Novel paradigms for drug discovery: computational multitarget screening

Abstract

An established paradigm in current drug development is (i) to identify a single protein target whose inhibition is likely to result in the successful treatment of a disease of interest; (ii) to assay experimentally large libraries of small-molecule compounds in vitro and in vivo to identify promising inhibitors in model systems; and (iii) to determine whether the findings are extensible to humans. This complex process, which is largely based on trial and error, is risk-, time- and cost-intensive. Computational (virtual) screening of drug-like compounds simultaneously against the atomic structures of multiple protein targets, taking into account protein-inhibitor dynamics, might help to identify lead inhibitors more efficiently, particularly for complex drug-resistant diseases. Here we discuss the potential benefits of this approach, using HIV-1 and Plasmodium falciparum infections as examples. We propose a virtual drug discovery 'pipeline' that will not only identify lead inhibitors efficiently, but also help minimize side-effects and toxicity, thereby increasing the likelihood of successful therapies.

Virtual Screening Strategies in Drug Design

“…Em condições fisiológicas um inibidor interage com conformações variadas da proteína e com maior afinidade quando comparado com a conformação sugerida por cristalografia de raios-X, por exemplo. 87 A não consideração de flexibilidade em um cálculo de docagem pode acarretar em pouca exatidão nas predições de modos de ligação, redução na eficiência de seleção de moléculas ativas durante a triagem virtual e baixa correlação entre escore e afinidade de ligação. Quando a flexibilidade do receptor é incorporada às simulações, os riscos associados à obtenção de conformações inadequadas da proteína para o sistema estudado são minimizados.…”

“…87,89 Outra limitação encontrada quando se trabalha com modelos farmacofóricos está associada à incerteza em relação a configuração espacial dos grupos farmacofóricos. Configurações específicas demais levam a seleção de compostos com diversidade estrutural muito pobre, e por outro lado, configurações mais gerais levam a um modelo farmacofórico que gera um grande número de resultados falsopositivos.…”

In Silico Screening of Antimalarial From Indonesian Medicinal Plants Database to Plasmepsin Target

“…The efficacy and efficiency of multi-target in silico screening provides the potential to considerably reduce time, effort, and cost to obtain promising candidates for drug development [21]. In silico screening orients and scores a library of small molecules in the binding site of a protein, ranking the compounds from best to worst.…”

Multi‐target QSAR Study in the Analysis and Design of HIV‐1 Inhibitors

“…Among them, inhibitors targeted on protease, integrase and reverse transcriptase (RT) are mainly investigated. [3][4][5][6][7][8][9][10] These compounds have shown great promise in the therapy of HIV infection, particularly in combination therapy because of their high selectivity and their diminished toxicity.…”

“…There has existed several pioneering work in multi-target drug discovery for HIV infection, such as the multi-target antiretroviral drug Cosalane, 6 which was developed to inhibit several HIV-1 proteins simultaneously. Nevertheless, for all these work, smallmolecule compounds needs to be assayed experimentally, both in vitro and in vivo.…”