Research

Cystic Fibrosis (CF)

Cystic Fibrosis is a lethal genetic disease caused by mutations to the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. Our research focuses on studying CFTR both at the level of its constituting domains and at the level of the full-length protein. Our basic research in this field focuses on understanding the dynamics of the protein and on the mechanism of action of deleterious, rescuing and stabilizing perturbations, in the form of mutations, to its domains. Our translation research focuses on CFTR as a target for drug discovery, in particular for rare CF-causing mutations.

Chemoinformatics and materials informatics

Another research area which is of great interest to us is cheminformatics and in particular machine learning (also known as QSAR). This field has evolved over the last decades to contribute to many areas including chemistry, biology, environmental sciences, and materials sciences. The application of methods borrowed from cheminformatics to materials sciences is often referred to as materials informatics which today is evolving into a field of research in its own right and with a unique set of challenges. Some of the basic questions in chemo / materials informatics still remain unanswered. Our research in these field focuses on the study of development of new machine learning algorithms as well as on their application in various areas, for example, for the analysis and development of solar cells with improved photovoltaic properties.

Computational agriculture

Over the last few years our lab has gradually invested increasing efforts in the field of computational agriculture. While the field or computer aided drug design is rather crowded, much less high level computational work was done in the field of agriculture. Yet food supplies are predicted to be under far greater stress than today with the expected growth in world population and the concomitant decrease in available land.

With this in mind we have started to apply computational tools typically used in the field of drug discovery to the development of “green” pesticides for crop protection. Our current work focuses on the following topics:

  • Plant disease biocontrol by means of non-infectious biodegradable proteinaceous nanoparticles: Within the framework of this project we are using computational tools (primarily MD simulations) to study new anti-bacterial peptides that could be expressed on virus nanoparticles (VNPs) that is, viral structures with normal virus architecture but without any genetic material. Such functionalized VNPs could be produced on large scale using plants as “bioreactors”, thus allowing an eco-friendly, cost-effective production.
  • Small molecule cocktails designed to impair virulence targets in soft rot Erwinias: During evolution, plants have developed multiple strategies to ward-off bacterial virulence. One such strategy is the production of phenolic compounds that interfere with the bacterial quorum sensing machinery. We have recently established that one of the components of this machinery, ExpI (signaling molecule synthase) is indeed a target for phenolic compounds. Furthermore, we have established a direct binding of Salicylic Acid, the most widely studied global resistance mediator in plants to ExpI. Within the framework of this project we therefore computationally design small molecules that could further inhibit ExpI. Moreover, since some phenolic compounds are also substrates of bacterial efflux systems of the ABC transporters family, we also design small molecules that will inhibit specific ABC transporters thereby increasing the level of phenolic compounds within bacteria cells. We hypothesize that the combined effect of ExpI and efflux system inhibition will effectively protect crops from bacteria attacks.
  • Novel Pesticides for a Sustainable Agriculture: Within the framework of this project we use computational tools to design first peptide aptamers and then small molecules that would interfere with cell building enzymes of bacteria and therefore could be used as new “green” sustainable pesticides.

 

Drug discovery

As one particular example, we work on GSK-3, a protein kinase which is a causative factor behind a broad spectrum of neurodegenerative disorders including Alzheimer’s diseases, mood behavior disorders and orphan indications. In collaboration with Prof. Hagit Eldar-Finkelman from Tel-Aviv University we developed a new type of GS3 inhibitors that function as substrate competitive inhibitors (SCIs). This type of inhibitors is highly specific, safer, and considered less prone to induced drug resistance than ATP competitive inhibitors.