Human protein tyrosine phosphatase 1B inhibitors: QSAR by genetic function approximation

Protein tyrosine phosphatase 1B (PTP 1B), a negative regulator of insulin receptor signaling system, has emerged as a highly validated, attractive target for the treatment of non-insulin dependent diabetes mellitus (NIDDM) and obesity. As a result there is a growing interest in the development of potent and specific inhibitors for this enzyme. This quantitative structure-activity relationship (QSAR) study for a series of formylchromone derivatives as PTP lB inhibitors was performed using genetic function approximation (GFA) technique. The QSAR models were developed using a training set of 29 compounds and the predictive ability of the QSAR model was evaluated against a test set of 7 compounds. The internal and external consistency of the final QSAR model was 0.766 and 0.785. The statistical quality of QSAR models was assessed by statistical parameters r2, r2 (crossvalidated r2), r2pred (predictive r2) and lack of fit (LOF) measure. The results indicate that PTP lB inhibitory activity of the formylchromone derivatives is strongly dependent on electronic, thermodynamic and shape related parameters.     

Molecular docking and 3D-QSAR studies of Yersinia protein tyrosine phosphatase YopH inhibitors

Three-dimensional quantitative structure-activity relationship (QSAR) studies were conducted on two classes of recently explored compounds with known YopH inhibitory activities. Docking studies were employed to position the inhibitors into the YopH active site to determine the probable binding conformation. Good correlations between the predicated binding free energies and the inhibitory activities were found for two subsets of phosphate mimetics: alpha-ketocarboxylic acid and squaric acid (R2=0.70 and 0.68, respectively). The docking results also provided a reliable conformational alignment scheme for 3D-QSAR modeling. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed based on the docking conformations, giving q2 of 0.734 and 0.754 for CoMFA and CoMSIA models, respectively. The 3D-QSAR models were significantly improved after removal of an outlier (q2=0.829 for CoMFA and q2=0.837 for CoMSIA). The predictive ability of the models was validated using a set of compounds that were not included in the training set. Mapping the 3D-QSAR models to the active site of YopH provides new insight into the protein-inhibitor interactions for this enzyme. These results should be applicable to the prediction of the activities of new YopH inhibitors, as well as providing structural implications for designing potent and selective YopH inhibitors as antiplague agents.     

Three-dimensional quantitative structure–activity relationship (3D-QSAR) of 3-aryloxazolidin-2-one antibacterials

Three-dimensional quantitative structure–activity relationship (3D-QSAR) studies for 3-aryloxazolidin-2-one antibacterials were performed using the genetic function approximation algorithm. This study was performed using 60 compounds, in which the QSAR models were developed using a training set of 50 compounds. The in vitro minimum inhibitory concentration (MIC) against Staphylococcus aureus SFCO-1a was used for the study. The predictive ability of the QSAR model was evaluated by using a test set of 10 compounds. The statistical quality of the QSAR models was assessed using statistical parameters r², r²_cv (cross-validated r²), r²_pred (predictive r²) and lack of fit measure (LOF). The results obtained indicate that the antibacterial activity of the 3-aryloxazolidin-2-ones is strongly dependent on electronic factor as expressed by lowest unoccupied molecular orbital energy (LUMO), spatial factor as expressed by density and thermodynamic factors accounted for by molar refractivity and heat of formation. The model is presently being used to design and predict new potent molecules prior to synthesis.     

A combined approach of docking and 3D QSAR study of beta-ketoacyl-acyl carrier protein synthase III (FabH) inhibitors

The enzyme FabH catalyzes the initial step of fatty acid biosynthesis via a type II fatty acid synthase. The pivotal role of this essential enzyme combined with its unique structural features and ubiquitous occurrence in bacteria has made it an attractive new target for the development of antibacterial and antiparasitic compounds. Three-dimensional quantitative structure-activity relationship (3D QSAR) studies such as comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) and docking simulations were conducted on a series of potent benzoylaminobenzoic acids. Docking studies were employed to position the inhibitors into the FabH active site to determine the probable binding conformation. A reasonable correlation between the predicated binding free energy and the inhibitory activity was found. CoMFA and CoMSIA were performed based on the docking conformations, giving q(2) of 0.637 and 0.697 for CoMFA and CoMSIA models, respectively. The predictive ability of the models was validated using a set of compounds that were not included in the training set and progressive scrambling test. Mapping the 3D QSAR models to the active site of FabH related that some important amino acid residues are responsible for protein-inhibitor interaction. These results should be applicable to the prediction of the activities of new FabH inhibitors, as well as providing structural understanding.     

Three-dimensional quantitative structure-activity relationship (3D-QSAR) studies of tricyclic oxazolidinones as antibacterial agents

Oxazolidinones exemplified by eprezolid and linezolid are a new class of antibacterials that are active against Gram positive and anaerobic bacteria including methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE) and vancomycin resistant enterococci (VRE). In an effort to have a better antibacterial agent in the oxazolidinone class, we have performed three-dimensional quantitative structure-activity relationship (3D-QSAR) studies for a series of tricyclic oxazolidinones. 3D-QSAR studies were performed using the Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) procedures. These studies were performed using 42 compounds; the QSAR model was developed using a training set of 33 compounds. The predictive ability of the QSAR model was assessed using a test set of 9 compounds. The predictive 3D-QSAR models have conventional r(2) values of 0.975 and 0.940 for CoMFA and CoMSIA respectively; similarly, cross-validated coefficient q(2) values of 0.523 and 0.557 for CoMFA and CoMSIA, respectively, were obtained. The CoMFA 3D-QSAR model performed better than the CoMSIA model.     

3D-QSAR and docking studies of aldehyde inhibitors of human cathepsin K

In order to better understand the structural and chemical features of human cathepsin K (CatK), which is an important cysteine protease in the pathogenesis of osteoporosis, the 3D-QSAR (CoMFA) studies were conducted on recently explored aldehyde compounds with known CatK inhibitory activities. The genetic algorithm of GOLD2.2 has been employed to position 59 aldehyde compounds into the active sites of CatK to determine the probable binding conformation. Good correlations between the predicted binding free energies and the experimental inhibitory activities suggested that the identified binding conformations of these potential inhibitors are reliable. The docking results also provided a reliable conformational alignment scheme for 3D-QSAR model. Based on the docking conformations, highly predictive comparative molecular field analysis (CoMFA) was performed with q2 value of 0.723. The predictive ability was validated by some compounds that were not included in the training set. Furthermore, the CoMFA model was mapped back to the binding sites of CatK, to get a better understanding of vital interactions between the aldehyde compounds and the protease. The CoMFA field distributions are in good agreement with the structural characteristics of the binding groove of the CatK, which suggested that the n-Bu in R4 position is the favor group substitute at P1 and moderate groups in R2 group are required on P2 substitute. In addition, 3D-QSAR results also demonstrated that aldehyde is an important pharmacophore because of electrostatic effect. These results, together with the good correlations between the inhibitory activities and the binding free energies predicted by GOLD2.2, demonstrated the power of combining docking/QSAR approach to explore the probable binding conformations of compounds at the active sites of the protein target, and further provided useful information in understanding the structural and chemical features of CatK in designing and finding new potential inhibitors.