Structure-based Ligand Design and the Promise Held for Antiprotozoan Drug Discovery

摘要

The development of the pharmaceutical industry, driven by progress in chemistry, biology, and technology, ranks as one of the most successful of human endeavors. However, serious health problems persist, among which are diseases caused by protozoan parasites, largely ignored in modern times. Advances in genomic sciences, molecular and structural biology, and computational and medicinal chemistry now set the scene for a renewed assault on such infections. A structure-centric approach to support discovery of antiparasitic compounds promises much. Current strategies and benefits of a structure-based approach to support early stage drug discovery will be described. The development of the pharmaceutical industry, driven by progress in chemistry, biology, and technology, ranks as one of the most successful of human endeavors. However, serious health problems persist, among which are diseases caused by protozoan parasites, largely ignored in modern times. Advances in genomic sciences, molecular and structural biology, and computational and medicinal chemistry now set the scene for a renewed assault on such infections. A structure-centric approach to support discovery of antiparasitic compounds promises much. Current strategies and benefits of a structure-based approach to support early stage drug discovery will be described. Molecular structure and chemical interactions define how cells and organisms live and die. Paul Ehrlich worked this out over a century ago and coined the term “pharmacophore” to define those properties of a compound responsible for a pharmacological response. Ehrlich addressed problems caused by the parasites Plasmodium sp. and Trypanosoma brucei, the organisms responsible for malaria and African sleeping sickness, respectively. His links to industry, in particular dyestuff manufacturers, were important because their chemistry expertise provided compounds. Investigations with dyes extended to arsenicals and ultimately produced Salvarsan, the first chemotherapeutic agent, for treatment of a bacterial infection, syphilis, and African sleeping sickness (1Travis A.S. Biochemist. 1991; 13: 9-12Google Scholar). The foundation of the pharmaceutical industry was therefore based in large part on discovery of drugs against protozoan parasites. Despite progress, diseases caused by protozoan parasites remain a serious health issue in much of the developing world. In particular, malaria (2Hay S.I. Guerra C.A. Tatem A.J. Noor A.M. Snow R.W. Lancet Infect. Dis. 2004; 4: 327-336Abstract Full Text Full Text PDF PubMed Scopus (682) Google Scholar), African sleeping sickness (3Barrett M.P. Boykin D.W. Brun R. Tidwell R.R. Br. J. Pharmacol. 2007; 152: 1155-1171Crossref PubMed Scopus (260) Google Scholar), Chagas disease (caused by Trypanosoma cruzi) (4Stuart K. Brun R. Croft S. Fairlamb A. Gürtler R.E. McKerrow J. Reed S. Tarleton R. J. Clin. Investig. 2008; 118: 1301-1310Crossref PubMed Scopus (418) Google Scholar), and cutaneous, mucocutaneous, and visceral leishmanises (Leishmania major and Leishmania donovani) (4Stuart K. Brun R. Croft S. Fairlamb A. Gürtler R.E. McKerrow J. Reed S. Tarleton R. J. Clin. Investig. 2008; 118: 1301-1310Crossref PubMed Scopus (418) Google Scholar, 5Reithinger R. Dujardin J.C. Louzir H. Pirmez C. Alexander B. Brooker S. Lancet Infect. Dis. 2007; 7: 581-596Abstract Full Text Full Text PDF PubMed Scopus (1013) Google Scholar) profoundly influence the lives of millions of people. Vaccination, an ideal method of dealing with pathogens, represents a holy grail in parasitology especially for malaria, but investment in antiprotozoan vaccine development has gained scant reward. Plasmodium, Leishmania, and T. cruzi infect and shelter from the immune system within host cells. Plasmodium species display variability and antigenic variation in their membrane-bound surface proteins (6Kyes S.A. Kraemer S.M. Smith J.D. Eukaryot. Cell. 2007; 6: 1511-1520Crossref PubMed Scopus (128) Google Scholar). This prolongs pa