Abstract
Enzymes govern a myriad of life’s essential cellular activities. Cell nutrition, physiology, metabolic processes, signalling pathways and microbial pathogenesis rely profoundly on the specificity and diversity of enzymes functions. The contribution of enzymes in the centre of crucial biochemical activities inevitably places them in the core of disease propagation. Unregulated enzyme activities have been the centre of onset of countless diseases. Human enzymes initiate diseases in two ways, via overexpression and mutations. In addition, bacterial enzymes may infect human hosts; this way foreign enzyme becomes responsible for disease states. Enzymes contribute in the onset of both non-communicable (cancer, obesity, neurodegenerative diseases and cardiovascular inflammation) and communicable diseases (hepatitis, herpes, infectious and parasitic). Enzyme inhibition has captured immense attention in the area of drug research and development. Drug discovery and development is an expensive and intricate process that takes up to 15 years in bringing a single new drug agent in the market. Newer and faster systems are required to reduce time and resources that lead to lengthy drug discovery process. Computer Aided Drug Development (CADD) has emerged as a technology to expedite drug discovery. Computer simulations are potent theoretical tools used to predict in-vitro and in-vivo chemical processes. These techniques are preferred tools aimed at combatting the financial and environmental costs associated with drug discovery. However, computational methods are theoretical assumptions based on classical physics approximation and do not serve as replacement for actual experiments. The impetus of this study was to demonstrate that computer simulations are a complementary technology and an accurate predictive tool to accelerate drug discovery. We carried out a combination of practical and theoretical methods to show that computer simulations can successfully speed up drug discovery process. We study the drug inhibition of two aspartic hydrolases namely human aspartic protease -site amyloid precursor protein-cleaving enzyme (hBACE1 or BACE1) and bacterial New Delhi Metallo enzyme (NDM-1). BACE1 is associated with the propagation of Alzheimer’s disease, a neurodegenerative disorder of the central nervous system (CNS) which currently has no definite cure. There is a series of BACE1 inhibitors (BACE1Is) in development stages that have entered late pre-clinical trials...
Ph.D. (Chemistry)