Quantum and molecular dynamics study for binding of macrocyclic inhibitors to human alpha-thrombin.
Molecular dynamics simulations followed by quantum mechanical calculation and Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) analysis have been carried out to study binding of proline- and pyrazinone-based macrocyclic inhibitors (L86 and T76) to human alpha-thrombin. Detailed binding interaction energies between these inhibitors and individual protein fragments are calculated using DFT method based on a new quantum mechanical approach for computing protein-ligand interaction energy. The analysis of detailed interaction energies provides insight on the protein-ligand binding mechanism. Study shows that T76 and L86 bind to thrombin in a very similar "inhibition mode" except that T76 has relatively weaker binding interaction with Glu(217). The analysis from quantum calculation of binding interaction is consistent with the MM-PBSA calculation of binding free energy, and the calculated free energies for L86/T76-thrombin binding agree well with the experimental data.
Wu
Emilia L
EL
Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.
Mei
Ye
Y
Han
KeLi
K
Zhang
John Z H
JZ
D001665:Binding Sites; D003198:Computer Simulation; D006801:Humans; D047028:Macrocyclic Compounds / Q000037:antagonists & inhibitors*; D008956:Models, Chemical; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D011789:Quantum Theory; D013917:Thrombin / Q000737:chemistry* / Q000648:ultrastructure*
D047028:Macrocyclic Compounds; D013917:Thrombin