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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.

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Transketolase structure model.A) Homology model of human transketolase showing the antiparallel alpha helices involved in dimerization. B) Close view of the alpha helix D200-G210 showing the selected residues of the 5-point pharmacophore. HY: hydrophobic contact, HA: hydrogen acceptor, HD: hydrogen donor.
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pone-0032276-g001: Transketolase structure model.A) Homology model of human transketolase showing the antiparallel alpha helices involved in dimerization. B) Close view of the alpha helix D200-G210 showing the selected residues of the 5-point pharmacophore. HY: hydrophobic contact, HA: hydrogen acceptor, HD: hydrogen donor.

Mentions: The dimer interface was evaluated through molecular dynamics simulations [15] (see Materials and Methods section) calculating the interaction energies between all residues of both monomers to conclude that the conserved sequence D200-G210 fulfils the criteria used for pharmacophore selection. The high sequence conservation of D200-G210 with respect to the template (50%) [15] was considered an important trend that could point to an area of dimer stabilization. This short sequence belongs to an alpha helix motif that interacts with the same fragment of the partner monomer forming the antiparallel alpha helices structure shown in Figure 1A. This sequence forms a hydrogen bond donor between the amino group of Q203, of the first monomer, and the oxygen atom of the carboxylate of E207, belonging to the second monomer. Carboxylate of E207 of the first monomer forms two hydrogen bond acceptors, with Q203 and K204 of the second subunit. Finally, terminal amino of K204 of the first monomer maintains a hydrogen bond donor with the carboxylate of E207, of the second monomer. On the other hand, the analysis of van der Waals energies revealed us that Q203 offers a major contribution when interacting with the fragment D200-G210, providing around −8 kcal/mol and that residues K204 and E207 provided high electrostatic energies (around −20 kcal/mol).


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)

Transketolase structure model.A) Homology model of human transketolase showing the antiparallel alpha helices involved in dimerization. B) Close view of the alpha helix D200-G210 showing the selected residues of the 5-point pharmacophore. HY: hydrophobic contact, HA: hydrogen acceptor, HD: hydrogen donor.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0032276-g001: Transketolase structure model.A) Homology model of human transketolase showing the antiparallel alpha helices involved in dimerization. B) Close view of the alpha helix D200-G210 showing the selected residues of the 5-point pharmacophore. HY: hydrophobic contact, HA: hydrogen acceptor, HD: hydrogen donor.
Mentions: The dimer interface was evaluated through molecular dynamics simulations [15] (see Materials and Methods section) calculating the interaction energies between all residues of both monomers to conclude that the conserved sequence D200-G210 fulfils the criteria used for pharmacophore selection. The high sequence conservation of D200-G210 with respect to the template (50%) [15] was considered an important trend that could point to an area of dimer stabilization. This short sequence belongs to an alpha helix motif that interacts with the same fragment of the partner monomer forming the antiparallel alpha helices structure shown in Figure 1A. This sequence forms a hydrogen bond donor between the amino group of Q203, of the first monomer, and the oxygen atom of the carboxylate of E207, belonging to the second monomer. Carboxylate of E207 of the first monomer forms two hydrogen bond acceptors, with Q203 and K204 of the second subunit. Finally, terminal amino of K204 of the first monomer maintains a hydrogen bond donor with the carboxylate of E207, of the second monomer. On the other hand, the analysis of van der Waals energies revealed us that Q203 offers a major contribution when interacting with the fragment D200-G210, providing around −8 kcal/mol and that residues K204 and E207 provided high electrostatic energies (around −20 kcal/mol).

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