Identification of a novel putative inhibitor of the Plasmodium falciparum purine nucleoside phosphorylase: exploring the purine salvage pathway to design new antimalarial drugs. 2017

Luciano Porto Kagami, and Gustavo Machado das Neves, and Ricardo Pereira Rodrigues, and Vinicius Barreto da Silva, and Vera Lucia Eifler-Lima, and Daniel Fábio Kawano
Laboratório de Síntese Orgânica Medicinal - LaSOM, Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul, Av. Ipiranga 2752, Porto Alegre, RS, 90610-000, Brazil.

Malaria, a tropical parasitic disease caused by Plasmodium spp., continues to place a heavy social burden, with almost 200 million cases and more than 580,000 deaths per year. Plasmodium falciparum purine nucleoside phosphorylase (PfPNP) can be targeted for antimalarial drug design since its inhibition kills malaria parasites both in vitro and in vivo. Although the currently known inhibitors of PfPNP, immucillins, are orally available and of low toxicity to animals and humans, to the best of our knowledge, none of these compounds has entered clinical trials for the treatment of malaria. Using a pharmacophore-based virtual screening coupled to a consensual molecular docking approach, we identified 59 potential PfPNP inhibitors that are predicted to be orally absorbed in a Caco-2 cell model. Although most of these compounds are predicted to have high plasma protein binding levels, poor water solubility (except for compound 25) and CYP3A4 metabolic stability (except for 4, 7 and 8), four structures (4, 7, 8 and 25) remain as potential leads because of their plausible interaction with a specific hydrophobic pocket of PfPNP, which would confer them higher selectivity for PfPNP over human PNP. Additionally, both predicted Gibbs free energies for binding and molecular dynamics suggest that compound 4 may form a more stable complex with PfPNP than 5[Formula: see text]-methylthio-immucillin-H, a potent and selective inhibitor of PfPNP.

UI MeSH Term Description Entries
D008958 Models, Molecular Models used experimentally or theoretically to study molecular shape, electronic properties, or interactions; includes analogous molecules, computer-generated graphics, and mechanical structures. Molecular Models,Model, Molecular,Molecular Model
D010963 Plasmodium falciparum A species of protozoa that is the causal agent of falciparum malaria (MALARIA, FALCIPARUM). It is most prevalent in the tropics and subtropics. Plasmodium falciparums,falciparums, Plasmodium
D011683 Purine-Nucleoside Phosphorylase An enzyme that catalyzes the reaction between a purine nucleoside and orthophosphate to form a free purine plus ribose-5-phosphate. EC 2.4.2.1. Inosine Phosphorylase,Nicotinamide Riboside Phosphorylase,Purine Nucleoside Phosphorylases,Nucleoside Phosphorylases, Purine,Phosphorylase, Inosine,Phosphorylase, Nicotinamide Riboside,Phosphorylase, Purine-Nucleoside,Phosphorylases, Purine Nucleoside,Purine Nucleoside Phosphorylase,Riboside Phosphorylase, Nicotinamide
D011687 Purines A series of heterocyclic compounds that are variously substituted in nature and are known also as purine bases. They include ADENINE and GUANINE, constituents of nucleic acids, as well as many alkaloids such as CAFFEINE and THEOPHYLLINE. Uric acid is the metabolic end product of purine metabolism.
D003198 Computer Simulation Computer-based representation of physical systems and phenomena such as chemical processes. Computational Modeling,Computational Modelling,Computer Models,In silico Modeling,In silico Models,In silico Simulation,Models, Computer,Computerized Models,Computer Model,Computer Simulations,Computerized Model,In silico Model,Model, Computer,Model, Computerized,Model, In silico,Modeling, Computational,Modeling, In silico,Modelling, Computational,Simulation, Computer,Simulation, In silico,Simulations, Computer
D004353 Drug Evaluation, Preclinical Preclinical testing of drugs in experimental animals or in vitro for their biological and toxic effects and potential clinical applications. Drug Screening,Evaluation Studies, Drug, Pre-Clinical,Drug Evaluation Studies, Preclinical,Drug Evaluations, Preclinical,Evaluation Studies, Drug, Preclinical,Evaluation, Preclinical Drug,Evaluations, Preclinical Drug,Medicinal Plants Testing, Preclinical,Preclinical Drug Evaluation,Preclinical Drug Evaluations,Drug Screenings,Screening, Drug,Screenings, Drug
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000962 Antimalarials Agents used in the treatment of malaria. They are usually classified on the basis of their action against plasmodia at different stages in their life cycle in the human. (From AMA, Drug Evaluations Annual, 1992, p1585) Anti-Malarial,Antimalarial,Antimalarial Agent,Antimalarial Drug,Anti-Malarials,Antimalarial Agents,Antimalarial Drugs,Agent, Antimalarial,Agents, Antimalarial,Anti Malarial,Anti Malarials,Drug, Antimalarial,Drugs, Antimalarial
D015800 Protozoan Proteins Proteins found in any species of protozoan. Proteins, Protozoan
D056004 Molecular Dynamics Simulation A computer simulation developed to study the motion of molecules over a period of time. Molecular Dynamics Simulations,Molecular Dynamics,Dynamic, Molecular,Dynamics Simulation, Molecular,Dynamics Simulations, Molecular,Dynamics, Molecular,Molecular Dynamic,Simulation, Molecular Dynamics,Simulations, Molecular Dynamics

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