A comparative 2D QSAR study on a series of hydroxamic acid-based histone deacetylase inhibitors vis-à-vis comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA).

A quantitative structure-activity relationship (QSAR) study was performed on a series of indole amide analogues reported by Dai et al. [Bioorg Med Chem Lett (2003), 13, 1897-1901] to act as histone deacetylase (HDAC) inhibitors. The multiple regression analysis (MRA) revealed a model showing the significant dependence of the activity on molar refractivity (MR) and global topological charge index (GTCI) of the compounds, suggesting that inhibition of the HDAC by this series of compounds might involve the dispersion interaction with the receptor, where charge transfer between pairs of atoms might greatly help to polarize the molecule. The MRA results were then compared with those obtained by Guo et al. [Bioorg Med Chem (2005), 13, 5424-5434] by comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). It was found that MRA gave as good results and had as good predictive ability as CoMFA and CoMSIA. Besides, MRA was also able to throw the light on the physicochemical properties of the molecules that were involved in drug-receptor interactions, while CoMFA and CoMSIA could not. The dispersion interaction between the molecule and the active site of the receptor is suggested to be the main interaction.

A quantitative structure-activity relationship (QSAR) study on a few series of potent, highly selective inhibitors of nitric oxide synthase.

QSAR study was performed on a series of 1,2-dihydro-4-quinazolinamines, 4,5-dialkylsubstituted-2-imino-1,3-thiazolidine derivatives and 4,5-disubstituted-1,3-oxazolidin-2-imine derivatives studied by Tinker et al. [J Med Chem (2003), 46, 913-916], Ueda et al. [Bioorg Med Chem (2004) 12, 4101-4116] and Ueda et al. [Bioorg Med Chem Lett (2004) 14, 313-316], respectively, as potent, highly selective inhibitors of inducible nitric oxide synthase (iNOS). The iNOS inhibition activity of the whole series of compounds was analyzed in relation to the physicochemical and molecular properties of the compounds. The QSAR analysis revealed that the inhibition potency of the compounds was controlled by a topological parameter 1v (Kier’s first order valence molecular connectivity index), density (D), surface tension (St) and length (steric parameter) of a substituent. This suggested that the drug-receptor interaction predominantly involved the dispersion interaction, but the bulky molecule would face steric problem because of which the molecule may not completely fit in active sites of the receptor and thus may not have the optimum interaction.

A QSAR study on a series of thiourea derivatives acting as anti-hepatitis C virus agents.

A quantitative structure-activity relationship (QSAR) study was performed on a large series of thiourea derivatives reported by Kang et al. [Bioorg Med Chem Lett (2009), 19, 1950-55 & 6063-68], acting as anti-hepatitis C virus (anti-HCV) agents. The activity of the compounds was found to be significantly correlated with their hydrophobic property and three indicator variables I1, I2 and I3, the first two specifying a negative effect of an alkyl and an aromatic group, respectively on their R-moiety and the third one specifying a negative effect of their Ar-moiety having a nitrogen-containing heterocyclic ring. The whole set containing 85 compounds was divided into two subsets: the training set and the test set containing 61 and 24 compounds, respectively. For the training set, the correlation coefficient (r) and the square of cross-validated correlation coefficient (r2cv) were found to be 0.926 and 0.83, respectively. The correlation obtained suggested that anti-HCV activity of the compounds would depend on their hydrophobic property, conformational flexibility and the steric effects of an alkyl or an aromatic group on the R-moiety. This suggested that the molecules might have significant hydrophobic interactions with the receptor which might be aided by their conformational flexibility, but hindered sterically by an alkyl or an aromatic group on their R-moiety. Using the correlation obtained, some new compounds having activity higher (>8.0) than the most active compound in the existing series were predicted.

A QSAR and molecular modeling study on a series of 3, 4-dihydro-1-isoquinolinamines and thienopyridines acting as nitric oxide synthase inhibitors.

A quantitative structure-activity relationship (QSAR) and molecular modeling study were performed on a series of 3,4-dihyro-1-isoquinolinamines and thienopyridines reported by Beaton et al. [Beaton et al. (2001) Bioorg Med Chem Lett 11, 1023-1026, 1027-1030] as potent, highly selective inhibitors of two isoforms of nitric oxide synthase (NOS) — neuronal NOS (nNOS) and endothelial NOS (eNOS), in order to find the physicochemical properties that governed their activity and the mode of interaction with the receptors, so that still more potent compounds in the series could be suggested. A multiple regression analysis revealed that nNOS and eNOS inhibition potency of these compounds could be controlled by their hydrophobic property and molar refractivity, respectively. Thus, nNOS and eNOS inhibition was indicated to involve the hydrophobic interaction and steric effects, respectively, suggesting some structural differences of the two isoforms of NOS. Based on the correlations obtained, some new, more potent compounds belonging to the series were predicted. These compounds were then docked into the receptors to see their interactions and find out the docking scores. The docked structures of two representative compounds, whose interaction energies with nNOS and eNOS, respectively were found to be the lowest, were given as an example to exhibit the possible orientation of the compounds to interact with the receptors.

A QSAR study on a series of N-methyl pyrimidones acting as HIV integrase inhibitors.

A quantitative structure-activity relationship (QSAR) study has been performed on integrase (IN) inhibition activity of a large series of N-methyl pyrimidones [Gardelli et al. (2007) J Med Chem 50, 4953-4975)] having varying heterocyclic ring substitution at 2-position of pyrimidone ring. The activity is found to be significantly correlated with surface tension and molar volume of the molecules. The whole series of compounds is divided into two subsets: a training set and a test set. A significant correlation is obtained for the training set, which is then used to predict the activity of compounds in the test set. The predicted activities of compounds in the test set are found to be very close to their observed activities. The predicting ability of the correlation obtained is judged by leave-one-out jackknife procedure. The correlation shows the effective role of the surface tension and molar volume of the molecules. From the correlation obtained, the integrase inhibition activities are predicted for some new prospective compounds.