Computer-aided exploration of novel drugs and drug targets

Prem Chapagain

Department of Physics, and Biomolecular Sciences Institue
Florida International University, Miami, FL 33199

The alarming rise in antimicrobial resistance in recent years has underscored a dire need for the development of new antibiotics utilizing novel modes of action as the emergence of drug-resistant strains is rendering our current antibiotics ineffective. The formation of the bacterial cell wall made up of a peptidoglycan layer is a common antibiotic target. A broad range of antibiotics such as penicillin and vancomycin work by inhibiting peptidoglycan synthesis, weakening the integrity of the protective cell wall. Current clinical drugs, including vancomycin, target the peptide moiety of lipid II, an essential component in cell wall synthesis. Resistant strains of bacteria have been able to change the peptide composition to evade drug-binding without affecting cell wall synthesis. Lanthipeptides, on the other hand, target the pyrophosphate group and therefore constitute a promising class of drugs targeting cell wall synthesis to overcome such resistance. Another important antibiotic target is the machinery involving DNA and RNA. Bacterial topoisomerase-I (Topo-I) is responsible for relaxing DNA that is negatively supercoiled, and the loss of topoisomerase activity leads to cell death, making the topoisomerase a promising drug target. Inhibitors of bacterial Topo-I may provide leads for novel antibacterial drugs against pathogens that are resistant to current antibiotics. In this talk, I will discuss the role of computer modeling, molecular docking, and simulations in understanding the molecular mechanisms and exploration of novel antibiotics. This will include modeling the bacterial cell wall, mechanisms of action of lanthipeptide drugs, and in silico drug screening targeting an active site pocket of Mycobacterium tuberculosis topoisomerase I. In addition to the antibacterial drugs, I will also discuss our drug development effort targeting the Ebola virus matrix protein to disrupt the matrix formation during Ebola virus budding.

Please schedule for Saturday.