Prof. Senderowitz' Lab
Drug Discovery, Design, and Delivery Research
Prof. Hanoch Senderowitz of the Department of Chemistry focuses on the development, implementation and application of new computational methodologies for the design of new and improved drugs.
Such methods have been shown in the past to greatly accelerate drug design efforts (e.g., the design of HIV protease inhibitors to combat the AIDS epidemic) and so could potentially help in providing a timely response to rapidly emerging epidemic threats.
Senderowitz's research in the field of CADD (Computer Aided Drug Design) and chemoinformatics involves modeling the structure and mode of action of pharmaceutically relevant bio-targets, studying the factors governing the interactions between such targets and their potential ligands, and predicting the pharmacological profile of drug candidates.
Research conducted in his lab is interdisciplinary, at the interface between chemistry, biology and computer sciences, and is done in close collaboration with experimentalists.
Developing New Optimization Tools
A successful drug candidate represents a compromise between numerous, sometimes competing objectives. Consequently, drug discovery could be formulated as a multi-objective optimization problem.
Senderowitz's lab is focused on the development of improved optimization methods and their application to a variety of problems in the field of CADD and chemoinformatics. One such application is the development of a new QSAR workflow for the derivation of predictive QSAR models.
Cystic Fibrosis (CF): Searching for the Cure
Cystic Fibrosis (CF) is the most common lethal genetic disease among Caucasians with an estimated worldwide patient population of 70,000 and a median survival age of only 37 years. The only available treatments for CF are symptomatic and the disease has no cure. CF is caused by mutations to the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) chloride channel, which typically lead to a misfolded, non-functioning protein.
Senderowitz's lab is part of an international consortium, whose mission is to find the 3-dimensional structure of CFTR, study the structural manifestations of its most prevalent mutations, and rationally design small molecules that would correct its folding defect and potentially cure CF.
Disrupting Protein-Protein Interactions
Many processes in the human body are mediated by the interactions of two or more proteins. Consequently, disrupting protein-protein interactions is a viable therapeutic approach. A potential starting point for modulating the association between two interacting proteins is a small peptide derived from one of them. This in turn requires knowledge of the 3-dimensional structure of the protein-protein complex.
Multiple projects in Senderowitz's lab employ this paradigm for the development of new drugs. One example is inhibition of sorcin phosphorylation by PKA, which is expected to be effective against cardiac arrhythmia.
Another example is inhibition of the interactions between specific junctional adhesion molecules, which is expected to modulate the leukocyte recruitment cascade and potentially provide an effective treatment against inflammatory and autoimmune disorders.
A 3-dimensional model of the human Junctional Adhesion Molecule (JAM-C) bound to a potential inhibitory peptide. Such a peptide may modulate the leukocyte recruitment cascade and potentially provide an effective treatment against inflammatory and autoimmune disorders
Design of Non-Hydrolyzable Nucleotide Analogs
Nucleosides (e.g., ATP, ADP and AMP) are endogenous ligands that control multiple cellular processes. However, their utility as pharmaceutical agents is severely limited by their poor stability and short half life. Senderowitz's lab designs novel non-hydrolyzable nucleotide analogs for the treatment of calcification-related diseases, as well as anti-coagulation.
Multi Drug Resistance (MDR)
MDR is one of the major reasons for the many failures of cancer-targeted chemotherapy. A major determinant of MDR is the P-glycoprotein (P-gp) transporter, which is over-expressed in many cancer cells and which effectively expels chemotherapeutic drugs from these cells.
Senderowitz and his team are developing a 3-dimensional model of P-gp in order to study the structural factors governing P-gp related MDR, and to design effective P-gp inhibitors as an aid to chemotherapy.