Investigation on Quantitative Structure-Activity Relationships of 1,3,4 Oxadiazole Derivatives as Potential Telomerase Inhibitors

The published manuscript is available at EurekaSelect via http://www.eurekaselect.com/164022/article, DOI : 10.2174/1570163815666180724113208. © 2018 Bentham ScienceA series of 1,3,4-oxadiazole derivatives with significant broad-spectrum anticancer activity against different cell lines, and demonstrated telomerase inhibition, was subjected to Quantitative Structure-Activity Relationships (QSAR) analysis. Validated models with high correlation coefficients were developed. The Multiple Linear Regression (MLR) models, by Ordinary Least Squares (OLS), showed good robustness and predictive capability, according to the Multi-Criteria Decision Making (MCDM = 0.8352), a technique that simultaneously enhances the performances of a certain number of criteria. The descriptors selected for the models, such as electrotopological state (E-state) descriptors, and extended topochemical atom (ETA) descriptors, showed the relevant chemical information contributing to the activity of these compounds. The results obtained in this study make sure about the identification of potential hits as prospective telomerase inhibitors.Peer reviewedFinal Accepted Versio

Predicting Skin Permeability by means of Computational Approaches : Reliability and Caveats in Pharmaceutical Studies

© 2019 American Chemical Society.The skin is the main barrier between the internal body environment and the external one. The characteristics of this barrier and its properties are able to modify and affect drug delivery and chemical toxicity parameters. Therefore, it is not surprising that permeability of many different compounds has been measured through several in vitro and in vivo techniques. Moreover, many different in silico approaches have been used to identify the correlation between the structure of the permeants and their permeability, to reproduce the skin behavior, and to predict the ability of specific chemicals to permeate this barrier. A significant number of issues, like interlaboratory variability, experimental conditions, data set building rationales, and skin site of origin and hydration, still prevent us from obtaining a definitive predictive skin permeability model. This review wants to show the main advances and the principal approaches in computational methods used to predict this property, to enlighten the main issues that have arisen, and to address the challenges to develop in future research.Peer reviewedFinal Accepted Versio

Study of the role of “gatekeeper” mutations V654A and T670I of c-kit kinase in the interaction with inhibitors by means mixed molecular dynamics/docking approach

The over-expression of c-kit proto-oncogene has been reported in hematopoietic cells, small cell lung cancer, and gastrointestinal stromal tumors. The clinical importance of c-kit expression in tumors focused the research towards inhibitors of this tyrosine kinase. Imatinib (Gleevec®) was the first compound used in therapy, but mutations on c-kit led to reduced effectiveness or ineffectiveness of this treatment. Other compounds are likely to be effective against mutants, such as Sunitinib (Sutent®), but the need for new and most effective inhibitors against mutants is still critical. We report mixed Molecular Dynamics/Docking study with the aim to unveil the molecular mechanism involved in the resistance of Imatinib, Sunitinib, and other known compounds against the “gatekeeper” mutants V654A and T670I. We tried to evidence strong and weak features of actual inhibitors in order to identify the guidelines to design new and most potent inhibitors against c-kit mutants

Studio del ruolo delle mutazioni “gatekeeper” V654A e T670I di c-kit kinase nell’interazione con inibitori attraverso un approccio misto Dinamica Molecolare/Docking

La sovraespressione del proto-oncogene c-kit è stata riscontrata nelle cellule ematopoietiche, nel cancro a piccole cellule del polmone e nei tumori stromali gastrointestinali1-3. L’importanza clinica dell’espressione di c-kit nei tumori ha indirizzato la ricerca verso inibitori di questa tirosina chinasi. Imatinib (Gleevec®) (in figura) è stato il primo farmaco utilizzato in terapia, ma la comparsa di mutazioni su c-kit ha portato ad una riduzione dell’efficacia o a completa resistenza a questo trattamento. In alternativa, altri composti si sono mostrati attivi anche nei confronti dei mutanti come ad esempio Sunitinib (Sutent®)4, ma la necessità di nuovi e più efficaci inibitori contro i mutanti rimane ancora un punto critico della ricerca. Si riporta uno studio misto Dinamica Molecolare/Docking (IFD) con lo scopo di svelare i meccanismi molecolari coinvolti nella resistenza a Imatinib, Sunitinib e altri inibitori contro le mutazioni “gatekeeper” V654A e T670I, provando ad evidenziare i punti forti e deboli degli attuali inibitori (Nilotinib, Sorafenib, Motesanib, PKC412, una tienopirimidina TPD, un aminobenzoisossazolo ABIOZ). Questo approccio in silico può consentire di identificare le linee guida per la progettazione di nuovi farmaci attivi contro i mutanti

Receptor-guided 3D-QSAR approach for the discovery of c-kit tyrosine kinase inhibitors

Studies of the the three-dimensional quantitative structure–activity relationships for ninety-five c-kit tyrosine kinase inhibitors were performed. Based on a cocrystallized compound (1 T46), known inhibitors were aligned with c-kit by induced-fit docking, and multiple training/test set splitting was performed to validate the selected pharmacophore model. The best pharmacophore model consisted of five features: one hydrogen-bond donor and four aromatic rings. Reliable statistics were obtained (R2=0.95, Rpred 2=0.75), and the model was validated by using it to select c-kit inhibitors from a database; 82.1% of the hits it retrieved were active. Accordingly, our model can be reliably used to identify new c-kit inhibitors, and can provide useful information when designing new inhibitors

Molecular Dynamics studies on Mdm2 complexes: an analysis of the inhibitor influence

p53 is a powerful anti-tumoral molecule frequently inactivated by mutations or deletions in cancer. However, half of all human tumors expresses wild-type p53, and its activation, by antagonizing its negative regulator Mdm2, might offer a new strategy for therapeutic protocol. In this work, we present a molecular dynamics study on Mdm2 structure bound to two different known inhibitors with the aim to investigate the structural transitions between apo-Mdm2 and Mdm2-inhibitor complexes. We tried to gain information about conformational changes binding a benzodiazepine derivative inhibitor with respect the known nutlin and the apo form. The conformational changes alter the size of the cleft and were mainly in the linker regions, suggesting that the overall dynamic nature of Mdm2 is related to dynamic movements in these regions