Hiroshi Chuman

VISCANA : Visualized cluster analysis of protein-ligand interaction based on the ab initio fragment molecular orbital method for virtual ligand screening

We have developed a visualized cluster analysis of protein-ligand interaction (VISCANA) that analyzes the pattern of the interaction of the receptor and ligand on the basis of quantum theory for virtual ligand screening. Kitaura et al. (Chem. Phys. Lett. 1999, 312, 319-324.) have proposed an ab initio fragment molecular orbital (FMO) method by which large molecules such as proteins can be easily treated with chemical accuracy. In the FMO method, a total energy of the molecule is evaluated by summation of fragment energies and interfragment interaction energies (IFIEs). In this paper, we have proposed a cluster analysis using the dissimilarity that is defined as the squared Euclidean distance between IFIEs of two ligands. Although the result of an ordered table by clustering is still a massive collection of numbers, we combine a clustering method with a graphical representation of the IFIEs by representing each data point with colors that quantitatively and qualitatively reflect the IFIEs. We applied VISCANA to a docking study of pharmacophores of the human estrogen receptor alpha ligand-binding domain (57 amino acid residues). By using VISCANA, we could classify even structurally different ligands into functionally similar clusters according to the interaction pattern of a ligand and amino acid residues of the receptor protein. In addition, VISCANA could estimate the correct docking conformation by analyzing patterns of the receptor-ligand interactions of some conformations through the docking calculation.

Effect of a conjugated quercetin metabolite, quercetin 3-glucuronide, on lipid hydroperoxide-dependent formation of reactive oxygen species in differentiated PC-12 cells

To assess the efficacy of conjugated quercetin metabolites as attenuators for oxidative stress in the central nervous system, we measured the 13-hydroperoxyoctadecadienoic acid (13-HPODE)-dependent formation of reactive oxygen species (ROS) in pheochromocytoma PC-12 cells in the presence of quercetin 3-O-β-glucuronide (Q3GA) and related compounds. A 2′,7′-dichlorofluorescin (DCFH) assay showed that Q3GA significantly suppressed the formation of ROS, when it was coincubated with 13-HPODE (coincubation system). However, it was less effective than quercetin aglycon in the concentration range from 0.5 to 10 μM. In an experiment in which the cells were incubated with the test compounds for 24 h before being exposed to 13-HPODE, Q3GA was also effective in suppressing the formation of ROS in spite that little Q3GA was taken up into the cells. These results suggest that antioxidative metabolites of quercetin are capable of protecting nerve cells from attack of lipid hydroperoxides.

Correlation Analyses on Binding Affinity of Sialic Acid Analogues with Influenza Virus Neuraminidase-1 Using ab Initio MO Calculations on Their Complex Structures

We carried out full ab initio molecular orbital calculations on complexes between neuraminidase-1 (N1-NA) in the influenza A virus and a series of eight sialic acid analogues including oseltamivir (Tamiflu) in order to quantitatively examine the binding mechanism and variation in the inhibitory potency at the atomic and electronic levels. FMO-MP2-IFIE (interfragment interaction energy at the MP2 level of ab initio fragment molecular orbital calculations) analyses quantitatively revealed (1) that the complex formation is driven by strong electrostatic interactions of charged functional groups in the analogues with ionized amino acid residues and water molecules in the active site of N1-NA, and (2) that the variation in the inhibitory potency among the eight analogues is determined by the dispersion and/or hydrophobic interaction energies of the 3-pentyl ether and charged amino moieties in oseltamivir with certain residues and water molecules in the active site of N1-NA. The current results will be useful for the development of new antiinfluenza drugs with high potency against various subtypes of wild-type and drug-resistant NAs.

Novel Quantitative Structure-Activity Studies of HIV-1 Protease Inhibitors of the Cyclic Urea Type Using Descriptors Derived from Molecular Dynamics and Molecular Orbital Calculations

Human immunodeficiency virus type 1 protease (HIV-1 PR) is an essential enzyme for the replication cycle of HIV-1. HIV-1 PR inhibitors have been extensively investigated as anti-AIDS drugs. For developments of HIV-1 PR inhibitors more promising than those utilized at the moment, the construction of reliable QSAR models that can elucidate the inhibitory mechanism as consistently as possible should be one of the most significant issues. Garg, Kurup, and their groups published comprehensive QSAR studies using past structure-activity data for HIV-1 PR inhibitors, and summarized some physicochemical structural factors of inhibitors that govern variations in the inhibitory activity for various structural types. There seem to exist much to be clarified further, especially for effects of electronic structure of inhibitors. It is also expected to incorporate structural and physicochemical information about the enzyme protein into the QSAR model. In this article, we reviewed our own QSAR study on a series of cyclic urea inhibitors with newly proposed QSAR descriptors. We performed molecular dynamics simulations of HIV-1 PR-inhibitor complexes to provide the accurate geometry to the fragment molecular orbital (FMO) calculations as well as to the estimation of an accessible surface area descriptor for inhibitors and amino acid residues. With the FMO procedure to cover full electronic feature of three-dimensional structure of protease-inhibitor complexes, we derived electronic descriptors for inhibitors and amino acid residues. The successful results are believed to provide a new insight into QSAR and understanding of binding mechanism of inhibitors with HIV-1 PR at atomic and electronic levels.

Assessment of free energy expressions in RISM integral equation theory: theoretical prediction of partition coefficients revisited

We assess the performance of free energy expressions so far available in the reference interaction site model (RISM) integral equation theory. Free energies of solvation in aqueous and chloroform solutions along with the partition coefficients of them are calculated for 16 organic molecules. Static polarity effects are included using hybrid RISM and Hartree–Fock methods. Our best estimates are obtained from the expression of the distributed partial wave expansion that leads to the standard deviations less than 1.3 kcal mol−1 and 1.1 in the solvation free energies and partition coefficients, respectively.

Correlation Analyses on Binding Affinity of Sialic Acid Analogues and Anti-Influenza Drugs with Human Neuraminidase Using ab Initio MO Calculations on Their Complex Structures – LERE-QSAR Analysis (IV)

We carried out full ab initio fragment molecular orbital (FMO) calculations for complexes comprising human neuraminidase-2 (hNEU2) and sialic acid analogues including anti-influenza drugs zanamivir (Relenza) and oseltamivir (Tamiflu) in order to examine the variation in the observed inhibitory activity toward hNEU2 at the atomic and electronic levels. We recently proposed the LERE (linear expression by representative energy terms)-QSAR (quantitative structure-activity relationship) procedure. LERE-QSAR analysis quantitatively revealed that the complex formation is driven by hydrogen-bonding and electrostatic interaction of hNEU2 with sialic acid analogues. The most potent inhibitory activity, that of zanamivir, is attributable to the strong electrostatic interaction of a positively charged guanidino group in zanamivir with negatively charged amino acid residues in hNEU2. After we confirmed that the variation in the observed inhibitory activity among sialic acid analogues is excellently reproducible with the LERE-QSAR equation, we examined the reason for the remarkable difference between the inhibitory potencies of oseltamivir as to hNEU2 and influenza A virus neuraminidase-1 (N1-NA). Several amino acid residues in close contact with a positively charged amino group in oseltamivir are different between hNEU2 and N1-NA. FMO-IFIE (interfragment interaction energy) analysis showed that the difference in amino acid residues causes a remarkably large difference between the overall interaction energies of oseltamivir with hNEU2 and N1-NA. The current results will be useful for the development of new anti-influenza drugs with high selectivity and without the risk of adverse side effects.

Correlation analyses on binding affinity of substituted benzenesulfonamides with carbonic anhydrase using ab initio MO calculations on their complex structures (II)

We proposed a novel QSAR (quantitative structure-activity relationship) procedure called LERE (linear expression by representative energy terms)-QSAR involving molecular calculations such as ab initio fragment molecular orbital and generalized Born/surface area ones. We applied LERE-QSAR to two datasets for the free-energy changes during complex formation between carbonic anhydrase and a series of substituted benzenesulfonamides. The first compound set (Set I) and the second one (Set II) include relatively small substituents and alkyl chains of different lengths in the benzene ring, respectively. Variation of the inhibitory activity in Set I is expressed as the combination of Hammett σ and the hydrophobic substituent constant π in classical QSAR, and variation in Set II only by π. LERE-QSAR analyses clearly revealed that effects of σ and π on the activity variations in Sets I and II are consistently explainable with the energy terms in the LERE formulation, and provide more detailed and direct information as to the binding mechanism. The proposed procedure was demonstrated to provide a quantitative basis for understanding ligand-protein interactions at the electronic and atomic levels.

Remarkable discrepancy in the predominant structures of acyl(or thioacyl)aminothiadiazoles, acyl(or thioacyl)aminooxadiazoles and related compounds having the potential for rotational, geometrical and tautomeric isomerism

X-Ray crystallographic structures of 5-ethyl-2-trifluorothioacetylamino-1,3,4-thiadiazole 2 , 5-ethyl-3- p -nitrobenzyl-2-trifluorothioacetylimino-1,3,4-thiadiazoline 4 and 5- n -propyl-2-trifluoroacetylamino-1,3,4-thiadiazole 7 proved to be monomeric or dimeric bearing intermolecular hydrogen bondings and/or an intramolecular nonbonded 1,5-type S⋯S or S⋯O interactions. In contrast, the X-ray crystallographic structure of 5-ethyl-2-trifluoroacetylamino-1,3,4-oxadiazole 5 was shown to be dimeric involving ordinal intra- and intermolecular hydrogen bondings without any close contact. The ab initio computational studies (HF/6-311G*) of the four monomeric formylamino- and thioformylaminothiadiazoles(or -oxadiazoles) and formylimino- and thioformyliminothiadiazolines(or -oxadiazolines) structures 8 – 11 clarified the relative structure–stability order and a remarkable discrepancy in the predominant structures of the acylamino- and thioacylaminothiadiazoles and -oxadiazoles having the potential for rotational, geometrical and tautomeric isomerism.

Binding Free-Energy Calculation Is a Powerful Tool for Drug Optimization: Calculation and Measurement of Binding Free Energy for 7-Azaindole Derivatives to Glycogen Synthase Kinase-3β

Present computational lead (drug)-optimization is lacking in thermodynamic tactics. To examine whether calculation of binding free-energy change (ΔG) is effective for the lead-optimization process, binding ΔGs of 7-azaindole derivatives to the ATP binding site of glycogen synthase kinase-3β (GSK-3β) were calculated. The result was a significant correlation coefficient of r = 0.895 between calculated and observed ΔGs. This indicates that calculated ΔG reflects the inhibitory activities of 7-azaindole derivatives. In addition to quantitative estimation of activity, ΔG calculation characterizes the thermodynamic behavior of 7-azaindole derivatives, providing also useful information for inhibitor optimization on affinity to water molecules.

A Novel Three‐Dimensional QSAR Procedure: Voronoi Field Analysis

A new procedure for 3D-QSAR analyses is proposed. The steric and electrostatic potential indices are calculated/estimated at lattice points, but the indices are manipulated to be assigned to superposed molecular regions defined by the Voronoi polyhedral division. The number of the descriptors from which latent variables are extracted by the partial least squares procedure is much lower than that used in the SYBYL-CoMFA. As the steric potential function, the hard-sphere model was used instead of the Lennard-Jones equation. The partial least squares procedure was applied to steric and electrostatic field variables, separately, so as to make the physicochemical meaning of the latent variables easily understandable. The procedure is shown to work almost equivalently with or even better than the classical QSAR as well as the conventional 3D-QSAR such as the CoMFA.