Chemical Biology as Defined in the Haystead Lab
Chemical Biology is an evolving discipline that combines the power organic synthetic chemistry with all aspects of modern day molecular biology to derive novel chemical probes as well as early starting points for a new generation of molecularly targeted drugs. The science underlying chemical biology approaches has its roots in the fundamental principles that are the foundations of pharmacology and biochemistry. These principles have driven drug discovery and the development of affinity tools in the past. Therefore, all newly discovered chemical probes must obey the same physiochemical rules we would apply to any drug. These rules are; that they obey classical Michaelis-Menten kinetics against their physiological targets; they can be defined as competitive or non-competitive inhibitors and in general compete with a physiological substrate or hormone targeting a binding pocket on an enzyme or receptor; they carry no chemical liabilities and generally obey Lipinski rules. Examples of useful compounds that fall outside these parameters are few and far between and inevitably often shrouded in controversy.
The process of deriving a new chemical probe or tool compound involves one of two approaches, high throughput (HT) screening against a chemical library or rationale in silico approaches based on a crystal structure of a targeted protein of interest. The majority of probes with a proven track record of reproducibility tend to have been discovered initially by HT screening. The path to useful probe develop typically follows; HT screen, hit resynthesis, enzymatic validation, establish tractable structure activity relations (SAR), co-crystallization, SAR refinement, target engagement in cell based assays, toxicity and PK studies in rodents, efficacy in a disease or physiological model. In the Haystead laboratory we like to add affinity column development to verify target engagement and define off target binding. This step also enables development of imaging tools for cell biology studies as well as live study of probe bio-distribution in animal models.
The strength of chemical biology as a discipline is its ability to cross platforms to address particular physiological questions. For example, the same chemical probe can interrogate a target across all cell types from all species in which the target is conserved. One can generate close inactive analogs to demonstrate specificity. One can look at acute or chronic responses for adaptation or mutation. One can move with the same molecule from cell to whole animal, and ultimately (if this is a goal) to human. No other discipline is as enabling. All of this of course relies upon a complete understanding of the probe. A major hurdle for any chemical biology program is to demonstrate specificity, first in vitro and then in vivo.
A major focus of the Haystead laboratory is to develop highly selective probes using a multifaceted approach exploiting medicinal chemistry, proteomics, imaging, molecular biology and classical biochemistry. Areas of interest include cancer biology, inflammation, viral and pathogen infections and cardiovascular biology.