Absorption, Distribution, Metabolism And Excretion Prediction Research Articles

Evaluation of the antibacterial and inhibitory activity of the MepA efflux pump of Staphylococcus aureus by riparins I, II, III, and IV

The efflux pump mechanism contributes to the antibiotic resistance of widely distributed strains of Staphylococcus aureus. Therefore, in the present work, the ability of the riparins N-(4-methoxyphenethyl)benzamide (I), 2-hydroxy-N-[2-(4-methoxyphenyl)ethyl]benzamide (II), 2, 6-dihydroxy-N-[ 2-(4-methoxyphenyl)ethyl]benzamide (III), and 3,4,5-trimethoxy-N-[2-(4-methoxyphenethyl)benzamide (IV) as potential inhibitors of the MepA efflux pump in S. aureus K2068 (fluoroquinolone-resistant). In addition, we performed checkerboard assays to obtain more information about the activity of riparins as potential inhibitors of MepA efflux and also analyzed the ability of riparins to act on the permeability of the bacterial membrane of S. aureus by the fluorescence method with SYTOX Green. A molecular coupling assay was performed to characterize the interaction between riparins and MepA, and ADMET (absorption, distribution, metabolism, and excretion) properties were analyzed. We observed that I-IV riparins did not show direct antibacterial activity against S. aureus. However, combination assays with substrates of MepA, ciprofloxacin, and ethidium bromide (EtBr) revealed a potentiation of the efficacy of these substrates by reducing the minimum inhibitory concentration (MIC). Furthermore, increased EtBr fluorescence emission was observed for all riparins. The checkerboard assay showed synergism between riparins I, II, and III, ciprofloxacin, and EtBr. Furthermore, riparins III and IV exhibited permeability in the S. aureus membrane at a concentration of 200 μg/mL. Molecular docking showed that riparins I, II, and III bound in a different region from the binding site of chlorpromazine (standard pump inhibitor), indicating a possible synergistic effect with the reference inhibitor. In contrast, riparin IV binds in the same region as the chlorpromazine binding site. From the in silico ADMET prediction based on MPO, it could be concluded that the molecules of riparin I-IV present their physicochemical properties within the ideal pharmacological spectrum allowing their preparation as an oral drug. Furthermore, the prediction of cytotoxicity in liver cell lines showed a low cytotoxic effect for riparins I-IV.

In vitro antitumor activity, molecular dynamics simulation, DFT study, ADME prediction, and Eg5 binding of enastron analogues.

The objective of this study is to evaluate a series of molecules based on cyclosulfamide as potential anticancer agents. Additionally, the study aims to analyze the obtained results through in silico studies; by conducting experiments and utilizing theoretical methods. In this context, we investigated the cytotoxic activity of enastron analogues on three human cell lines PRI (lymphoblastic cell line) derived from B-cell lymphoma. JURKAT (ATCC TIB-152) acute T cell leukaemia and K562 (ATCC CLL-243) is a chronic myelogenous leukaemia. Most of the tested compounds showed good inhibitory activity compared with the reference ligand (chlorambucil). The 5a derivative demonstrated the strongest effect against all cancer cells used. Furthermore, molecular docking simulations of the Eg5-enastron analogue complex revealed that studied molecules have the ability to inhibit the Eg5 enzyme, as evidenced by their calculated docking score. Following the promising results from the molecular docking study, the complex Eg5-4a underwent a 100 ns molecular dynamics simulation using Desmond. During the simulation, the receptor-ligand pairing demonstrated substantial stability after the initial 70 ns. In addition, we used DFT calculations to analyze the electronic and geometric characteristics of the studied compounds. The HOMO and LUMO band gap energies, and the molecular electrostatic potential surface were also deducted for the stable structure of each compound. Also, we studied the prediction of absorption, distribution, metabolism and excretion (ADME) of the compounds.

New 1(2H)-phthalazinone derivatives as potent nonpeptidic HIV-1 protease inhibitors: molecular docking studies, molecular dynamics simulation, oral bioavailability and ADME prediction

Molecular docking simulations of compounds 1–7, the newly synthesised 1(2H)-phthalazinone derivatives with N-(dimethylamino)ethyl pendant arm, as potent inhibitors of HIV-1 protease (HIV-1 PR) were performed. The results of calculations show that compounds 1–7 can form stable complexes with HIV-1 PR and their inhibitory action is mainly based on combination of intermolecular hydrogen bonds and ionic interactions between flexible cationic ammonium moiety of ligands and deprotonated carboxylic residues Asp25 and Asp29 of the target receptor. Molecular dynamics calculation in explicit water environment of the best ranked complex of compound 3 with HIV-1 PR reveals its high stability with conservation of strong salt bridge interactions during all simulation time. Per-residue decomposition of the binding free energy of HIV-1 PR complex with compound 3 calculated with the MM-PBSA method shows electrostatic and van der Waals interactions as the main favourable components. Estimated oral bioavailability and calculated absorption, distribution, metabolism and excretion (ADME) descriptors, namely, intestinal absorption, aqueous solubility and blood–brain barrier penetration, for compounds 1–7 indicate their good pharmacokinetic profile in humans after oral administration. Enthalpically favourable contribution of ligand–receptor salt bridge interactions and hydrogen bonds to binding free energy in calculated complexes of compounds 1–7 with HIV-1 PR also suggests a potent feature to combat a drug resistance to HIV-1 PR inhibitors.

Structure – ADME relationship: still a long way to go?

Background: Theoretical models for predicting absorption, distribution, metabolism and excretion (ADME) properties play increasingly important roles in support of the drug development process. Objective: We briefly review the in silico prediction models for three important ADME properties, namely, aqueous solubility, human intestinal absorption, and oral bioavailability. Methods: Rather than giving detailed descriptions of the ADME prediction models, we focus on the discussions of the prediction accuracies of the in silico models. Results/conclusion: We find that the robustness and predictive capability of the ADME models are directly associated with the complexity of the ADME property. For the ADME properties involving complex phenomena, such as bioavailability, the in silico models usually cannot give satisfactory predictions. Moreover, the lack of large and high-quality data sets also greatly hinder the reliability of ADME predictions. While considerable progress has been achieved in ADME predictions, many challenges remain to be overcome.

TruPK – human pharmacokinetic models for quantitative ADME prediction

The use of in silico prediction of absorption, distribution, metabolism and excretion (ADME) properties is gaining acceptance as a useful assessment tool for early identification of likely drug candidate failures. However, it has been difficult to locate reliable models for the prediction of human pharmacokinetics (PK) in silico Currently available methods for estimating ADME and toxicity properties, such as in vitro and animal models, are not very predictive of what is observed in the clinic. Existing in silico ADME prediction tools concentrate on physicochemical properties, such as solubility, log P, rule-of-five compliance, Caco-2 permeability, blood–brain barrier and so on, or only classify drug-like candidates as ‘poor’, ‘medium’ or ‘good’ for a PK parameter, without ascribing values. Although physiology-based pharmacokinetic -models can predict ADME properties, they rely on using various measured properties as input for better accuracy. Strand Genomics has developed a tool, truPK, that predicts the properties of a molecule (bioavailability, protein binding, volume of distribution, elimination half-life and absorption rate) that affect its dose and dose frequency in humans. truPK’s five models built using sophisticated machine methods have predicted with > 75% accuracies in external validation sets.