Exploring the Molecular Basis of Qo bc1 Complex Inhibitors Activity to Find Novel Antimalarials Hits (original) (raw)
Related papers
Journal of Computational Medicine, 2013
Cytochrome bc1 (EC 1.10.2.2, bc1) is an essential component of the cellular respiratory chain, which catalyzes electron transfer from quinol to cytochrome c and concomitantly the translocation of protons across the membrane. It has been identified as a promising target in malaria parasites. The structure-based pharmacophore modelling and molecular dynamic simulation approach have been employed to identify novel inhibitors of cytochrome bc1. The best structure-based pharmacophore hypothesis (Hypo1) consists of one hydrogen bond acceptor (HBA), one general hydrophobic (HY), and two hydrophobic aromatic features (HYAr). Further, hydrogen interactions and hydrophobic interactions of known potent inhibitors with cytochrome bc1 were compared with Hypo1, which showed that the Hypo1 has good predictive ability. The validated Hypo1 was used to screen the chemical databases. The hits obtained were subsequently subjected to the molecular docking analysis to identify false-positive hits. Moreover, the molecular docking results were further validated by molecular dynamics simulations. Binding-free energy analysis using MM-GBSA method reveals that the van der Waals interactions and the electrostatic energy provide the basis for favorable absolute free energy of the complex. The five virtual hits were identified as possible candidates for the designing of potent cytochrome bc1 inhibitors. of Hindawi Publishing Corporation
Asian Journal of Chemistry, 2018
Malaria continues to be one of the major causes of morbidity even today since its discovery. It is mainly caused by Plasmodium falciparum and is prevalent in subtropical countries. Due to vituperative nature it drastically affected the health of the people and created a financial setback in developing countries. To ease this problem United Nation Development Program (UNDP) has mentioned this as a millennium development goal. The inefficient control of this disease is due to lack of novel anti plasmodial drugs [1], transpiring resistance [2] and slow progress in the development of new approved vaccines [3]. Further resistance of Plasmodium species towards primaquine, artemisinin and quinoline based drugs have contributed to its wide spread. Hence, there is an urgent need to develop new drugs which can help in combating malaria. Mutations in the active sites of receptors are primarily responsible for drug resistance. Lactate dehydrogenase (LDH)
Memórias do Instituto Oswaldo Cruz, 2017
BACKGROUND Malaria persists as a major public health problem. Atovaquone is a drug that inhibits the respiratory chain of Plasmodium falciparum, but with serious limitations like known resistance, low bioavailability and high plasma protein binding. OBJECTIVES The aim of this work was to perform molecular modelling studies of 2-hydroxy-1,4-naphthoquinones analogues of atovaquone on the Q o site of P. falciparum cytochrome bc 1 complex (Pfbc 1) to suggest structural modifications that could improve their antimalarial activity. METHODS We have built the homology model of the cytochrome b (CYB) and Rieske iron-sulfur protein (ISP) subunits from Pfbc 1 and performed the molecular docking of 41 2-hydroxy-1,4-naphthoquinones with known in vitro antimalarial activity and predicted to act on this target. FINDINGS Results suggest that large hydrophobic R2 substituents may be important for filling the deep hydrophobic Q o site pocket. Moreover, our analysis indicates that the H-donor 2-hydroxyl group may not be crucial for efficient binding and inhibition of Pfbc 1 by these atovaquone analogues. The C1 carbonyl group (H-acceptor) is more frequently involved in the important hydrogen bonding interaction with His152 of the Rieske ISP subunit. MAIN CONCLUSIONS Additional interactions involving residues such as Ile258 and residues required for efficient catalysis (e.g., Glu261) could be explored in drug design to avoid development of drug resistance by the parasite.
Development Of Antimalarial Drugs by Computational Analysis of Malarial Parasite Ligands
IRJET, 2023
This research paper explores the application of computational analysis in the investigation of different ligands that target malarial parasites, with the objective of advancing the development of antimalarial drugs. This study aims to identify possible lead compounds with efficacy against malarial parasites by employing several computational tools, such as molecular docking, virtual screening, and quantitative structure-activity relationship (QSAR) modelling. The findings provided in this study provide valuable insights into the interactions between ligands and receptors, as well as the binding affinities and predictive models associated with these interactions. These results contribute significantly to the current efforts aimed at treating malaria.
2D, 3D-QSAR and molecular docking of 4(1H)-quinolones analogues with antimalarial activities
Journal of Molecular Graphics and Modelling, 2013
Cytochrome bc 1 has become a major focus as a molecular target in malaria parasites, which are the most important vector-borne infectious disease in the world. The inhibition of cytochrome bc 1 blocks the mitochondrial respiratory chain and the consequent arrest of pyrimidine biosynthesis, which is essential for parasite development. The authors developed a theoretical study of two-dimensional, three-dimensional quantitative structure-activity relationships and a docking analysis of a series of 4(1H)-quinolones acting as cytochrome bc 1 inhibitors. The predictive ability of the quantitative structure-activity relationship models was assessed using internal (leave-one-out cross-validation) and external (test set with 8 compounds) validation. From the two-dimensional quantitative structure-activity relationship models, the authors emphasized the following descriptors: GCUT SLOGP 0, SLogP VSA 5, Kier molecular flexibility index, electrophilicity index, the partition coefficient and the charge of atom 5 of the quinolone ring as the most important to explain the antimalarial activity of the compounds studied. Three-dimensional quantitative structure-activity relationship models showed that the substituents R1 and R4 in 4(1H)-quinolones analogues are key modulators to enhance the antimalarial activity. The appropriate binding conformations and orientations of these compounds interacting with cytochrome bc 1 were also revealed by molecular docking. Based on the established models, 8 new compounds with highly predicted antimalarial activity have been theoretically designed and presented as a reference for synthesis and antimalarial evaluation.
Structural Insights into Ligand-Parasite Interactions for Antimalarial Drug Design
IRJET, 2023
Malaria, an extensively destructive illness resulting from Plasmodium parasites, persists in affecting a substantial number of individuals globally, hence necessitating the expeditious pursuit of efficacious antimalarial medications. The present research work explores the domain of structural insights obtained from computational analyses of interactions between ligands and parasites, with a specific emphasis on their crucial contribution to the development of antimalarial drugs. This study aims to elucidate the complex mechanisms underlying ligand binding by utilizing sophisticated computational methods, including molecular dynamics simulations and binding free energy calculations. The ultimate goal is to establish a logical foundation for the design and synthesis of highly effective and specific antimalarial drugs [1]
Identification of new antimalarial leads by use of virtual screening against cytochrome bc₁
Bioorganic & medicinal chemistry, 2011
Cytochrome bc1 is a validated drug target in malaria parasites. The spread of Plasmodium falciparum strains resistant to multiple antimalarials emphasizes the urgent need for new drugs. We screened in silico the ZINC and MOE databases, using ligand- and structure-based approaches, to identify new leads for development. The most active compound presented an IC50 value against cultured P. falciparum of 2 μM and a docking pose consistent with its activity.
PLoS ONE, 2011
The Plasmodium falciparum lactate dehydrogenase enzyme (PfLDH) has been considered as a potential molecular target for antimalarials due to this parasite's dependence on glycolysis for energy production. Because the LDH enzymes found in P. vivax, P. malariae and P. ovale (pLDH) all exhibit ,90% identity to PfLDH, it would be desirable to have new anti-pLDH drugs, particularly ones that are effective against P. falciparum, the most virulent species of human malaria. Our present work used docking studies to select potential inhibitors of pLDH, which were then tested for antimalarial activity against P. falciparum in vitro and P. berghei malaria in mice. A virtual screening in DrugBank for analogs of NADH (an essential cofactor to pLDH) and computational studies were undertaken, and the potential binding of the selected compounds to the PfLDH active site was analyzed using Molegro Virtual Docker software. Fifty compounds were selected based on their similarity to NADH. The compounds with the best binding energies (itraconazole, atorvastatin and posaconazole) were tested against P. falciparum chloroquine-resistant blood parasites. All three compounds proved to be active in two immunoenzymatic assays performed in parallel using monoclonals specific to PfLDH or a histidine rich protein (HRP2). The IC 50 values for each drug in both tests were similar, were lowest for posaconazole (,5 mM) and were 40-and 100-fold less active than chloroquine. The compounds reduced P. berghei parasitemia in treated mice, in comparison to untreated controls; itraconazole was the least active compound. The results of these activity trials confirmed that molecular docking studies are an important strategy for discovering new antimalarial drugs. This approach is more practical and less expensive than discovering novel compounds that require studies on human toxicology, since these compounds are already commercially available and thus approved for human use.
Bioinformation, 2020
Malaria remains a global public health burden with significant mortality and morbidity. Despite the several approved drugs available for its management, the parasite has developed resistance to virtually all known antimalarial drugs. The development of a new drug that can combat resistant to Artemisinin based Combination Therapies (ACTs) for malaria is imperative. Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH), a flavin-dependent mitochondrial enzyme is vital in the parasite's pyrimidine biosynthesis is a well-known drug target. Therefore, it is of interest to document the MOLECULAR DOCKING analysis (using Maestro, Schrodinger) data of DIHYDROOROTATE DEHYDROGENASE PfDHODH from P. falciparum towards the design of effective inhibitors. The molecular docking features of 10 compounds with reference to chloroquine with PfDHODH are documented in this report for further consideration.