Pharmacophore Synergism in Diverse Scaffold Clinches in Aurora Kinase B.

Aurora kinase B (AKB) is a crucial signaling kinase with an important role in cell division. Therefore, inhibition of AKB is an attractive approach to the treatment of cancer. In the present work, extensive quantitative structure-activity relationships (QSAR) analysis has been performed using a set of 561 structurally diverse aurora kinase B inhibitors. The Organization for Economic Cooperation and Development (OECD) guidelines were used to develop a QSAR model that has high statistical performance (R2tr = 0.815, Q2LMO = 0.808, R2ex = 0.814, CCCex = 0.899). The seven-variable-based newly developed QSAR model has an excellent balance of external predictive ability (Predictive QSAR) and mechanistic interpretation (Mechanistic QSAR). The QSAR analysis successfully identifies not only the visible pharmacophoric features but also the hidden features. The analysis indicates that the lipophilic and polar groups-especially the H-bond capable groups-must be present at a specific distance from each other. Moreover, the ring nitrogen and ring carbon atoms play important roles in determining the inhibitory activity for AKB. The analysis effectively captures reported as well as unreported pharmacophoric features. The results of the present analysis are also supported by the reported crystal structures of inhibitors bound to AKB.

Exploring the Prominent and Concealed Inhibitory Features for Cytoplasmic Isoforms of Hsp90 Using QSAR Analysis.

Cancer is a major life-threatening disease with a high mortality rate in many countries. Even though different therapies and options are available, patients generally prefer chemotherapy. However, serious side effects of anti-cancer drugs compel us to search for a safer drug. To achieve this target, Hsp90 (heat shock protein 90), which is responsible for stabilization of many oncoproteins in cancer cells, is a promising target for developing an anti-cancer drug. The QSAR (Quantitative Structure-Activity Relationship) could be useful to identify crucial pharmacophoric features to develop a Hsp90 inhibitor. Therefore, in the present work, a larger dataset encompassing 1141 diverse compounds was used to develop a multi-linear QSAR model with a balance of acceptable predictive ability (Predictive QSAR) and mechanistic interpretation (Mechanistic QSAR). The new developed six-parameter model satisfies the recommended values for a good number of validation parameters such as R2tr = 0.78, Q2LMO = 0.77, R2ex = 0.78, and CCCex = 0.88. The present analysis reveals that the Hsp90 inhibitory activity is correlated with different types of nitrogen atoms and other hidden structural features such as the presence of hydrophobic ring/aromatic carbon atoms within a specific distance from the center of mass of the molecule, etc. Thus, the model successfully identified a variety of reported as well as novel pharmacophoric features. The results of QSAR analysis are further vindicated by reported crystal structures of compounds with Hsp90.

CoMSIA and POM analyses of anti-malarial activity of synthetic prodiginines.

In present work, 53 synthetic prodiginines were selected to establish thriving CoMSIA (Comparative Molecular Similarity Indices Analysis) model to explore the structural features influencing their anti-malarial activity. POM (Petra/Osiris/Molinspiration) was carried out to get insight into requirements that can lead to the improvement of the activity of these molecules. The CoMSIA model, based on a combination of steric, electrostatic and H-bond acceptor/donor effects, is with R(2)(cv)=0.738 and R(2)=0.911. The analyses reveal that lipophilicity, hydrogen donor/acceptor and steric factors play crucial role. The study with constructive propositions could be useful for the design of new analogues with enhanced activity.