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).