Computational Insight into the Selective Allosteric Inhibition for PTP1B versus TCPTP: a molecular modelling study

All over the world, diabetes mellitus type 2 has spread as a problematic pandemic. Despite currently available treatments, approved drugs still show undesirable side effects and loss of efficacy or target symptoms instead of causes. Protein tyrosine phosphatase 1B (PTP1B), since its discovery, has emerged as a very promising target against this disease. Although the information regarding the enzyme is immense, little is known about the selectivity between this enzyme and its closest homologue, lymphocyte T tyrosine phosphatase (TCPTP), which is responsible for complicated side effects. In this study, on the basis of different computational approaches, we are able to highlight the importance of a phenylalanine residue located in PTP1B, but not in TCPTP, as a crucial hotspot that causes selectivity and stability for the whole ligand bound system. These results not only allow to explain the selectivity determinants of PTP1B but also provide a useful guide for the design of new allosteric inhibitors. Communicated by Ramaswamy H. Sarm

Dynamic Structure-Based Pharmacophore Model Development: A New and Effective Addition in the Histone Deacetylase 8 (HDAC8) Inhibitor Discovery

Histone deacetylase 8 (HDAC8) is an enzyme involved in deacetylating the amino groups of terminal lysine residues, thereby repressing the transcription of various genes including tumor suppressor gene. The over expression of HDAC8 was observed in many cancers and thus inhibition of this enzyme has emerged as an efficient cancer therapeutic strategy. In an effort to facilitate the future discovery of HDAC8 inhibitors, we developed two pharmacophore models containing six and five pharmacophoric features, respectively, using the representative structures from two molecular dynamic (MD) simulations performed in Gromacs 4.0.5 package. Various analyses of trajectories obtained from MD simulations have displayed the changes upon inhibitor binding. Thus utilization of the dynamically-responded protein structures in pharmacophore development has the added advantage of considering the conformational flexibility of protein. The MD trajectories were clustered based on single-linkage method and representative structures were taken to be used in the pharmacophore model development. Active site complimenting structure-based pharmacophore models were developed using Discovery Studio 2.5 program and validated using a dataset of known HDAC8 inhibitors. Virtual screening of chemical database coupled with drug-like filter has identified drug-like hit compounds that match the pharmacophore models. Molecular docking of these hits reduced the false positives and identified two potential compounds to be used in future HDAC8 inhibitor design

Drug design for ever, from hype to hope

In its first 25 years JCAMD has been disseminating a large number of techniques aimed at finding better medicines faster. These include genetic algorithms, COMFA, QSAR, structure based techniques, homology modelling, high throughput screening, combichem, and dozens more that were a hype in their time and that now are just a useful addition to the drug-designers toolbox. Despite massive efforts throughout academic and industrial drug design research departments, the number of FDA-approved new molecular entities per year stagnates, and the pharmaceutical industry is reorganising accordingly. The recent spate of industrial consolidations and the concomitant move towards outsourcing of research activities requires better integration of all activities along the chain from bench to bedside. The next 25 years will undoubtedly show a series of translational science activities that are aimed at a better communication between all parties involved, from quantum chemistry to bedside and from academia to industry. This will above all include understanding the underlying biological problem and optimal use of all available data