<i>In Silico</i>Drug Discovery Strategies Identified ADMET Properties of Decoquinate RMB041 and Its Potential Drug Targets against Mycobacterium tuberculosis

Knoll, Kirsten Elke; Walt, Mietha M. Van der; Loots, Du Toit

doi:10.1128/spectrum.02315-21

Cited by 12 publications

(4 citation statements)

References 93 publications

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“…Our results also demonstrated that plumbagin has neither an inhibition nor a substrate profile with the main enzymes of the cytochrome P540 family. Cytochrome P450 is the main metabolic enzyme to be considered in the process of drug metabolism, which can oxidize xenobiotics to facilitate their elimination [ 56 ]. The inhibition of these enzymes suggests the potential for the occurrence of toxicity and possible interference with the pharmacokinetics of co-administered compounds.…”

Section: Discussionmentioning

confidence: 99%

Antiparasitic Activity of Plumbago auriculata Extracts and Its Naphthoquinone Plumbagin against Trypanosoma cruzi

et al. 2023

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Chagas disease (CD) caused by the protozoan Trypanosoma cruzi affects more than six million people worldwide. Treatment is restricted to benznidazole (Bz) and nifurtimox (Nf) that display low activity in the later chronic stage besides triggering toxic events that result in treatment abandonment. Therefore, new therapeutic options are necessary. In this scenario, natural products emerge as promising alternatives to treat CD. In the family Plumbaginaceae, Plumbago sp. exhibits a broad spectrum of biological and pharmacological activities. Thus, our main objective was to evaluate, in vitro and in silico, the biological effect of crude extracts of root and of aerial parts of P. auriculata, as well as its naphthoquinone Plumbagin (Pb) against T. cruzi. The phenotypic assays revealed potent activity of the root extract against different forms (trypomastigote and intracellular forms) and strains (Y and Tulahuen), with a compound concentration that reduced 50% of the number of the parasite (EC50) values ranging from 1.9 to 3.9 µg/mL. In silico analysis showed that Pb is predicted to have good oral absorption and permeability in Caco2 cells, besides excellent probability of absorption by human intestinal cells, without toxic or mutagenic potential effects, not being predicted as a substrate or inhibitor of P-glycoprotein. Pb was as potent as Bz against intracellular forms and displayed a superior trypanosomicidal effect (about 10-fold) in bloodstream forms (EC50 = 0.8 µM) as compared to the reference drug (8.5 µM). The cellular targets of Pb on T. cruzi were evaluated using electron microscopy assays and the findings on bloodstream trypomastigotes showed several cellular insults related to the autophagic process. Regarding toxicity in mammalian cells, the root extracts and the naphthoquinone present a moderate toxic profile on fibroblasts and cardiac cell lines. Then, aiming to reduce host toxicity, the root extract and Pb were tested in combination with Bz, and the data showed additive profiles with the sum of the fractional inhibitory concentration indexes (ΣFICIs) being 1.45 and 0.87, respectively. Thus, our work reveals the promising antiparasitic activity of Plumbago auriculata crude extracts and its purified naphthoquinone Plumbagin against different forms and strains of Trypanosoma cruzi in vitro.

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Section: Discussionmentioning

confidence: 99%

Antiparasitic Activity of Plumbago auriculata Extracts and Its Naphthoquinone Plumbagin against Trypanosoma cruzi

et al. 2023

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“…Undesirable pharmacokinetics is one of the main reasons for the failure of drug development, therefore, essential evaluation needs to be undertaken during the discovery stage. Currently, ADME properties can be obtained through in silico methods [ 15 , 16 ], but the determination of drug exposure in plasma and target tissue remains challenging.…”

Section: Introductionmentioning

confidence: 99%

In Silico and In Vivo Pharmacokinetic Evaluation of 84-B10, a Novel Drug Candidate against Acute Kidney Injury and Chronic Kidney Disease

Su,

Liu,

Zhao

et al. 2023

Molecules

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Acute kidney injury (AKI) and chronic kidney disease (CKD) have become public health problems due to high morbidity and mortality. Currently, drugs recommended for patients with AKI or CKD are extremely limited, and candidates based on a new mechanism need to be explored. 84-B10 is a novel 3-phenylglutaric acid derivative that can activate the mitochondrial protease, Lon protease 1 (LONP1), and may protect against cisplatin-induced AKI and unilateral ureteral obstruction- or 5/6 nephrectomy [5/6Nx]-induced CKD model. Preclinical studies have shown that 84-B10 has a good therapeutic effect, low toxicity, and is a good prospect for further development. In the present study, the UHPLC-MS/MS method was first validated then applied to the pharmacokinetic study and tissue distribution of 84-B10 in rats. Physicochemical properties of 84-B10 were then acquired in silico. Based on these physicochemical and integral physiological parameters, a physiological based pharmacokinetic (PBPK) model was developed using the PK-Sim platform. The fitting accuracy was estimated with the obtained experimental data. Subsequently, the validated model was employed to predict the pharmacokinetic profiles in healthy and chronic kidney injury patients to evaluate potential clinical outcomes. Cmax in CKD patients was about 3250 ng/mL after a single dose of 84-B10 (0.41 mg/kg), and Cmax,ss was 1360 ng/mL after multiple doses. This study may serve in clinical dosage setting in the future.

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“…Incorporating ADMET analysis is crucial for exploring the potential of the selected compounds from molecular docking [14]. ADMET analysis provides insights into a compound's pharmacokinetic properties and potential safety risks, aiding in identifying compounds with favorable ADMET profiles [15].…”

Section: Introductionmentioning

confidence: 99%

Unleashing Black Sea Cucumber's Potential: Identifying Anti-Cancer Compounds Through In Silico Drug Discovery

Romdendine,

Kusuma,

Annisa

et al. 2023

Preprint

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Despite being an abundant marine organism in Indonesia, black sea cucumber is still underutilised due to its slightly bitter taste. Previous studies have hinted at the potential of black sea cucumber as an anti-cancer agent. However, specific identification of bioactive compounds that can interact with cancer proteins is still lacking. In the same place, cancer ranks third as Indonesia's leading cause of death. Therefore, this study aims to identify potential anti-cancer compounds from black sea cucumbers using a comprehensive in silico drug discovery approach. This research uses machine learning, molecular docking, and ADMET analysis to identify bioactive compounds that specifically interact with cancer proteins. A combination of the Cascade Deep Forest algorithm and ECFP-AAIndex1 feature combination proved to be the most effective in predicting these interactions. Through molecular docking validation, four bioactive compounds with strong binding affinity were identified: Afimoxifene, Danazol, Taxifolin, and Terfenadine. ADMET analysis highlighted Taxifolin as the most promising candidate, as it passed most ADMET parameters. Further wet laboratory studies are required to confirm the effects and potential of these compounds as anti-cancer agents. This study builds a foundation for future investigations into alternative cancer treatments using abundant natural resources.

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In SilicoDrug Discovery Strategies Identified ADMET Properties of Decoquinate RMB041 and Its Potential Drug Targets against Mycobacterium tuberculosis

Cited by 12 publications

References 93 publications

Antiparasitic Activity of Plumbago auriculata Extracts and Its Naphthoquinone Plumbagin against Trypanosoma cruzi

Antiparasitic Activity of Plumbago auriculata Extracts and Its Naphthoquinone Plumbagin against Trypanosoma cruzi

In Silico and In Vivo Pharmacokinetic Evaluation of 84-B10, a Novel Drug Candidate against Acute Kidney Injury and Chronic Kidney Disease

Unleashing Black Sea Cucumber's Potential: Identifying Anti-Cancer Compounds Through In Silico Drug Discovery

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