TY - JOUR
T1 - Docking and DFT Studies to explore the Topoisomerase II ATP Pocket employing 3-Substituted 2,6-Piperazindiones for drug design
AU - Correa-Basurto, J.
AU - Ramos-Morales, F. R.
AU - Matus, M. H.
AU - Rosales-Hernández, M. C.
AU - Mancilla-Percino, T.
AU - Trujillo-Ferrara, J.
AU - Ilizaliturri-Flores, I.
N1 - Funding Information:
We thank CONACyT for financial support (Grant: 132353), ICyTDF and SIP-COFAA/IPN to JCB) and PROMEP/ 103.5/08/1073, PTC-249 to FRR-M. MHM thanks PROMEP México for financial support (Grant: PROMEP/103.5/10/5006, UV-PTC-459). We are very grateful to Prof. David A. Dixon from the University of Alabama and to Prof. Marcelo Galván from the Universidad Autónoma Metropolitana – Iztapalapa for the computational resources provided to carry out DFT calculations.
PY - 2012/11/1
Y1 - 2012/11/1
N2 - Topoisomerases (Topos) are very important protein targets for drug design in cancer treatment. Human Topo type II (hTopo II) has been widely studied experimentally and theoretically. Here, we performed protein rigid/flexible side-chain docking to study a set of thirty-nine 3-substituted-2,6- piperazindiones (labelled 1a, (R)-[(2-20)a] and (S)-[(2-20)b]) derived from -amino acids. To explain the ligand-protein complexes at the electronic level [using the highest occupied and the lowest unoccupied molecular orbitals (HOMO and LUMO) energies], density functional theory calculations were carried out. Finally, to show adenosine triphosphate (ATP) binding-site constituents, the Q-SiteFinder program was used. The docking results showed that all of the test compounds bind to the ATP-binding site on hTopo II. Recognition is mediated by the formation of several hydrogen bond acceptors or donators. This site was the largest (631Å 3) according to the Q-SiteFinder program. When using the protein rigid docking protocol, compound 13a derived from (R)-Lys showed the highest affinity. However, when a flexible side-chain docking protocol was used, the compound with the highest affinity was 16a, derived from (R)-Trp. Frontier molecular orbital studies showed that the HOMO of the ligand interacts with the LUMO located at side-chain residues from the protein-binding site. The HOMO of the binding site interacts with the LUMO of the ligand. We conclude that some ligand properties including the hindrance effect, hydrogen bonds, - interactions and stereogenic centres are important for the ligand to be recognised by the ATP-binding site of hTopo II.
AB - Topoisomerases (Topos) are very important protein targets for drug design in cancer treatment. Human Topo type II (hTopo II) has been widely studied experimentally and theoretically. Here, we performed protein rigid/flexible side-chain docking to study a set of thirty-nine 3-substituted-2,6- piperazindiones (labelled 1a, (R)-[(2-20)a] and (S)-[(2-20)b]) derived from -amino acids. To explain the ligand-protein complexes at the electronic level [using the highest occupied and the lowest unoccupied molecular orbitals (HOMO and LUMO) energies], density functional theory calculations were carried out. Finally, to show adenosine triphosphate (ATP) binding-site constituents, the Q-SiteFinder program was used. The docking results showed that all of the test compounds bind to the ATP-binding site on hTopo II. Recognition is mediated by the formation of several hydrogen bond acceptors or donators. This site was the largest (631Å 3) according to the Q-SiteFinder program. When using the protein rigid docking protocol, compound 13a derived from (R)-Lys showed the highest affinity. However, when a flexible side-chain docking protocol was used, the compound with the highest affinity was 16a, derived from (R)-Trp. Frontier molecular orbital studies showed that the HOMO of the ligand interacts with the LUMO located at side-chain residues from the protein-binding site. The HOMO of the binding site interacts with the LUMO of the ligand. We conclude that some ligand properties including the hindrance effect, hydrogen bonds, - interactions and stereogenic centres are important for the ligand to be recognised by the ATP-binding site of hTopo II.
KW - ATP-binding site
KW - Density functional theory
KW - Docking
KW - HOMO-LUMO energies
KW - Topoisomerase
UR - http://www.scopus.com/inward/record.url?scp=84867471495&partnerID=8YFLogxK
U2 - 10.1080/08927022.2012.690877
DO - 10.1080/08927022.2012.690877
M3 - Artículo
SN - 0892-7022
VL - 38
SP - 1072
EP - 1084
JO - Molecular Simulation
JF - Molecular Simulation
IS - 13
ER -