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Objectives: Three strong interactions between amino acid side chains (salt bridge, cation-π, and amide bridge) are studied that are stronger than (or comparable to) the common hydrogen bond interactions, and play important roles in protein-protein interactions., Methods: Quantum chemical methods MP2 and CCSD(T) are used in calculations of interaction energies and structural optimizations., Results: The energies of three types of amino acid side chain interactions in gaseous phase and in aqueous solutions are calculated using high level quantum chemical methods and basis sets. Typical examples of amino acid salt bridge, cation-π, and amide bridge interactions are analyzed, including the inhibitor design targeting neuraminidase (NA) enzyme of influenza A virus, and the ligand binding interactions in the HCV p7 ion channel. The inhibition mechanism of the M2 proton channel in the influenza A virus is analyzed based on strong amino acid interactions., Conclusion: (1) The salt bridge interactions between acidic amino acids (Glu- and Asp-) and alkaline amino acids (Arg+, Lys+ and His+) are the strongest residue-residue interactions. However, this type of interaction may be weakened by solvation effects and broken by lower pH conditions. (2) The cation- interactions between protonated amino acids (Arg+, Lys+ and His+) and aromatic amino acids (Phe, Tyr, Trp and His) are 2.5 to 5-fold stronger than common hydrogen bond interactions and are less affected by the solvation environment. (3) The amide bridge interactions between the two amide-containing amino acids (Asn and Gln) are three times stronger than hydrogen bond interactions, which are less influenced by the pH of the solution. (4) Ten of the twenty natural amino acids are involved in salt bridge, or cation-, or amide bridge interactions that often play important roles in protein-protein, protein-peptide, protein-ligand, and protein-DNA interactions.

A new phenylethanoid glycoside, named taraffinisoside A (1), together with five known glycosides were isolated from the stems and leaves of Tarphochlamys affinis. The structure of taraffinisoside A was identified on the basis of detailed spectral analysis. Compounds 1-4 and 6 showed potent antioxidant activities with IC50 values of 10.36, 19.73, 43.95, 15.30 and 46.04 μM by 1,1-diphenyl-2-picryhydrazyl radical-scavenging assay. Compounds 1, 2 and 4 showed anti-HBV activities, with IC50 values of 0.50, 0.72 and 0.26 mM for HBsAg and 0.93, 0.42 and 0.07 mM for HBeAg, respectively.

Background: The recently solved solution structure of HCV (hepatitis C virus) p7 ion channel provides a solid structure basis for drug design against HCV infection. In the p7 channel the ligand amantadine (or rimantadine) was determined in a hydrophobic pocket. However the pharmocophore (-NH2) of the ligand was not assigned a specific binding site., Results: The possible binding sites for amino group of adamantane derivatives is studied based on the NMR structure of p7 channel using QM calculation and molecular modeling. In the hydrophobic cavity and nearby three possible binding sites are proposed: His17, Phe20, and Trp21. The ligand binding energies at the three binding sites are studied using high level QM method CCSD(T)/6-311+G(d,p) and AutoDock calculations, and the interaction details are analyzed. The potential application of the binding sites for rational inhibitor design are discussed., Conclusions: Some useful viewpoints are concluded as follows. (1) The amino group (-NH2) of adamantane derivatives is protonated (-NH3+), and the positively charged cation may form cation-π interactions with aromatic amino acids. (2) The aromatic amino acids (His17, Phe20, and Trp21) are the possible binding sites for the protonated amino group (-NH3+) of adamantane derivatives, and the cation-π bond energies are 3 to 5 times stronger than the energies of common hydrogen bonds. (3) The higher inhibition potent of rimantadine than amantadine probably because of its higher pKa value (pKa = 10.40) and the higher positive charge in the amino group. The potential application of p7 channel structure for inhibitor design is discussed.

For quite a long period of time in history, many intense efforts have been made to determine the 3D (three-dimensional) structure of the M2 proton channel. The reason why the M2 proton channel has attracted so many attentions is because (1) it is the key for really understanding the life cycle of influenza viruses, and (2) it is indispensable for conducting rational drug design against the flu viruses. Recently, the long-sough 3D structures of the M2 proton channels for both influenza A and B viruses were consecutively successfully determined by the high-resolution NMR spectroscopy (Schnell J.R. and Chou, J.J., Nature, 2008, 451: 591-595; Wang, J., Pielak, R.M., McClintock, M.A., and Chou, J.J., Nature Structural & Molecular Biology, 2009,16: 1267-1271). Such a milestone work has provided a solid structural basis for in-depth understanding the action mechanism of the M2 channel and rationally designing effective drugs against influenza viruses. This review is devoted to, with the focus on the M2 proton channel of influenza A, addressing a series of relevant problems, such as how to correctly understand the novel allosteric inhibition mechanism inferred from the NMR structure that is completely different from the traditional view, what the possible impacts are to the previous functional studies in this area, and what kind of new strategy can be stimulated for drug development against influenza.

The inhibitions of enzymes (proteins) are determined by the binding interactions between ligands and targeting proteins. However, traditional QSAR (quantitative structure-activity relationship) is a one-side technique, only considering the structures and physicochemical properties of inhibitors. In this study, the structure-based and multiple potential three-dimensional quantitative structure-activity relationship (SB-MP-3D-QSAR) is presented, in which the structural information of host protein is involved in the QSAR calculations. The SB-MP-3D-QSAR actually is a combinational method of docking approach and QSAR technique. Multiple docking calculations are performed first between the host protein and ligand molecules in a training set. In the targeting protein, the functional residues are selected, which make the major contribution to the binding free energy. The binding free energy between ligand and targeting protein is the summation of multiple potential energies, including van der Waals energy, electrostatic energy, hydrophobic energy, and hydrogen-bond energy, and may include nonthermodynamic factors. In the foundational QSAR equation, two sets of weighting coefficients {aj} and {bp} are assigned to the potential energy terms and to the functional residues, respectively. The two coefficient sets are solved by using iterative double least-squares (IDLS) technique in the training set. Then, the two sets of weighting coefficients are used to predict the bioactivities of inquired ligands. In an application example, the new developed method obtained much better results than that of docking calculations.

Background: M2 proton channel of H1N1 influenza A virus is the target protein of anti-flu drugs amantadine and rimantadine. However, the two once powerful adamantane-based drugs lost their 90% bioactivity because of mutations of virus in recent twenty years. The NMR structure of the M2 channel protein determined by Schnell and Chou (Nature, 2008, 451, 591-595) may help people to solve the drug-resistant problem and develop more powerful new drugs against H1N1 influenza virus., Methodology: Docking calculation is performed to build the complex structure between receptor M2 proton channel and ligands, including existing drugs amantadine and rimantadine, and two newly designed inhibitors. The computer-aided drug design methods are used to calculate the binding free energies, with the computational biology techniques to analyze the interactions between M2 proton channel and adamantine-based inhibitors., Conclusions: 1) The NMR structure of M2 proton channel provides a reliable structural basis for rational drug design against influenza virus. 2) The channel gating mechanism and the inhibiting mechanism of M2 proton channel, revealed by the NMR structure of M2 proton channel, provides the new ideas for channel inhibitor design. 3) The newly designed adamantane-based inhibitors based on the modeled structure of H1N1-M2 proton channel have two pharmacophore groups, which act like a "barrel hoop", holding two adjacent helices of the H1N1-M2 tetramer through the two pharmacophore groups outside the channel. 4) The inhibitors with such binding mechanism may overcome the drug resistance problem of influenza A virus to the adamantane-based drugs.

The neuraminidase (NA) of influenza virus is the target of anti-flu drugs oseltamivir and zanamivir. Clinical practices showed that oseltamivir was effective to treat the 2009-H1N1 influenza but failed to the 2006-H5N1 avian influenza. To perform an in-depth analysis on such a drug-resistance problem, the 2009-H1N1-NA structure was developed. To compare it with the crystal 2006-H5N1-NA structure as well as the 1918 influenza virus H1N1-NA structure, the multiple sequential and structural alignments were performed. It has been revealed that the hydrophobic residue Try347 in H5N1-NA does not match with the hydrophilic carboxyl group of oseltamivir as in the case of H1N1-NA. This may be the reason why H5N1 avian influenza virus is drug-resistant to oseltamivir. The finding provides useful insights for how to modify the existing drugs, such as oseltamivir and zanamivir, making them not only become more effective against H1N1 virus but also effective against H5N1 virus.

Understanding the mechanism of the M2 proton channel of influenza A is crucially important to both basic research and drug discovery. Recently, the structure was determined independently by high-resolution NMR and X-ray crystallography. However, the two studies lead to completely different drug-binding mechanisms: the X-ray structure shows the drug blocking the pore from inside; whereas the NMR structure shows the drug inhibiting the channel from outside by an allosteric mechanism. Which one of the two is correct? To address this problem, we conducted an in-depth computational analysis. The conclusions drawn from various aspects, such as energetics, the channel-gating dynamic process, the pK(a) shift and its impact on the channel, and the consistency with the previous functional studies, among others, are all in favour to the allosteric mechanism revealed by the NMR structure. The findings reported here may stimulate and encourage new strategies for developing effective drugs against influenza A, particularly in dealing with the drug-resistant problems.

A new drug design method, the multiple field three-dimensional quantitative structure-activity relationship (MF-3D-QSAR), is proposed. It is a combination and development of classical 2D-QSAR and traditional 3D-QSAR. In addition to the electrostatic and van der Waals potentials, more potential fields (such as lipophilic potential, hydrogen bonding potential, and nonthermodynamic factors) are integrated in the MF-3D-QSAR. Meanwhile, a principal component analysis (PCA) and iterative double least square (IDLS) technique is developed for predicting the bioactivity of query drug candidates. As an example, the MF-3D-QSAR is applied to the design of neuraminidase inhibitor and to prove its predictive power, and some useful findings are obtained for developing drugs against influenza virus., ((c) 2007 Wiley Periodicals, Inc. J Comput Chem, 2008.)