Abstract
Malaria remains one of the most burdensome human infectious diseases, with a high rate of resistance outbreaks and a constant need for the discovery of novel antimalarials and drug targets. For several reasons, Plasmodial proteins are difficult to characterise structurally using traditional physical approaches. However, these problems can be partially overcome using a number of in silico approaches. This review describes the peculiarities of malaria proteins and then details various in silico strategies to select and allow descriptions of the molecular structures of drug target candidates as well as subsequent rational approaches for drug design. Chiefly, homology modelling with specific focus on unique aspects of malaria proteins including low homology, large protein size and the presence of parasite-specific inserts is addressed and alternative strategies including multiple sequence and structure-based prediction methods, samplingbased approaches that aim to reveal likely global or shared features of a Plasmodial structure and the value of molecular dynamics understanding of unique features of Plasmodial proteins are discussed. Once a detailed description of the drug target is available, in silico approaches to the specific design of an inhibitory drug thereof becomes invaluable as an economic and rational alternative to chemical library screening.
Keywords: Malaria, antimalarials, pharmacophore, structure-based drug discovery, in silico
Infectious Disorders - Drug Targets
Title: Antimalarial Drug Discovery: In Silico Structural Biology and Rational Drug Design
Volume: 9 Issue: 3
Author(s): TAP de Beer, GA Wells, PB Burger, F. Joubert, E. Marechal, L. Birkholtz and AI Louw
Affiliation:
Keywords: Malaria, antimalarials, pharmacophore, structure-based drug discovery, in silico
Abstract: Malaria remains one of the most burdensome human infectious diseases, with a high rate of resistance outbreaks and a constant need for the discovery of novel antimalarials and drug targets. For several reasons, Plasmodial proteins are difficult to characterise structurally using traditional physical approaches. However, these problems can be partially overcome using a number of in silico approaches. This review describes the peculiarities of malaria proteins and then details various in silico strategies to select and allow descriptions of the molecular structures of drug target candidates as well as subsequent rational approaches for drug design. Chiefly, homology modelling with specific focus on unique aspects of malaria proteins including low homology, large protein size and the presence of parasite-specific inserts is addressed and alternative strategies including multiple sequence and structure-based prediction methods, samplingbased approaches that aim to reveal likely global or shared features of a Plasmodial structure and the value of molecular dynamics understanding of unique features of Plasmodial proteins are discussed. Once a detailed description of the drug target is available, in silico approaches to the specific design of an inhibitory drug thereof becomes invaluable as an economic and rational alternative to chemical library screening.
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Cite this article as:
de Beer TAP, Wells GA, Burger PB, Joubert F., Marechal E., Birkholtz L. and Louw AI, Antimalarial Drug Discovery: In Silico Structural Biology and Rational Drug Design, Infectious Disorders - Drug Targets 2009; 9 (3) . https://dx.doi.org/10.2174/1871526510909030304
DOI https://dx.doi.org/10.2174/1871526510909030304 |
Print ISSN 1871-5265 |
Publisher Name Bentham Science Publisher |
Online ISSN 2212-3989 |
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