Jump to main content
Jump to site search

Issue 5, 2010
Previous Article Next Article

Meta-analysis of molecular property patterns and filtering of public datasets of antimalarial “hits” and drugs

Author affiliations

Abstract

Neglected infectious diseases such as tuberculosis (TB) and malaria kill millions of people annually and the oral drugs used are subject to resistance requiring the urgent development of new therapeutics. Several groups, including pharmaceutical companies, have made large sets of antimalarial screening hit compounds and the associated bioassay data available for the community to learn from and potentially optimize. We have examined both intrinsic and predicted molecular properties across these datasets and compared them with large libraries of compounds screened against Mycobacterium tuberculosis in order to identify any obvious patterns, trends or relationships. One set of antimalarial hits provided by GlaxoSmithKline appears less optimal for lead optimization compared with two other sets of screening hits we examined. Active compounds against both diseases were identified to have larger molecular weight (∼350–400) and logP values of ∼4.0, values that are, in general, distinct from the less active compounds. The antimalarial hits were also filtered with computational rules to identify potentially undesirable substructures. We were surprised that approximately 75–85% of these compounds failed one of the sets of filters that we applied during this work. The level of filter failure was much higher than for FDA approved drugs or a subset of antimalarial drugs. Both antimalarial and antituberculosis drug discovery should likely use simple available approaches to ensure that the hits derived from large scale screening are worth optimizing and do not clearly represent reactive compounds with a higher probability of toxicity in vivo.

Graphical abstract: Meta-analysis of molecular property patterns and filtering of public datasets of antimalarial “hits” and drugs

Back to tab navigation

Publication details

The article was received on 30 Jul 2010, accepted on 03 Sep 2010 and first published on 30 Sep 2010


Article type: Concise Article
DOI: 10.1039/C0MD00129E
Citation: Med. Chem. Commun., 2010,1, 325-330
  •   Request permissions

    Meta-analysis of molecular property patterns and filtering of public datasets of antimalarial “hits” and drugs

    S. Ekins and A. J. Williams, Med. Chem. Commun., 2010, 1, 325
    DOI: 10.1039/C0MD00129E

Search articles by author

Spotlight

Advertisements