The need to develop safer and more efficacious drugs to treat Chagas disease has motivated the search for cruzain inhibitors. Cruzain is the recombinant, truncated version of cruzipain, a cysteine protease from Trypanosoma cruzi with important roles during the parasite life cycle. Several computational techniques have been applied to discover and optimise cruzain inhibitors, providing a molecular basis to guide this process. Here, we review some of the most recent computational studies that provided important information for the design of cruzain inhibitors. Moreover, we highlight the diversity of applications of in silico techniques and their impact.

ABSTRACT In the search for new anti-schistosomal agents, a series of fifteen ortho-nitrobenzyl derivatives was assayed in vitro against both the schistosomulum (somule) and adult forms of Schistosoma mansoni. Compounds 8 and 12 showed significant activity against somules at low micromolar concentrations, but none was active against adults. The SAR demonstrated that the compounds most active against the parasite were mutagenic to the human cell line RKO-AS45-1 only at concentrations 10- to 40-fold higher than the worm-killing dose. Given their electrophilicity, compounds were also screened as inhibitors of the S. mansoni cysteine protease (cathepsin B1) in vitro. Amides 5 and 15 exhibited a modest inhibition activity with values of 55.7 and 50.6 % at 100 µM, respectively. The nitrobenzyl compounds evaluated in this work can be regarded as hits in the search for more active and safe anti-schistosomal agents.

Reverse transcriptase (RT) is a multifunctional enzyme in the human immunodeficiency virus (HIV)-1 life cycle and represents a primary target for drug discovery efforts against HIV-1 infection. Two classes of RT inhibitors, the nucleoside RT inhibitors (NRTIs) and the nonnucleoside transcriptase inhibitors are prominently used in the highly active antiretroviral therapy in combination with other anti-HIV drugs. However, the rapid emergence of drug-resistant viral strains has limited the successful rate of the anti-HIV agents. Computational methods are a significant part of the drug design process and indispensable to study drug resistance. In this review, recent advances in computer-aided drug design for the rational design of new compounds against HIV-1 RT using methods such as molecular docking, molecular dynamics, free energy calculations, quantitative structure-activity relationships, pharmacophore modelling and absorption, distribution, metabolism, excretion and toxicity prediction are discussed. Successful applications of these methodologies are also highlighted.

A infecção por Ascaris lumbricoides decorre da ingestão de ovos embrionados deste parasita, o que justifica a pesquisa de substâncias que tenham efeito deletério sobre estes ovos. Nosso objetivo foi estudar a ação de 16 produtos detergentes e desinfetantes, de uso doméstico e laboratorial, sobre a embriogênese deste helminto. Crianças portadoras desta infecção foram tratadas com levamisol e os vermes fêmeas expelidos foram recolhidos e dissecados, para obtenção dos ovos intra-uterinos. Os ovos foram postos em contato com os produtos em diversas diluições e tempos, lavados e incubados a 28ºC, por 20 dias, para teste da viabilidade e determinação da porcentagem de embrionamento. Apenas um produto inibiu completamente o embrionamento dos ovos, em todos os tempos e diluições testados. Cinco produtos inibiram o embrionamento dos ovos em mais de 50%, seis inibiram o embrionamento em menos de 50% e três não tiveram efeito sobre o embrionamento dos ovos. Por outro lado, com um produto observou-se aumento da porcentagem de embrionamento dos ovos em relação aos controles.

Ascaris lumbricoides infection is acquired via ingestion of embryonated eggs of the parasite, thus justifying the search for ovicidal compounds. We studied the effect of 16 household and laboratory detergents and disinfectants on the embryogenesis of this helminth. Children carrying this infection were treated with levamisole. Eliminated female worms were collected and dissected to obtain eggs from the uteri. The eggs were placed in contact with various products at different dilutions and for various periods of time. After washing, eggs were incubated at 28ºC for 20 days, for viability tests and to determine the embryonation rate. Only one product completely inhibited the embryonation of eggs at every dilution and for every time period tested. Five products inhibited more than 50% of embryonation, while six inhibited less than 50%. Three products showed no effect on embryonation, while for one the percentage of embryonated eggs was higher than in the control tubes.

A infecção por Ascaris lumbricoides decorre da ingestão de ovos embrionados deste parasita, o que justifica a pesquisa de substâncias que tenham efeito deletério sobre estes ovos. Nosso objetivo foi estudar a ação de 16 produtos detergentes e desinfetantes, de uso doméstico e laboratorial, sobre a embriogênese deste helminto. Crianças portadoras desta infecção foram tratadas com levamisol e os vermes fêmeas expelidos foram recolhidos e dissecados, para obtenção dos ovos intra-uterinos. Os ovos foram postos em contato com os produtos em diversas diluições e tempos, lavados e incubados a 28ºC, por 20 dias, para teste da viabilidade e determinação da porcentagem de embrionamento. Apenas um produto inibiu completamente o embrionamento dos ovos, em todos os tempos e diluições testados. Cinco produtos inibiram o embrionamento dos ovos em mais de 50%, seis inibiram o embrionamento em menos de 50% e três não tiveram efeito sobre o embrionamento dos ovos. Por outro lado, com um produto observou-se aumento da porcentagem de embrionamento dos ovos em relação aos controles.

Ascaris lumbricoides infection is acquired via ingestion of embryonated eggs of the parasite, thus justifying the search for ovicidal compounds. We studied the effect of 16 household and laboratory detergents and disinfectants on the embryogenesis of this helminth. Children carrying this infection were treated with levamisole. Eliminated female worms were collected and dissected to obtain eggs from the uteri. The eggs were placed in contact with various products at different dilutions and for various periods of time. After washing, eggs were incubated at 28ºC for 20 days, for viability tests and to determine the embryonation rate. Only one product completely inhibited the embryonation of eggs at every dilution and for every time period tested. Five products inhibited more than 50% of embryonation, while six inhibited less than 50%. Three products showed no effect on embryonation, while for one the percentage of embryonated eggs was higher than in the control tubes.

Foi estudada, in vitro, a ação do tiabendazol, contra ovos de Ascaris lumbricoides , retirados de úteros de vermes eliminados após tratamento. Foram utilizadas quatro concentrações da droga: 1 -- 2,5 - 5 e 10 ppm em três diferentes períodos de tempo: 24, 48 e 72 horas. Decorridos estes tempos a suspensão com os ovos foi centrifugada, lavada por três vezes com água destilada, adicionada de solução de H2SO4, 0,1N e mantida em estufa a 28°C por 20 dias. Em seguida, os ovos foram levados ao microscópio óptico, no aumento de 100X, para observação do percentual de embrionamento. Na concentração de 10ppm, nos tempos de 48 e 72 horas de exposição à droga, verificou-se completa inibição do embrionamento dos ovos.

The in vitro activity of thiabendazole on Ascaris lumbricoides eggs, which were recovered from uteri of worm excreted after chemotherapeutic treatment, was studied. Four concentrations of the drug were used: 1 -- 2.5 -- 5 -- and 10 ppm during 24, 48 and 72 hours of exposure. Subsequently, the eggs were centrifuged, washed three times and H2SO4 0.1N was added. The eggs were maintained in an incubator for 20 days at 28°C. Finally, the percentage of embryonated eggs was determined under a lightmicroscope at a 100X magnification. After 48 and 72 hours of thiabendazole exposure, at a concentration of 10ppm, the drug showed complete inhibition of egg embryonation.