The Synaptic Leap

THE SUBCELLULAR DRUG TRANSPORT LABORATORY (click here to visit our lab website)  

Our Research Group studies the microscopic transport properties of small drug-like molecules inside cells.  As an overarching hypothesis, we propose that a drug's microscopic distribution within cellular organelles is a major determinant of drug efficacy and toxicity, as important as its macroscopic distribution in the organs of the body.   Experimentally, we use high throughput microscopic imaging instruments to capture the local distribution and dynamics of small molecules inside cells. For image data analysis, we are developing innovative computational tools and statistical strategies, combining cheminformatics and machine vision to relate the chemical structure of small molecules of varying chemical structures to their subcellular distribution.  We are also developing biochemical analysis methods to study the microdistribution and cellular pharmacokinetics of small drug-like molecules. Lastly, with the information gained through experiments, we build mathematical models that are used to simulate drug transport and distribution in single cells and higher order cellular organizations, based on biophysical principles governing molecular transport phenomena at the cellular level. 

OUR VISION

We envision a day when drugs will be designed, optimized and ultimately approved for clinical use in terms of their site of action, as much as drugs today are designed, optimized and approved based on their molecular mechanism of action.  Complementary to in vivo and in vitro models used in drug discovery today, in silico models (such as cell-based molecular transport simulations we use in our experiments) can be applied to pharmaceutical discovery and development. Indeed, computer simulations of drug distribution in biological systems remain largely unexplored as a tool for screening drug candidates. Nevertheless, computers are becoming increasingly fast, reliable and inexpensive research tools.  For drug design, we are exploring cell-based molecular transport simulations as a way to probe the role of microscopic drug transport as a determinant of drug. absorption, distribution, metabolism and excretion.  Within virtual environments, cell-based molecular transport simulations make it possible to observe and manipulate the distribution of large numbers of drug candidates inside cells, in a manner that is practically impossible to perform experimentally.  We are already exploring how cell-based molecular transport simulations can be used, for example, to analyze the most desirable physicochemical features of molecules targeting extracellular domains of cell surface receptors, imparting maximal tissue penetration while minimizing intracellular accumulation in non-target sites. Furthermore, by making modeling and simulation tools available for free and disseminating them via the internet, our ultimate aim is to help educate the next generation of pharmaceutical scientists and medicinal chemists throughout the world, as much as it is to facilitate the practical development of drugs against diseases neglected by the pharmaceutical industry, such as parasitic infections.

WHAT WE WILL PROVIDE TO THE MALARIA RESEARCH COMMUNITY

We were introduced to The Synaptic Leap by Rajarshi Guha from Indiana University and Jean-Claude Bradley from Drexel University, with whom we will start to collaborate in the development of falcipain-2 inhibitors.  Effectively our goal will be to become part of this Open Science project, so that others can learn to use the computational tools we are developing, and help us develop new computational tools.  As part of this open science project, we realize that scientific progress often relies on making many mistakes before achieving some success. Accordingly, all the results we post should be considered tentative or preliminary.  Nevertheless, as we proceed with our work, we will be able to provide the antimalarial drug development community with crucial guidance in the pharmaceutical sciences, that should facilitate selection of antimalarial drug candidates with optimal pharmaceutical properties, for clinical development.  For example, we will be performing computational analysis of the absorption, distribution, metabolism, excretion properties of the a library of candidate antimalarial agents under development, using cell-based molecular transport simulations to analyze the intracellular distribution of small drug-like molecules in the target cells (the malaria parasite), as well as off-target cells (the cells of the human body).  One goal will be to identify a subset of molecules that  accumulate maximally in the subcellular compartment in which the drug target is localized --in the case of falcipain-2, the parasite's lysosomes.  Another goal will be to identify those molecules that have the highest transcellular permeability in intestinal epithelial cells, so that they can be administered via the oral route.  Yet another goal will be to identify those molecules that show lowest intracellular accumulation in off-target cells, which should minimize metabolism and off-target toxicity, while maximizing the concentration of drug in the blood.  As we proceed with our analysis, we will integrate our results with results from our collaborators (ie. docking studies, biochemical screening assays, parasite cytotoxicity assays, and other bioaassays) to assist in the prioritization of antimalarial drug candidates for advancement into clinical trials.  Beyond falcipain-2 inhibitors, lysosomes are a key subcellular target of antimalarial drugs of widespread clinical use, such as chloroquine. Therefore, the increased understanding we obtain from this research project should be broadly applicable to the development of future generations of lysosome-targeted antimalarial agents.