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Pharmacokinetic and molecular docking studies to design antimalarial compounds targeting Actin I.

ABSTRACT: Objective:Malaria is an ancient disease that still causes more than 200 million of cases 7 with high mortality globally. Identification of new drug targets and development of novel antimalarial drugs with unique mode of action encounter the drug resistance and reduce the mortality by Plasmodium parasites. Actin protein is one of the key proteins in Plasmodium falciparum playing multifarious important roles including transport, cell motility, cell division, and shape determination. This study investigated Actin I as a drug target, in silico screening of diverse molecules through molecular docking was considered. Further, pharmacokinetic parameters of the selected molecules from the docking and interaction studies were planned to propose the lead molecules.b. Methods:Molecules were selected according to score and protein ligand interaction and selected molecules were subjected for pharmacokinetic studies to investigate important drug parameters. Results:The docked molecules were ranked according to the binding score and good interaction pattern was observed with Actin I within top 20 scoring molecules. The selected molecules also had optimum pharmacokinetic parameters. Conclusion:The current study provides a set of hit molecules which can be further explored through in vitro and in vivo experiments for the development of potential drugs against malaria, there by encountering drug resistance and establishing Actin I as an important drug target.

SUBMITTER: Guleria V

PROVIDER: S-EPMC8589829 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundThe emergence of antimalarial drug resistance encourages the search for new antimalarial agents. Mammea siamensis belongs to the Calophyllaceae family, which is a medicinal plant that is used in traditional Thai preparations. The hexane and dichloromethane extracts of this plant were found to have potent antimalarial activity. Therefore, this study aimed to isolate active compounds from M. siamensis flowers and evaluate their antimalarial potential and their interactions with Plasmodium falciparum lactate dehydrogenase (PfLDH).MethodsThe compounds from M. siamensis flowers were isolated by chromatographic techniques and evaluated for their antimalarial activity against chloroquine (CQ)-resistant P. falciparum (K1) strains using a parasite lactate dehydrogenase (pLDH) assay. Interactions between the isolated compounds and the PfLDH enzyme were investigated using a molecular docking method.ResultsThe isolation produced the following thirteen compounds: two terpenoids, lupeol (1) and a mixture of β-sitosterol and stigmasterol (5); two mammea coumarins, mammea A/AA cyclo D (6) and mammea A/AA cyclo F (7); and nine xanthones, 4,5-dihydroxy-3-methoxyxanthone (2), 4-hydroxyxanthone (3), 1,7-dihydroxyxanthone (4), 1,6-dihydroxyxanthone (8), 1-hydroxy-5,6,7-trimethoxyxanthone (9), 3,4,5-trihydroxyxanthone (10), 5-hydroxy-1-methoxyxanthone (11), 2-hydroxyxanthone (12), and 1,5-dihydroxy-6-methoxyxanthone (13). Compound 9 exhibited the most potent antimalarial activity with an IC50 value of 9.57 µM, followed by 10, 1, 2 and 13 with IC50 values of 15.48, 18.78, 20.96 and 22.27 µM, respectively. The molecular docking results indicated that 9, which exhibited the most potent activity, also had the best binding affinity to the PfLDH enzyme in terms of its low binding energy (-7.35 kcal/mol) and formed interactions with ARG109, ASN140, and ARG171.ConclusionThese findings revealed that isolated compounds from M. siamensis flowers exhibited antimalarial activity. The result suggests that 1-hydroxy-5,6,7-trimethoxyxanthone is a possible lead structure as a potent inhibitor of the PfLDH enzyme.

Project description:BackgroundAt present, the emergence and spread of antimalarial drug resistance has become a significant problem worldwide. There has been a challenge in searching for natural products for the development of novel antimalarial drugs. Therefore, this study aims to evaluate compounds from Dioscorea bulbifera responsible for antimalarial properties and investigate potential interactions of the compounds with Plasmodium falciparum lactate dehydrogenase (PfLDH), an essential glycolytic enzyme in the parasite's life cycle.MethodsAn in vitro study of antimalarial activity against chloroquine (CQ)-resistant Plasmodium falciparum (K1 strain) and CQ-sensitive P. falciparum (3D7 strain) was performed using the 3H-hypoxanthine uptake inhibition method. The cytotoxic effects of the pure compounds were tested against Vero cells using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The interactions of the compounds with the PfLDH active site were additionally investigated using a molecular docking method.ResultsQuercetin (6) exhibited the highest antimalarial activity against the P. falciparum K1 and 3D7 strains, with IC50 values of 28.47 and 50.99 μM, respectively. 2,4,3',5'-Tetrahydroxybibenzyl (9), 3,5-dimethoxyquercetin (4) and quercetin-3-O-β-D-galactopyranoside (14) also possessed antimalarial effects against these two strains of P. falciparum. Most pure compounds were nontoxic against Vero cells at a concentration of 80 μg/ml, except for compound 9, which had a cytotoxic effect with a CC50 value of 16.71 μM. The molecular docking results indicated that 9 exhibited the best binding affinity to the PfLDH enzyme in terms of low binding energy (- 8.91 kcal/mol) and formed strong hydrogen bond interactions with GLY29, GLY32, THR97, GLY99, PHE100, THR101 and ASN140, amino acids as active sites. In addition, 6 also possessed remarkable binding affinity (- 8.53 kcal/mol) to PfLDH by interacting with GLY29, ILE31, ASP53, ILE54, THR97 and THR101.ConclusionQuercetin is a major active compound responsible for the antimalarial activity of D. bulbifera and is an inhibitor of PfLDH. These findings provide more evidence to support the traditional use of D. bulbifera for malaria treatment. Structural models of its interactions at the PfLDH active site are plausibly useful for the future design of antimalarial agents.

Project description:BackgroundDue to the migratory flow of infected people with severe acute respiratory syndrome virus (SARS COV-2), the number of confirmed cases of coronavirus disease 2019 (COVID-19) is accelerating globally; preclinical evidence of antiviral agents that can combat this pandemic is still elusive. We identified published articles on SARS-COV efficacy experiments in which some selected compounds were used to test the reduction of the virus load in mice.MethodsA systematic search of articles was conducted in PubMed, Web of Science, and Scopus. We then developed a combined model based on a systematic review, meta-analyses, and molecular docking studies to evaluate the effect size of preclinical studies of compounds that have been tested against SARS-COV. Because substantial heterogeneity was expected, random effect model meta-analyses were carried out to estimate the overall pooled disease's prevalence. All meta-analyses were performed with Stata version 15.0. Subgroup analyses on therapies were conducted as well. Molecular docking studies of the inhibitors in the active pocket of COVID-19 protease were also performed.ResultsFrom all screened articles, six studies were appropriate for ultimate meta-analysis and systematic review. The residual amount of heterogeneity was high (τ2 =0.02; heterogeneity I2 =85.5 % with heterogeneity chi-square =103.57, a degree of freedom =15, and p <0.001). The overall random pooled prevalence of infected mice treated with the selected compounds was 78.1 % [95 % Confidence Interval (CI): 14.7-17.0 %]. Prophylactic has a significantly higher pooled prevalence than therapeutic, with 21.8 % (95 % CI: 16.4 % to 28.8 %). Our results indicated that most of the SARS-COV inhibitors analyzed were less effective in reducing the lung virus titer of SARS-COV infection in animal models. The findings from molecular docking studies also identified COVID-19 inhibitors that are good for optimization and drug development to fight against COVID-19 infection.ConclusionsFindings from the review showed that studies on the preclinical compounds targeting SARS-COV and COVID-19 are limited. Furthermore, molecular docking studies and meta-analysis results substantiated three compounds, i.e., EIDD-2801, GS-5734, and amodiaquine. HIPPOKRATIA 2020, 24(3): 99-106.

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Pharmacokinetic and molecular docking studies to design antimalarial compounds targeting Actin I.

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