Pharmacophore modelling and atom-based 3D-QSAR studies on N-methyl pyrimidones as HIV-1 integrase inhibitors.

Pharmacophore modelling and atom-based 3D-QSAR studies were carried out for a series of compounds belonging to N-methyl pyrimidones as HIV-1 integrase inhibitors. Based on the ligand-based pharmacophore model, we got 5-point pharmacophore model AADDR, with two hydrogen bond acceptors (A), two hydrogen bond donors (D) and one aromatic ring (R). The generated pharmacophore-based alignment was used to derive a predictive atom-based 3D-QSAR model for the training set (r(2) = 0.92, SD = 0.16, F = 84.8, N = 40) and for test set (Q(2) = 0.71, RMSE = 0.06, Pearson R = 0.90, N = 10). From these results, AADDR pharmacophore feature was selected as best common pharmacophore hypothesis, and atom-based 3D-QSAR results also support the outcome by means of favourable and unfavourable regions of hydrophobic and electron-withdrawing groups for the most potent compound 30. These results can be useful for further design of new and potent HIV-1 IN inhibitors.

Investigation of the structural requirement for inhibiting HIV integrase: QSAR study.

HIV integrase has emerged as a promising target for discovery of agents against the acquired immunodeficiency syndrome (AIDS) pandemic. With the purpose of designing new chemotypes with enhanced potencies against the HIV integrase enzyme, the QSAR study carried out on 37 novel phthalimide derivatives is presented. The developed QSAR model was validated by standard statistical parameters and through a detailed structural study of how it reproduces and explains the quantitative differences seen in experimentally known pharmacological data. The model showed a good correlative and predictive ability having a cross-validated correlation coefficient (r2 cv) of 0.709 and a conventional correlation coefficient (r2) of 0.949. The predictive correlation coefficient (r2 pred) was found to be 0.512. The study revealed that the antiretroviral activity is predominantly explained by the substituent size, shape and polarity and provided insights into how modulation of the steric bulkiness and polarities of the substituents could be made to optimize the integrase-inhibitor interaction chemistry. A detailed investigation was made of the structural basis for the antiretroviral activity and the findings from the study could be usefully employed to design antagonists with a much more enhanced potency and selectivity.

QSAR study on dual SET and NET reuptake inhibitors: an insight into the structural requirement for antidepressant activity.

Monoamine transporters have emerged as important drug targets with a multitude of therapeutic potentials for their inhibitors. With the purpose of designing new chemical entities with enhanced inhibitory potencies against norepinephrine and serotonin transporters, the QSAR study carried out on N-arylmethylpiperidinamine derivatives as known inhibitors of these transporters is presented. The developed model was validated by standard QSAR parameters and through a detailed structural analysis on how it reproduces and explains the differences in the experimentally known activity data. The model showed a good correlative and predictive ability having a squared cross validated correlation co-efficient of 0.716 and 0.700 respectively for SET and NET inhibition. The squared conventional correlation coefficient was found to be 0.731 for SET antagonism and 0.777 for norepinephrine reuptake inhibition. The study confirmed that the serotonin reuptake inhibitory activity exhibited by the series is largely explained by steric factors of substituents emphasizing the role of size and shape of the inhibitors in making effective inhibitor-SET binding interactions whereas substituent lipophilicity was found to govern inhibitor-NET interaction chemistry. A detailed comparative investigation was made between the two models and the insights gleaned from the study could be usefully employed to design inhibitors with a much more enhanced potency and selectivity.

3D-QSAR CoMFA and CoMSIA study on benzodipyrazoles as cyclin dependent kinase 2 inhibitors.

Cyclin dependent kinase 2 (CDK2) has appeared as an important drug target over the years with a multitude of therapeutic potentials. With the intention of designing compounds with enhanced inhibitory potencies against CDK2, the 3D-QSAR CoMFA and CoMSIA study on benzodipyrazoles series is presented here. The developed models showed a strong correlative and predictive capability having a cross validated correlation co-efficient of (r(2)(cv)) 0.699 for CoMFA and 0.794 for CoMSIA models. A very good conventional and predicted correlation co-efficients were also obtained: CoMFA (r(2)(ncv), r(2)(pred): 0.883, 0.754), CoMSIA (0.937, 0.815). The models were found to be statistically robust and are expected to be of an aid to design and/or prioritize drug likes for synthesis.

QSAR study on dual 5-HT1A and 5-HT1B antagonists: an insight into the structural requirement for antidepressant activity.

The 5-HT autoreceptors have received considerable attention as potential targets for the development of antidepressants. With the purpose of designing new chemical entities with enhanced antagonist potencies against 5-HT1A and 5-HT1B, a QSAR study carried out on thienopyrimidinone derivatives as antagonists of serotonin autoreceptors is presented. The developed models were validated by standard QSAR parameters and through a detailed structural analysis on how the QSARs reproduce and explain the differences in the experimentally known activity data. The developed models showed a good correlative and predictive ability having a squared cross validated correlation co-efficients (r2 cv) of 0.780 for 5-HT1A and 0.638 5-HT1B antagonism. The squared conventional correlation co-efficients (r2) were found to be 0.824 for the 5-HT1A model and 0.745 for 5-HT1B antagonism. The study indicated that the 5-HT autoreceptor antagonistic activity exhibited by the series is largely explained by steric factors of substituents which underline the role of size and shape of thienopyrimidinones in making effective antagonist-autoreceptor interaction chemistry. A detailed comparative investigation was made between the two models and the insights gleaned from the study could be usefully employed to design dual antagonists with a much more enhanced potency and selectivity.

Structure-based approaches in the design of GSK-3 selective inhibitors.

Glycogen Synthase Kinase-3 (GSK-3) is a serine/threonine kinase with varied number of actions in cellular signalling systems making it an emerging target for diseases such as diabetes mellitus, cancer, chronic inflammation, bipolar affective disorders and Alzheimer's disease. Various efforts have produced many potent small molecule inhibitors of GSK-3, which are being tested for modulation of glycogen metabolism, gene transcription, apoptosis and enhancement of insulin-stimulated glucose transport. Majority of the reported inhibitors show their inhibitory effects towards other phylogenetically related kinases also, like cyclin dependant kinases (CDKs). Thus it is important to develop inhibitors that can inhibit GSK-3 selectively. Rational approaches based on the knowledge of the receptor are best suited to address the selectivity problem. Several crystal structures of GSK-3beta with different ligands are being reported. These are providing the necessary clues regarding the interaction in the ligand binding domain. Several molecular docking efforts are being taken up to identify the clues for enhancing selectivity towards GSK-3. In this review we present current efforts and future opportunities in designing selective GSK-3 inhibitors.

Identification of potential glycogen kinase-3 inhibitors by structure based virtual screening.

Glycogen synthase kinase-3 (GSK3) is a serine/threonine kinase that has attracted much drug discovery attention in recent years. Structural crystallography of the kinase has produced several high resolution inhibitor-GSK3 complexes and this is offering valuable information about the important pharmacophoric features present in the inhibitor, the protein target and the bioactive conformation. The availability of several GSK3-inhibitor co-crystals was successfully exploited to derive a pharmacophore query which retains the all important inhibitor-GSK3 interaction chemistry. A hypothesis containing three features: two hydrogen bond donors and one hydrogen acceptor was found to explain much of the inhibitor-GSK3 interaction. Subsequently, the query has been submitted to three databases for electronic screening. The hits obtained were docked into glycogen synthase kinase-3beta active site. A total of 21 novel potential leads were proposed after thorough examination by a combination of methods: (i) visual examination of how well they dock into the glycogen synthase kinase-3beta binding site, (ii) detailed analysis of their FlexX, G_Score, PMF_Score, ChemScore and D_Score values, (iii) comparative investigation of the docking scores of the hits with that of the thus far reported inhibitors (iv) determination of the binding mode and examination of how the hits retain interactions with the important amino acid residues of the kinase binding site. The hydrophobic heterocycles identified in this investigation are expected to be important additions to the armamentarium of GSK3 hyperactivity antagonism. Further more, the present work may further our current knowledge of the molecular basis of activation, inhibition and regulation of this pharmaceutically important kinase.

Structure based de novo design of novel glycogen synthase kinase 3 inhibitors.

Glycogen synthase kinase 3 (GSK-3) is a serine/threonine kinase that has captured great attention in drug discovery projects. Structure based design has been successfully carried out to find a novel class of GSK-3 inhibitors using the Ludi de novo ligand design program. A total of 15 potential leads are suggested from the study. The structures have been validated through detailed analysis of the Ludi score values and by molecular docking experiment using FlexX. The hits have been further verified through: (1) visual examination of how well the hits dock into the GSK-3beta binding site; (2) comparative analysis of their FlexX, G_Score, PMF_Score, ChemScore, and D_scores values; (3) a comparative investigation of the docking scores of the hits with those of the reported inhibitors after calibration of the docking procedure with 17 previously reported inhibitors; (4) determination of the binding mode of the hits and comparison with that of the so far known inhibitors. Hits retaining interactions with the common amino acids of GSK-3beta binding site were taken to represent potential leads. Structurally the hits designed are mainly flat nitrogen heterocycles. These hits are expected to be important additions to the search of GSK-3 inhibitors and may provide invaluable insights to further understand the structural basis of catalysis and inhibition of this kinase.

3D-QSAR and molecular docking study on bisarylmaleimide series as glycogen synthase kinase 3, cyclin dependent kinase 2 and cyclin dependent kinase 4 inhibitors: an insight into the criteria for selectivity.

Selective glycogen synthase kinase 3 (GSK3) inhibition over cyclin dependent kinases such as cyclin dependent kinase 2 (CDK2) and cyclin dependent kinase 4 (CDK4) is an important requirement for improved therapeutic profile of GSK3 inhibitors. The concepts of selectivity and additivity fields have been employed in developing selective CoMFA models for these related kinases. Initially, sets of three individual CoMFA models were developed, using 36 compounds of bisarylmaleimide series to correlate with the GSK3, CDK2 and CDK4 inhibitory potencies. These models showed a satisfactory statistical significance: CoMFA-GSK3 (r(2)(con), r(2)(cv): 0.931, 0.519), CoMFA-CDK2 (0.937, 0.563), and CoMFA-CDK4 (0.892, 0.725). Three different selective CoMFA models were then developed using differences in pIC(50) values. These three models showed a superior statistical significance: (i) CoMFA-Selective1 (r(2)(con), r(2)(cv): 0.969, 0.768), (ii) CoMFA-Selective 2 (0.974, 0.835) and (iii) CoMFA-Selective3 (0.963, 0.776). The selective models were found to outperform the individual models in terms of the quality of correlation and were found to be more informative in pinpointing the structural basis for the observed quantitative differences of kinase inhibition. An in-depth comparative investigation was carried out between the individual and selective models to gain an insight into the selectivity criterion. To further validate this approach, a set of new compounds were designed which show selectivity and were docked into the active site of GSK3, using FlexX based incremental construction algorithm.

3D-QSAR CoMFA study on oxindole derivatives as cyclin dependent kinase 1 (CDK1) and cyclin dependent kinase 2 (CDK2) inhibitors.

Cyclin dependent kinases have emerged as important drug targets with a multitude of therapeutic potentials for their inhibitors. With the purpose of designing new chemical entities with enhanced inhibitory potencies against cyclin dependent kinase 2 (CDK2) and cyclin dependent kinase 1 (CDK1), the 3D-QSAR CoMFA study carried out on oxindole derivatives as inhibitors of these kinases is presented here. The developed model showed a good correlative and predictive ability having a cross validated correlation co-efficient of 0.518 for CDK1 and 0.613 for CDK2. The conventional and predictive correlation coefficients were found to be respectively 0.943 and 0.508 for CDK1 and 0.957 and 0.585 for CDK2. The models could be usefully employed to design dual CDK1 and CDK2 inhibitors and/or to find novel scaffolds through screening of chemical databases.

3D-QSAR and molecular docking studies on pyrazolopyrimidine derivatives as glycogen synthase kinase-3beta inhibitors.

Glycogen synthase kinase-3 (GSK-3), a serine/threonine kinase, is a fascinating enzyme with diverse biological actions in intracellular signaling systems, making it an emerging target for diseases such as diabetes mellitus, cancer, chronic inflammation, bipolar disorders and Alzheimer's disease. It is important to inhibit GSK-3 selectively and the net effect of the GSK-3 inhibitors thus should be target specific, over other phylogenetically related kinases such as CDK-2. In the present work, we have carried out three-dimensional quantitative structure activity relationship (3D-QSAR) studies on novel class of pyrazolopyrimidine derivatives as GSK-3 inhibitors reported to have improved cellular activity. Docked conformation of the most active molecule in the series, which shows desirable interactions in the receptor, was taken as template for alignment of the molecules. Statistically significant CoMFA and CoMSIA models were generated using 49 molecules in training set. By applying leave-one-out (LOO) cross-validation study, r(cv)2 values of 0.53 and 0.48 for CoMFA and CoMSIA, respectively and non-cross-validated (r(ncv)2) values of 0.98 and 0.92 were obtained for CoMFA and CoMSIA models, respectively. The predictive ability of CoMFA and CoMSIA models was determined using a test set of 12 molecules which gave predictive correlation coefficients (r(pred)2) of 0.47 and 0.48, respectively, indicating good predictive power. Based upon the information derived from CoMFA and CoMSIA contour maps, we have identified some key features that explain the observed variance in the activity and have been used to design new pyrazolopyrimidine derivatives. The designed molecules showed better binding affinity in terms of estimated docking scores with respect to the already reported systems; hence suggesting that newly designed molecules can be more potent and selective towards GSK-3beta inhibition.

Investigation of potential glycogen synthase kinase 3 inhibitors using pharmacophore mapping and virtual screening.

Glycogen synthase kinase-3 is a serine/threonine kinase that has attracted significant drug discovery attention in recent years. To investigate the identification of new potential glycogen synthase kinase-3 inhibitors, a pharmacophore mapping study was carried out using a set of 21 structurally diverse glycogen synthase kinase-3 inhibitors. A hypothesis containing four features: two hydrophobic, one hydrogen bond donor and another hydrogen bond acceptor was found to be the best from the 10 common feature hypotheses produced by HipHop module of Catalyst. The best hypothesis has a high cost of 156.592 and higher best fit values were obtained for the 21 inhibitors using this best hypothesis than the other HipHop hypotheses. The best hypothesis was then used to screen electronically the NCI2000 database. The hits obtained were docked into glycogen synthase kinase-3beta active site. A total of five novel potential leads were proposed after: (i) visual examination of how well they dock into the glycogen synthase kinase-3beta-binding site, (ii) comparative analysis of their FlexX, G-Score, PMF-Score, ChemScore and D-Scores values, (iii) comparison of their best fit value with the known inhibitors and (iv) examination of the how the hits retain interactions with the important amino acid residues of glycogen synthase kinase-3beta-binding site.