Rahul Agarwal, Swarnima Kumari, Vikrant Nain, Shakti Sahi
School of Biotechnology, Gautam Buddha University, Greater Noida-201310, India.

ABSTRACT

Malaria remains a widespread and devastating disease. The CDC estimates that there are 300-500 million cases of malaria each year and more than 1 million people die from it. Recent reports on the emergence of resistance to highly effective artemisinin-based combination therapy (ACT) regimens makes it crucially important to identify chemical classes and parasite targets that have not previously been exploited in antimalarial chemotherapy. In order to find novel and efficacious lead compounds, malarial alanyl aminopeptidase (PfA-M1) was taken as the target. PfA-M1 is involved in the terminal stages of hemoglobin digestion and is essential for the amino acids used for Plasmodium growth and development within the erythrocyte. To gain insight into the structure activity relationship of the PfA-M1 inhibitors and to identify promising new structurally diverse lead compounds structure based virtual screening was done. In a step wise filtering protocol, structure based virtual screening of 1.0 million compounds from various publicly available databases of small molecules was carried out. These molecules were docked into the active site of the receptor utilizing three levels of accuracy; ligands passing the HTVS (high throughput VS) step were subsequently analyzed in Glide SP and finally in Glide XP to estimate the receptor ligand binding affinities. The screened compounds were analyzed on the basis of energetics, stereochemical considerations and ADMET properties.Read more…