USA-Determination of Molecular Descriptors of drug targets, anti-targets and counter targets for Cancer therapy

Many potent Matrix metalloproteinases inhibitors (MMPIs) have been developed for the treatment of cancer in recent years with great expectations. Many of them have been tested in clinical trials and discontinued. These inhibitors lack specificities betwee n cancer producing and cancer inhibiting Matrix metalloproteinases (MMPs) and other related proteins resulting in unwanted side effects. This project aims at determination of molecular descriptors of the various MMPs and the related proteins with the goal of development of highly specific MMPIs that can differentiate between the various MMPs and their relatives. This will be achieved through a combination of both experimental and sophisticated computational and bioinformatics techniques. Structural featur es of various MMPs (apo and complexes) will be extensively explored and analysed, by modelling of MMP-protein inhibitor interactions, with emphasis on both the active site and exosites of MMPs. Furthermore, the interactions of various MMPIs will be studie d, by docking them into the active sites and exosites of MMPs. Molecular dynamics simulations studies of the complexes and calculation of the binding free energies will be done. De novo design of novel MMPIs that can interact on the nonprime sides of the active sites of MMPs will be attempted based on the derived structural descriptors of each MMP. Such inhibitors have been suggested to offer more opportunities for specificities. The specificities and selectivities of the MMPIs will also be optimised rela tive to other related proteins to reduce unwanted and unexpected side effects.