (in white and thick residues).
Mentions: During the course of this research, the crystal structure of human transketolase was made public (pdb code 3MOS) [8] allowing its comparison with our previously reported homology model [15] that was used in the virtual screening protocol. Figure 4A shows a superimposition of our initial homology model and the crystal structure of transketolase highlighting a high similarity with a backbone RMSd of only 1.1 Å (for modeled monomer 1 and 331 atom pairs) and 1.2 Å (for modeled monomer 2 and 330 atom pairs). Overall our model predicted correctly the main structural parts of the protein, although the uncommon long loop of transketolase found in K282-A320 was not well predicted (Figure 4A between arrows). Nonetheless, this sequence is solvent exposed not participating in dimer stabilization nor catalytical activity. It is worth mentioning that the proposed pharmacophore used in this study (formed by Q203, K204 and E207) can be also extracted, with minor distances differences (all atom RMSd of 1.77 Å and 1.82 Å for modeled monomer 1 and 2, respectively), from the crystal structure of human transketolase (Figure 4B). Thereby, either our model or the crystal structure should be considered equally representative for the alpha helix fragment used in our virtual screening protocol.

Bottom Line: Transketolase is an enzyme involved in a critical step of the non-oxidative branch of the pentose phosphate pathway whose inhibition could lead to new anticancer drugs.Here, we report new human transketolase inhibitors, based on the phenyl urea scaffold, found by applying structure-based virtual screening.These inhibitors are designed to cover a hot spot in the dimerization interface of the homodimer of the enzyme, providing for the first time compounds with a suggested novel binding mode not based on mimicking the thiamine pyrophosphate cofactor.

View Article: PubMed Central - PubMed

Affiliation: Departamento de Química Física, Facultat de Química, Universitat de Barcelona and Institut de Recerca en Química Teòrica i Computacional, Barcelona, Spain.

ABSTRACT
Transketolase is an enzyme involved in a critical step of the non-oxidative branch of the pentose phosphate pathway whose inhibition could lead to new anticancer drugs. Here, we report new human transketolase inhibitors, based on the phenyl urea scaffold, found by applying structure-based virtual screening. These inhibitors are designed to cover a hot spot in the dimerization interface of the homodimer of the enzyme, providing for the first time compounds with a suggested novel binding mode not based on mimicking the thiamine pyrophosphate cofactor.

Show MeSH
Related in: MedlinePlus