Computational Insights into ADAMTS4, ADAMTS5 and MMP13 Inhibitor Selectivity.

The results obtained by means of Molecular Dynamics simulations and Multiway Explorative Data Analysis on ADAMTS4, ADAMTS5 and MMP13 complexed with Marimastat and two cis-1(S)2(R)-amino-2-indanol ligands suggest that determinant characteristics for ligand binding and selectivity among the three enzymes are to be found in the different protein conformation flexibility. Moreover, the role of the TS-domain in the inhibitor binding to ADAMTS enzymes has been investigated for the first time in this work. The results obtained suggest that the influence of the TS-domain on the S1' loop fluctuations of ADAMTS4 and ADAMTS5 could be exploited for the design of therapeutics for chronic osteoarthritis diseases.

Insights into MAPK p38alpha DFG flip mechanism by accelerated molecular dynamics.

The DFG motif at the beginning of the activation loop of the MAPK p38alpha undergoes a local structural reorganization upon binding of allosteric type-II and type-III inhibitors, which causes the residue F169 to move from a buried conformation (defined as DFG-in) to a solvent exposed conformation (defined as DFG-out). Although both experimental and computer simulation studies had been performed with the aim of unveiling the details of the DFG-in to DFG-out transition, the molecular mechanism is still far from being unequivocally depicted. Here, the accelerated molecular dynamics (AMD) technique has been applied to model the active loop flexibility of p38alpha and sample special protein conformations which can be accessible only in some conditions or time periods.

Progress towards the identification of new aggrecanase inhibitors.

Degenerative diseases are still a challenging issue in clinical therapy; even though in several cases it is possible to treat symptoms, drugs able to block disease progression are lacking at present. Osteoarthritis (OA) and Rheumatoid Arthritis (RA) are degenerative diseases leading to serious cartilage destruction, affecting joint functions and giving rise to restricted movement, pain and chronic disability. Current clinical treatment for arthritis is confined to Non Steroidal Anti-Inflammatory Drugs (NSAIDs), which are effective in treating symptoms but fail to block the progression of the disease.