Abstract: We have generated docking poses for the FKBP-GPI complex using eight docking programs, and compared their scoring functions with scoring based on NMR chemical shift perturbations (NMRScore). Because the chemical shift perturbation (CSP) is exquisitely sensitive on the orientation of the ligand inside the binding pocket, NMRScore offers an accurate and straightforward approach to score different poses. All scoring functions were inspected by their abilities to highly rank the native-like structures and separate them from decoy poses generated for a protein-ligand complex. The overall performance of NMRScore is much better than that of energy-based scoring functions associated with docking programs in both aspects. In summary, we find that the combination of docking programs with NMRScore results in an approach that can robustly determine the binding site structure for a protein-ligand complex, thereby providing a new tool facilitating the structure-based drug discovery process.

Authors: Bing Wang, Lance M. Westerhoff, and Kenneth M. Merz Jr.

Reference: J. Med. Chem., 50 (21), 5128-5134, 2007. (see link for full paper).

Abstract: Herein we will focus on the use of quantum mechanics (QM) in drug design (DD) to solve disparate problems from scoring protein–ligand poses to building QM QSAR models. Through the variational principle of QM we know that we can obtain a more accurate representation of molecular systems than classical models, and while this is not a matter of debate, it still has not been shown that the expense of QM approaches is offset by improved accuracy in DD applications. Objectively validating the improved applicability and performance of QM over classical-based models in DD will be the focus of research in the coming years along with research on the conformational sampling problem as it relates to protein–ligand complexes.

Authors: Kaushik Raha, Martin B. Peters, Bing Wang, Ning Yu, Andrew M. Wollacott, Lance M. Westerhoff, and Kenneth M. Merz Jr.

Reference: Drug Discovery Today. 2007, 12:17-18, 725-731. (see link for full paper).

Abstract: A fast approach to calculate nuclear magnetic resonance (NMR) chemical shifts within the quantum mechanical/molecular mechanical (QM/MM) framework has been developed. The QM treatment is based on our recently implemented MNDO/NMR method (Wang et al. J. Chem. Phys. 2004, 120, 11392). The effect of the QM/MM partitioning on chemical shifts has been investigated by test calculations on the water dimer and on the protein crambin. It has been shown that the quantum mechanical treatment of the hydrogen bond and nearby groups with significant magnetic susceptibilities is necessary in order to reproduce the full QM results. The method is also applied to a protein-ligand complex FKBP-GPI, and excellent agreement for proton chemical shifts of the ligand is obtained by including the side-chain atoms of the binding site residues into the QM region. The NMR chemical shift calculations using QM/MM-minimized structures still yield satisfactory results. Our results demonstrate that this QM/MM NMR method is able to treat critical regions of very large macromolecules without compromising accuracy if a relatively large QM region is used.

Authors: Bing Wang and Kenneth M. Merz, Jr.

Reference: J. Chem. Theory Comput. 2005, 2(1), 209-215. (see link for full paper).

Abstract: Recently, we have developed a fast approach to calculate NMR chemical shifts using the divide and conquer method at the semiempirical level. To demonstrate the utility of this approach for characterizing protein-ligand interactions, we used the deviation of calculated chemical shift perturbations from experiment to determine the orientation of a ligand (GPI-1046) in the binding pocket of the FK506 binding protein (FKBP12). Moreover, we were able to select the native state of the ligand from a collection of decoy poses. A key hydrogen bond between O1 and HN in Ile56 was also identified. Our results suggest that ligand-induced chemical shift perturbations can be used to refine protein/ligand structures.

Authors: Bing Wang, Kaushik Raha, and Kenneth M. Merz, Jr.

Reference: J. Am. Chem. Soc. 2004, 126(37), 11430-11431. (see link for full paper).

Abstract: A new approach to calculate nuclear magnetic resonance chemical shifts has been implemented at the semiempirical modified neglect of diatomic overlap level using gauge-including atomic orbitals. The perturbed density matrix with respect to the magnetic field is obtained by the diagonalization of the complex Fock matrix using the divide and conquer (DC) method, instead of by solving the computationally expensive coupled perturbed Hartree–Fock equations. Adopting the Patchkovskii and Thiel parameters [S. Patchkovskii and W. Thiel J. Comput. Chem. 20, 1220 (1999)], we were able to reproduce their results for small organic molecules. The errors introduced by DC method are negligible, as shown by the calculations on a series of polyalaine structures. Test calculations on proteins have demonstrated that our approach makes it possible to calculate chemical shifts routinely on systems with hundreds of atoms with good accuracy.

Authors: Bing Wang, Edward N. Brothers, Arjan van der Vaart, and Kenneth M. Merz, Jr.

Reference: J. Chem. Phys. 2004, 120(24), 11329-11400. (see link for full paper).