COMPUTATIONAL PROTEIN AND DRUG DESIGN

PMC-AT's Division of Fundamental Research is devoting considerable effort toward developing various components of a high-resolution approach to enzyme design that aims to improve catalytic activities by substantially reducing the emphasis on combinatorial screening in favor of computational sampling.

The essential difference between our approach to enzyme design and others is its emphasis on protein structure refinement, including attention to the physics of aqueous solvation, hydrogen-bonding, and electrostatic interactions, and the quantum chemical details of reactive chemistry. Our methods have been cited as representing the state-of-the-art in the field today.

PMC-AT's Division of Fundamental Research is also developing new drug discovery workflows for the computationally driven design of pharmaceutically active molecules based on mechanistic modeling of target enzymes. Whereas conventional approaches to drug discovery focus on the inhibition of enzymatic activity, these workflows may be applied to the rational design of both activators as well as inhibitors. The primary application of current interest is the design of small molecule modulators of enzymes, such as sirtuins, that are involved in the regulation of mammalian longevity. Many severe diseases often occur later in life (e.g., diabetes, neurodegenerative diseases, cancer, cardiovascular disease, pro-inflammatory diseases, and osteoporosis), indicating that aging is an important risk factor for these conditions. Hence modulators of longevity are expected to occupy a central role in the pharmaceutical industry of the future.

Sirtuins are key regulators of many cellular functions including cell growth, apoptosis, metabolism, and genetic control of age-related diseases. Increasing the activity of sirtuins has been the subject of intense pharmacological interest due to its implications for the treatment of aging and age related diseases. However, understanding of the scope for activation of mammalian sirtuins is limited. Structure based design of allosteric sirtuin activators, such as resveratrol, is challenging. Hence prior efforts to discover sirtuin modulators, especially activators, which can upregulate longevity enhancing pathways have generally relied on combinatorial experimental screening in the absence of a mechanistic model.

PMC-AT's Division of Fundamental Research is developing approaches to the computational design of mechanism-based design of sirtuin inhibitors and activators. As part of this effort, using state of the art experimental and computational methodologies, we have developed a generalized kinetic model of sirtuin inhibition by its endogenous regulator nicotinamide. PMC-AT scientists are applying this model to the rational design of novel sirtuin-modulating compounds.

1. Invited Talks (selected)

Carnegie Mellon University Center for Advanced Process Decision Making (2013).

University of Minnesota Department of Chemical Engineering (2012).
2. Working Papers (selected)

Mechanism of Inhibition of the Human Sirtuin Enzyme SIRT3 by Nicotinamide: Computational and Experimental Studies.
3. Research Plan.

PMC-AT Enzyme Engineering Research Overview.
4. Lecture Notes / University Courses Taught.

Introduction to Thermodynamics (Lecture Notes for Carnegie Mellon University Course 06-221, Fall 2012)