Simulation Models for Prediction of Bioavailability of Medicinal Drugs—the Interface Between Experiment and Computation

Soliman, Mahmoud E. S.; Adewumi, Adeniyi T.; Akawa, Oluwole B.; Subair, Temitayo I.; Okunlola, Felix O.; Akinsuku, Oluwayimika E; Khan, Shahzeb

doi:10.1208/s12249-022-02229-5

Cited by 17 publications

(10 citation statements)

References 145 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In silico models predict drug behaviour based on physicochemical properties of drug candidates in combination with crystal structures of a protein (target) and a database of ADME (absorption, distribution, metabolism, and elimination) properties generated in laboratories [2]. These studies are often capable of faithfully predicting absorption, target organ concentration, clearance, efficacy, and toxicity or other adverse effects early in the drug discovery and development processes [3,4]. In vitro pharmacokinetics assays include permeability and metabolic stability.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic Evaluation of New Drugs Using a Multi-Labelling Approach and PET Imaging: Application to a Drug Candidate with Potential Application in Neuromuscular Disorders

et al. 2023

View full text Add to dashboard Cite

Background and objective: The determination of pharmacokinetic properties of new chemical entities is a key step in the process of drug development. Positron emission tomography (PET) is an ideal technique to obtain both biodistribution and pharmacokinetic parameters of new compounds over a wide range of chemical modalities. Here, we use a multi-radionuclide/multi-position labelling approach to investigate distribution, elimination, and metabolism of a triazole-based FKBP12 ligand (AHK2) with potential application in neuromuscular disorders. Methods: Target engagement and stabilizing capacity of the drug candidate (AHK2) towards FKBP12-RyR was evaluated using competitive ligand binding and proximity ligation assays, respectively. Subsequently, AHK2 was labelled either with the positron emitter carbon-11 (11C) via 11C-methylation to yield both [11C]AHK2.1 and [11C]AHK2.2, or by palladium-catalysed reduction of the corresponding 5-iodotriazole derivative using 3H gas to yield [3H]AHK2. Metabolism was first investigated in vitro using liver microsomes. PET imaging studies in rats after intravenous (IV) administration at different doses (1 µg/Kg and 5 mg/Kg) were combined with determination of arterial blood time-activity curves (TACs) and analysis of plasma samples by high performance liquid chromatography (HPLC) to quantify radioactive metabolites. Arterial TACs were obtained in continuous mode by using an in-house developed system that enables extracorporeal blood circulation and continuous measurement of radioactivity in the blood. Pharmacokinetic parameters were determined by non-compartmental modelling of the TACs. Results: In vitro studies indicate that AHK2 binds to FKBP12 at the rapamycin-binding pocket, presenting activity as a FKBP12/RyR stabilizer. [11C]AHK2.1, [11C]AHK2.2 and [3H]AHK2 could be obtained in overall non-decay corrected radiochemical yields of 14 ± 2%, 15 ± 2% and 0.05%, respectively. Molar activities were 60–110 GBq/µmol, 68–122 GBq/µmol and 0.4–0.5 GBq/μmol, respectively. In vitro results showed that oxidation of the thioether group into sulfoxide, demethylation of the CH3O-Ar residue and demethylation of –N(CH3)2 were the main metabolic pathways. Fast metabolism was observed in vivo. Pharmacokinetic parameters obtained from metabolite-corrected arterial blood TACs showed a short half-life (12.6 ± 3.3 min). Dynamic PET imaging showed elimination via urine when [11C]AHK2.2 was administered, probably reflecting the biodistribution of [11C]methanol as the major metabolite. Contrarily, accumulation in the gastrointestinal track was observed after administration of [11C]AKH2.1. Conclusion: AHK2 binds to FKBP12 at the rapamycin-binding pocket, presenting activity as a FKBP12/RyR stabilizer. Studies performed with the 3H- and 11C-labelled FKBP12/RyR stabilizer AHK2 confirm fast blood clearance, linear pharmacokinetics and rapid metabolism involving oxidation of the sulfide and amine moieties and oxidative demethylation of the CH3-O-Ar and tertiary amine groups as the main pathways. PET studies suggest that knowledge about metabolic pathways is paramount to interpret images.

show abstract

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic Evaluation of New Drugs Using a Multi-Labelling Approach and PET Imaging: Application to a Drug Candidate with Potential Application in Neuromuscular Disorders

et al. 2023

View full text Add to dashboard Cite

show abstract

“…Mathematical modeling is of great help to medicine [ 30 , 31 ]. Through effective mathematical model analysis, the risk of disease occurrence or intervention can be predicted [ 32 , 33 ].…”

Section: Discussionmentioning

confidence: 99%

Risk Prediction of Ureaplasma urealyticum Affecting Sperm Quality Based on Mathematical Model and Cross-Sectional Study

Liu

Yang

He³

et al. 2022

Computational and Mathematical Methods in Medicine

View full text Add to dashboard Cite

Objective. To explore the risk of Ureaplasma urealyticum (UU) affecting sperm quality. Methods. Prospective cross-sectional study was conducted. In total, 340 semen samples were collected. According to whether they were infected with UU, the samples were divided into the UU-positive group (observation group) and UU-negative group (control group). The patients with UU-positive were followed up to obtain treatment and collected the semen again after treatment. The semen characteristics and sperm parameters were detected and compared, and the relationship of UU and the sperm quality was analyzed by mathematical models. Results. There were 104 UU-positive semen samples in all, with an overall infection rate of 30.6%, which was highest in 31 to 40-year-old men, and over 40-year-old men were the lowest. The pH, PR, VCL, VSL, and STR in the observation group were significantly lower than those in the control group (all P < 0.001 ), while SV, NP, and WOB were significantly higher (all P < 0.001 ). After treatment, the pH, VSL, LIN, WOB, and STR in the observation group were significantly higher than before (all P < 0.001 ), while SV and VCL were significantly lower (all P < 0.001 ). UU infection was closely correlated with pH, PR, NP, VCL, VSL, WOB, and STR. During the treatment, pH, PR, VSL, WOB, and STR increased, but NP and VCL decreased. 7 major factors that would affect SQ were extracted, of which VAP, LIN, and UU were the first three main factors. The risk of SQ declining after UU infection increased nearly twice with the change of PR and VCL and increased 0.08 times with STR. Conclusion. UU may approximately double the risk of altering the sperm’s curvilinear movement rate and straightness to affect the sperm quality.

show abstract

“…40 A ligand will be deemed orally inert if it breaches two or more of Lipinski's requirements, including those requiring five H-bond donors, ten H-bond acceptors, a molecular weight of 500 g/mol, and a log P of 5.43 for an orally active medication. 41 In light of these requirements, cymbopogonol satisfies the prerequisites for oral bioavailability as evidenced by its Consensus (Table 4). © 2022 the authors.…”

Section: Admet Profilementioning

confidence: 99%

In silico Evaluation of the Inhibitory Potential of Cymbopogonol from Cymbopogon citratus Towards Falcipain-2 (FP2) Cysteine Protease of Plasmodium falciparum

2022

TJNPR

View full text Add to dashboard Cite

Antimicrobial resistance is a major challenge militating against the health of people globally. Plasmodium falciparum has developed resistance to current drugs used in tackling malaria, and this has remarkably contributed to an increased mortality rate in Sub-Saharan Africa. The inhibitory potential of cymbopogonol against Falcipain-2 (FP2) of the Plasmodium falciparum parasite was evaluated and achieved using a computational approach in this study. SwissADME, ADMETLab, and PROTOX-II servers were used to evaluate cymbopogonol's absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties in comparison to the other ligands. The test compound had a better docking score of -8.40 kcal/mol compared to the standard and co-crystallized ligand. The compound also had a hydrophobic interaction with LEU I:78, MET I:29, VAL I:44, VAL I:47, LEU I:25, and ARG I:43 present in the FP2 receptorbinding motif of the malaria parasite. The compound also possesses a favorable ADMET characteristics and demonstrated no tendency towards hERG inhibition, hepatotoxicity, carcinogenicity, mutagenicity, or drug-liver injury. Therefore, cymbopogonol may be used for experimental research and future medication development for the successful treatment of malaria.

show abstract

Simulation Models for Prediction of Bioavailability of Medicinal Drugs—the Interface Between Experiment and Computation

Cited by 17 publications

References 145 publications

Pharmacokinetic Evaluation of New Drugs Using a Multi-Labelling Approach and PET Imaging: Application to a Drug Candidate with Potential Application in Neuromuscular Disorders

Pharmacokinetic Evaluation of New Drugs Using a Multi-Labelling Approach and PET Imaging: Application to a Drug Candidate with Potential Application in Neuromuscular Disorders

Risk Prediction of Ureaplasma urealyticum Affecting Sperm Quality Based on Mathematical Model and Cross-Sectional Study

In silico Evaluation of the Inhibitory Potential of Cymbopogonol from Cymbopogon citratus Towards Falcipain-2 (FP2) Cysteine Protease of Plasmodium falciparum

Contact Info

Product

Resources

About