New Opportunities in the Structure-based Design of Anti-Protozoan Agents

Abstract

Abstract:Since the recent renaissance of phenotypic screening in the field of protozoan drug discovery, is there still an opportunity for the structure-based design of new anti-protozoan agents? Target-based approaches should be used in parallel to phenotypic screening to strengthen the pipeline of anti-protozoan agents. We give an overview of the protozoan drug discovery landscape highlighting four protein targets of interest: cytochrome bc1, dihydroorotate dehydrogenase, dihydrofolate reductase and calcium-dependent protein kinase 1. We discuss recent structure-based design efforts to inhibit these targets, reviewing their crystal structures and their ability to accommodate potent and selective compounds. Finally, we discuss future opportunities to apply structure-based methods to promising molecular targets within protozoan parasites discovered using chemical genomics.

An isoxazole strategy for the synthesis of 4-oxo-1,4-dihydropyridine-3-carboxylates

“…Pyridine fragments are used in drugs due to their specific characteristics such as basicity, hydrogen bond forming ability, water solubility, and especially because of pyridine rings are bioisosteres of amines, amides, N-heterocyclic rings and benzene rings [1][2][3][4][5]. A special type of pyridine, the 4-pyridones, is also fairly well represented among drugs [5][6][7][8][9][10][11][12]. Some of bioactive compounds, such as ciprofloxacin, levofloxacin, delafloxacin, and elvitegravir, contain the fragment of 4-oxo-1,4-dihydropyridine-3-carboxylic acid [6,8] and some others, ivacaftor, dolutegravir, bictegravir, aspernigrin B, and 4PYR, contain the fragment of 4-oxo-1,4-dihydropyridine-3-carboxamide [5][6][7].…”

The Growing Role of Electron Microscopy in Anti-parasitic Drug Discovery

“…Furthermore, structural information for the target parasitic protein and comparisons to its homologous proteins can be exploited to design new compounds which are selective for their target. Structural information has underpinned many different anti-parasitic drug discovery projects, which have been reviewed elsewhere 8,9 . A recent example is the work by Philips et al who targeted the Plasmodium falciparum dihydroorotate dehydrogenase (DHODH) enzyme.…”