Quantitative Structure-activity Relationship Investigations Research Articles

QSAR study of neuraminidase inhibitors based on heuristic method and radial basis function network

Neuraminidase (NA) is a critical enzyme of the influenza virus and many inhibitors targeting this enzyme are quite efficient anti-influenza agents. In this paper, quantitative structure–activity relationship (QSAR) method was used to predict the activity of different kinds of 46 NA inhibitors. Heuristic method (HM) and radial basis function network (RBFNN) were first used to build linear and nonlinear models, respectively. The prediction results were in agreement with the experimental value. The proposed model is simple and can be extended to other QSAR investigations.

A quantitative structure–activity relationship investigation into agonist binding at GABA C receptors

The quantitative structure–activity relationship (QSAR) model constructed in this work represents the first quantitative investigation into agonist binding at GABA C receptors. This model is based upon the three-dimensional structures of (γ-aminobutyric acid (GABA) and 12 other biologically active GABA analogues. These structures are obtained by geometry optimization and conformational exploration at MP2/6-31+G* within the conductor-like screening solvation model (COSMO). The biological activity data are obtained from previous two-electrode voltage clamp electrophysiological studies on recombinant GABA C ρ1 receptors expressed in Xenopus laevis oocytes. A QSAR model to predict GABA C agonist binding is constructed from molecular superposition data, generated by least-squares superposition of the stable aqueous phase conformations of GABA and its known biologically active analogues to the bioactive conformation of TACA, the most potent GABA C receptor agonist. A significant relationship is found between the root-mean-squared deviation in atomic position for the stable conformer of each GABA analogue most closely fitting the template TACA structure and the natural log of the normalized biological activity ( R 2=0.91, p<0.0001), On the basis of molecular superposition and QSAR results, a pharmacophore model describing three-dimensional features and key interactions at the GABA C receptor binding site is proposed. As there exists no direct experimental knowledge of structure of the GABA C binding site, this approach provides a feasible and reliable alternative to gain insight into its three-dimensional structure.

Synthesis and QSAR Studies of Pyrimido[4,5‐d]pyrimidine‐2,5‐dione Derivatives as Potential Antimicrobial Agents.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Esters, amides and substituted derivatives of cinnamic acid: synthesis, antimicrobial activity and QSAR investigations

A series of esters ( I a–k ), substituted derivatives ( II a–d ) and amides ( III a–q ) of cinnamic acid were synthesized and evaluated as antibacterial and antifungal agents. All the derivatives belonging to the series I, II and III showed antimicrobial activity comparable to the standard. Compounds I f and II c proved to be the most effective compounds. Quantitative structure–activity relationship (QSAR) investigation with multiple linear regression analysis was applied to find a correlation between different calculated physicochemical parameters of the compounds and biological activity. The quantitative models relating the structural features of cinnamic acid derivatives I a–k, II a–d and III a–q and their antimicrobial activity showed that Gram negative Escherichia coli and Candida albicans (fungus) were the most sensitive microorganisms.

Synthesis and QSAR studies of pyrimido[4,5- d]pyrimidine-2,5-dione derivatives as potential antimicrobial agents

A number of pyrimido[4,5- d]pyrimidine-2,5-dione derivatives were synthesized and screened for antibacterial and antifungal activities. All the synthesized compounds showed the potent antimicrobial activity. The quantitative structure–activity relationship investigation was applied to find a correlation between the different physicochemical parameters of the compounds studied and their biological activity.

Quantitative structure-activity relationship (QSAR) study of polyhydroxyxanthones

In the present study 13C-chemical shift additivity rules are developed for polyhydroxyxanthones with antituberculotic activity against Mycobacterium tuberculosis. QSAR investigations are performed by correlating 13C-chemical shifts and calculated dipole moments of several 1,3-substituted polyhydroxyxanthones with their antituberculotic activity and by using the CoMFA approach as a threedimensional QSAR method.

Molecular modelling of mammalian CYP2B isoforms and their interaction with substrates, inhibitors and redox partners

1. The construction of three-dimensional models of CYP2B isozymes from rat (CYP2B1), rabbit (CYP2B4) and man (CYP2B6), based on a multiple sequence alignment with CYP102,a unique eukaryotic-like bacterial P450 (in terms of possessing an NADPHdependent FAD- and FMN-containing oxidoreductase redox partner) of known crystal structure, is reported. 2. The enzyme models described are shown to be consistent with experimental evidence from site-directed mutagenesis studies, antibody recognitionsites and amino acid residues identified as being associated with redox partner interactions, together with the location of a key serine residue (Ser-128) likely to be involved in protein kinaseA-mediated phosphorylation. 3. A substantial number of known substrates and inhibitors of CYP2B isozymes are shown to fit the putative active sites of the enzyme models inagreement with their reported position of metabolism or mode of inhibition respectively. In particular, there is complementarity between the characteristic non-planar geometries of CYP2B substrates and key groups in the enzymes' active sites. 4. Molecular modelling of CYP2B isozymes appears to rationalize a number of the reported findings from quantitative structure-activity relationship investigations on series of CYP2B substrates and inhibitors.

Structure-activity relationships for unsaturated dialdehydes 6. The mutagenic activity of 11 compounds in the V79/HGPRT assay

The mutagenic activity of 11 sesquiterpenoid unsaturated dialdehydes in the V79/HGPRT assay has been determined, and is compared with previously published data on the mutagenicity of the same compounds towards Ames Salmonella strains. One compound, isovelleral, is a potent mutagen in both assays, while six compounds, which are positive in the Ames Salmonella/microsome assay, show no significant activity in this study. One compound, acetylmerulidial, is negative in the Ames Salmonella/microsome assay but significantly although weakly mutagenic in the V79/HGPRT assay. The remaining three compounds are inactive in both assays. The study is part of a general investigation of quantitative structure-activity relationships for unsaturated dialdehydes, a class of natural occurring compounds known for their potent and numerous biological activities.

A Molecular shape analysis and quantitative structure-activity relationship investigation of some triazine-antifolate inhibitors of Leishmania dihydrofolate reductase

Molecular shape analysis (MSA) is used to develop quantitative structure-activity relationships (QSARs) for a set of 45 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-(3-substituted-phenyl)-s-triazine inhibitors of Leishmania major dihydrofolate reductase (DHFR). The MSA-QSARs are equally significant to a QSAR developed by R. G. Booth et al. ((1987) J. Med. Chem. 30, 1218) using linear free energy descriptors. However, the MSA-QSARs have the same general form as all other QSARs developed for DHFR inhibitors using MSA. Molecular shape, as represented by common overlap steric volume of each inhibitor with a shape reference standard triazine from the set of 45 compounds, and relative lipophilicity account for the large majority of the variance in inhibition potency as a function of substituent choice. A general method of evaluating the impact of different conformational states of flexible substituents upon the form and significance of MSA-QSARs is developed. The results of applying this method to the 45 triazines indicate that the MSA-QSARs are relatively independent of the type of conformation assigned to the large flexible substituents. It is important to note, however, that the types of substituent conformations used in this analysis cannot necessarily be related to an “active” substituent conformation.