Identification of Novel Parasitic Cysteine Protease Inhibitors by Use of Virtual Screening. 2. The Available Chemical Directory

• Published in: Journal of medicinal chemistry Vol. 49; no. 5; pp. 1576 - 1584
• Main Authors: Desai, Prashant V, Patny, Akshay, Gut, Jiri, Rosenthal, Philip J, Tekwani, Babu, Srivastava, Anuradha, Avery, Mitchell
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 09.03.2006
• Subjects: Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antimalarials - chemistry; Antimalarials - pharmacology; Antiparasitic agents; Antiparasitic Agents - chemistry; Antiparasitic Agents - pharmacology; Binding Sites; Biological and medical sciences; Cysteine Endopeptidases - chemistry; Cysteine Proteinase Inhibitors - chemistry; Cysteine Proteinase Inhibitors - pharmacology; Databases, Factual; Leishmania donovani - drug effects; Leishmania donovani - enzymology; Medical sciences; Models, Molecular; Pharmacology. Drug treatments; Plasmodium falciparum - drug effects; Quantitative Structure-Activity Relationship; Antimalarial; Imidazole derivatives; Cysteine endopeptidases; Leishmania donovani; Non peptide compound; Modeling; Organic halogen compounds; Pyridine derivatives; Antiprotozoal agent; Plasmodium falciparum; Structure activity relation; Chemical compound library; Molecular model; Kinetoplastida; Protozoa; Apicomplexa; Enzyme; Enzyme inhibitor; Virtual screening; In vitro; Peptidases; Hydrolases; Parasiticide; Pyrimidine derivatives; Conformation
• DOI: 10.1021/jm0505765
• ISSN: 0022-2623

The incidence of parasitic infections such as malaria, leishmaniasis, and trypanosomiasis has been steadily increasing. Since the existing chemotherapy of these diseases suffers from lack of safe and effective drugs and/or the presence of widespread drug resistance, there is an urgent need for development of potent, mechanism-based antiparasitic agents against these diseases. Cysteine proteases have been established as valid targets for this purpose. The Available Chemical Directory consisting of nearly 355 000 compounds was screened in silico against the homology models of plasmodial cysteine proteases, falcipain-2, and falcipain-3, to identify structurally diverse non-peptide inhibitors. The study led to identification of 22 inhibitors of parasitic cysteine proteases out of which 18 compounds were active against falcipain-2 and falcipain-3. Eight compounds exhibited dual activity against both enzymes. Additionally, four compounds were found to inhibit L. donovani cysteine protease. While one of the cysteine protease inhibitors also exhibited in vitro antiplasmodial activity with an IC50 value of 9.5 μM, others did not show noticeable antiplasmodial activity up to 20 μM. A model identifying important pharmacophoric features common to the structurally diverse falcipain-2 inhibitors has also been developed. Very few potent non-peptide inhibitors of the parasitic cysteine proteases have been reported so far, and identification of these novel and chemically diverse inhibitors should provide leads to be optimized into candidates to treat protozoal infections.