Glutathione-S-transferase (GST) inhibition is a strategy to overcome drug resistance. Several isoforms of human GSTs are present and they are expressed in almost all the organs. Specific expression levels of GSTs in various organs are collected from the human transcriptome data and analysis of the organ-specific expression of GST isoforms is carried out. The variations in the level of expressions of GST isoforms are statistically significant. The GST expression differs in diseased conditions as reported by many investigators and some of the isoforms of GSTs are disease markers or drug targets. Structure analysis of various isoforms is carried out and literature mining has been performed to identify the differences in the active sites of the GSTs. The xenobiotic binding H site is classified into H1, H2, and H3 and the differences in the amino acid composition, the hydrophobicity and other structural features of H site of GSTs are discussed. The existing inhibition strategies are compared. The advent of rational drug design, mechanism-based inhibition strategies, availability of high-throughput screening, target specific, and selective inhibition of GST isoforms involved in drug resistance could be achieved for the reversal of drug resistance and aid in the treatment of diseases.
Plasmodium falciparum has limited capacity for de novo amino acid synthesis and rely on degradation of host hemoglobin to
maintain protein metabolism and synthesis of proteins. M1 alanine aminopeptidase enzyme of the parasite involved in the terminal
degradation of host hemoglobin was subjected to in silico screening with low molecular weight protease inhibitors. The km (avg) of
the enzyme M1 alanine aminopeptidase for the substrate DL – Alanine β Napthylamide Hydrochloride was estimated as 322.05µM.
The molecular interactions between the enzyme and the substrate and the mechanism of enzyme action were analyzed which
paved way for inhibition strategies. Among all the inhibitors screened, Sitagliptin was found to be most potent inhibitor with ki of
0.152 µM in its best orientation whereas the ki(avg) was 2.0055 µM. The ki of Sitagliptin is lower than the km of M1 alanine
aminopeptidase for the substrate DL – Alanine β Napthylamide Hydrochloride (322.05 µM) and Ki of the known inhibitor Bestatin.
Therefore Sitagliptin may serve as a potent competitive inhibitor of the enzyme M1 alanine aminopeptidase of Plasmodium
falciparum.
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