Insights into cytochrome bc1 complex binding mode of antimalarial 2-hydroxy-1,4-naphthoquinones through molecular modelling (original) (raw)
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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]
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)
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.
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.
Biology
Antimalarials targeting the ubiquinol-oxidation (Qo) site of the Plasmodium falciparum bc1 complex, such as atovaquone, have become less effective due to the rapid emergence of resistance linked to point mutations in the Qo site. Recent findings showed a series of 2-aryl quinolones mediate inhibitions of this complex by binding to the ubiquinone-reduction (Qi) site, which offers a potential advantage in circumventing drug resistance. Since it is essential to understand how 2-aryl quinolone lead compounds bind within the Qi site, here we describe the co-crystallization and structure elucidation of the bovine cytochrome bc1 complex with three different antimalarial 4(1H)-quinolone sub-types, including two 2-aryl quinolone derivatives and a 3-aryl quinolone analogue for comparison. Currently, no structural information is available for Plasmodial cytochrome bc1. Our crystallographic studies have enabled comparison of an in-silico homology docking model of P. falciparum with the mammalia...
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
Exploring the Molecular Basis of Qo bc1 Complex Inhibitors Activity to Find Novel Antimalarials Hits
Mol. Inf., 2013
Cytochrome bc1 complex is a crucial element in the mitochondrial respiratory chain, being indispensable for the survival of several species of Plasmodia that cause malaria and, therefore, it is a promising target for antimalarial drug development. We report a molecular docking study building on the most recently obtained X-ray structure of the Saccharomyces cerevisiae bc1 complex (PDB code: 3CX5) using several reported inhibitors with experimentally determined IC50 values against the Plasmodium falciparum bc1 complex. We produced a molecular docking model that correlated the calculated binding free energy with the experimental inhibitory activity of each compound. This Qo model was used to search the drug-like database included in the MOE package for novel potential bc1 complex inhibitors. Twenty three compounds were chosen to be tested for their antimalarial activity and four of these compounds demonstrated activity against the chloroquine-resistant W2 strain of P. falciparum. The most active compounds were also active against the atovaquone-resistant P. falciparum FCR3 strain and S. cerevisiae. Our study suggests the validity of the yeast bc1 complex structure as a model for the discovery of new antimalarial hits.
Organic & biomolecular chemistry, 2018
The synthesis of a 2-methyl-substituted analogue of the natural product, neopeltolide, is reported in an effort to analyze the importance of molecular conformation and ligand-target interactions in relation to biological activity. The methyl substitution was incorporated via highly diastereoselective ester enolate alkylation of a late-stage intermediate. Coupling of the oxazole sidechain provided 2-methyl-neopeltolide and synthetic neopeltolide via total synthesis. The substitution was shown to maintain the conformational preferences of its biologically active parent compound through computer modeling and NMR studies. Both compounds were shown to be potential antimalarial compounds through the inhibition of mitochondrial respiration in P. falciparum parasites.