Ramaiah Muthyala, PhD, FRSC

Research Summary

The vision of our research program is to translate biological and chemical information into leads to drug-like molecules and optimize the lead small molecules to drug molecules using synthetic organic chemistry. The drug discovery will be combined with structure information obtained from ligand-protein structures, enzyme data derived from computational, modeling and biological experiments. The potential for speedy optimization of drug discovery, selective and carefully designed combinatorial small libraries along with rapid, sensitive and specific assay procedures are being explored. Natural products with desired biological activity at nanomolar range are considered as informed lead compounds for further development into drug candidates.

Antibacterials:
Over the last two decades, antibacterial agents that are effective against drug resistant strains are in short supply due to a lack of interest by the drug industry. Our focus in this area is to identify novel chemotherapeutic agents based on well recognized cell wall biosynthetic processes of the bacterial life cycle. Potential inhibitors for signaling pathway that connects the binding of b-lactam antibiotics by the sensor BlaR1 anf MecR1 or repressors BlaI and MecI which help transcription of b-lactam gene are also contemplated. The emergence of resistance to vancomycin has aroused considerable concern. Vancomycin is a bi-functional molecule consisting of two biologically active components that interact with different cellular targets. The aglycone bonds to the peptidoglycan precursor and the disaccharide interacts with proteins involved in the trans-glycosylation step. Our strategy is to provide a carbon framework which will fulfill the requirements of the necessary fragments to imitate vancomycin.

Neurological diseases:
The cholinergic hypothesis has lead to the first and perhaps the only successful drug treatment for Alzheimer's disease (AD) with acetylcholinesterase (AChE) inhibitors. AChE inhibitors, especially a mixed-type inhibitor which interacts with the peripheral site of the enzyme and acts as a potential inhibitor of the formation of bA42 amyloid protein is highly desirable. In this context, we have focused on the search for novel potent and selective AChE inhibitors that interact with the peripheral site of the enzyme. Neuro-degeneration in AD may be caused by the deposition of amyloid peptide (Ab) in plaques in brain tissue. Amyloid precursor protein (APP) is cleaved in concert with a-, b-, and g- secretases which provided a genetic framework for the emerging amyloid hypothesis for the AD treatment. Recent advancements in the isolation and characterization of secretases allowed us to formulate selective novel inhibitors.