Predictable Pharmacokinetics Research Articles

Development and Application of a Physiologically Based Pharmacokinetic Model for Elagolix in the Adult and Adolescent Population.

Endometriosis, a common and distressing gynecological condition, affects fertility and causes pain, is often managed with medications such as Elagolix. The present study aimed to construct a physiologically based pharmacokinetic (PBPK) model for elagolix to predict its pharmacokinetics in different populations, including those with special conditions, to enhance treatment strategies for endometriosis. The PBPK model was optimized using observational data based on the oral administration of elagolix in a healthy Chinese population under fasting conditions. Model accuracy was further verified by comparing the predicted postprandial elagolix concentration data for healthy Chinese individuals with observed data and by comparing these values with the predicted values in a US population model with renal injury or following multiple-dose administration. Elagolix pharmacokinetic (PK) profiles in the Chinese and American populations exhibited no differences that were attributable to ethnicity. The model predicted in vivo PK in adolescents aged 14-18 years, revealing no clinically significant differences in the effects of elagolix between adolescents and adults. In addition, no predicted PK differences in individuals with overweight were observed. However, notable variations emerged in those classified as obesity class 2 and above compared to healthy individuals. Our study presents a novel PBPK model for elagolix in healthy Chinese women, addressing a clinical data gap for its use in adolescents and obese patients. By validating the model with real-world factors, including diet and renal impairment, we provide initial pharmacokinetic predictions for these populations, contributing to a more informed clinical approach.

Antiplasmodial potential of isolated xanthones from Mesua ferrea Linn. roots: an in vitro and in silico molecular docking and pharmacokinetics study

BackgroundMalaria is a major global health concern, particularly in tropical and subtropical countries. With growing resistance to first-line treatment with artemisinin, there is an urgent need to discover novel antimalarial drugs. Mesua ferrea Linn., a plant used in traditional medicine for various purposes, has previously been investigated by our research group for its cytotoxic properties. The objective of this study was to explore the compounds isolated from M. ferrea with regards to their potential antiplasmodial activity, their interaction with Plasmodium falciparum lactate dehydrogenase (PfLDH), a crucial enzyme for parasite survival, and their pharmacokinetic and toxicity profiles.MethodsThe isolated compounds were assessed for in vitro antiplasmodial activity against a multidrug-resistant strain of P. falciparum K1 using a parasite lactate dehydrogenase (pLDH) assay. In vitro cytotoxicity against Vero cells was determined using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. The interactions between the isolated compounds and the target enzyme PfLDH were investigated using molecular docking. Additionally, pharmacokinetic and toxicity properties were estimated using online web tools SwissADME and ProTox-II, respectively.ResultsAmong the seven compounds isolated from M. ferrea roots, rheediachromenoxanthone (5), which belongs to the pyranoxanthone class, demonstrated good in vitro antiplasmodial activity, with the IC50 being 19.93 µM. Additionally, there was no toxicity towards Vero cells (CC50 = 112.34 µM) and a selectivity index (SI) of 5.64. Molecular docking analysis revealed that compound (5) exhibited a strong binding affinity of − 8.6 kcal/mol towards PfLDH and was stabilized by forming hydrogen bonds with key amino acid residues, including ASP53, TYR85, and GLU122. Pharmacokinetic predictions indicated that compound (5) possessed favorable drug-like properties and desired pharmacokinetic characteristics. These include high absorption in the gastrointestinal tract, classification as a non-substrate of permeability glycoprotein (P-gp), non-inhibition of CYP2C19, ease of synthesis, a high predicted LD50 value of 4,000 mg/kg, and importantly, non-hepatotoxic, non-carcinogenic, and non-cytotoxic effects.ConclusionsThis study demonstrated that compounds isolated from M. ferrea exhibit activity against P. falciparum. Rheediachromenoxanthone has significant potential as a scaffold for the development of potent antimalarial drugs.

PBPK Modeling of Entrectinib and Its Active Metabolite to Derive Dose Adjustments in Pediatric Populations Co-Administered with CYP3A4 Inhibitors.

Physiologically based pharmacokinetic (PBPK) models of entrectinib and its equipotent metabolite, M5, were established in healthy adult subjects and extrapolated to pediatric patients to predict increases in steady-state systemic exposure on co-administration of strong and moderate CYP3A4 inhibitors (itraconazole at 5 mg/kg, erythromycin at 7.5-12.5 mg/kg and fluconazole at 3-12 mg/kg, respectively). Adult model establishment involved the optimization of fraction metabolized by CYP3A4 (0.92 for entrectinib and 0.98 for M5) using data from an itraconazole DDI study. This model captured well the exposure changes of entrectinib and M5 seen in adults co-administered with the strong CYP3A4 inducer rifampicin. In pediatrics, reasonable prediction of entrectinib and M5 pharmacokinetics in ≧2 year olds was achieved when using the default models for physiological development and enzyme ontogenies. However, a two to threefold misprediction of entrectinib and M5 exposures was seen in <2 year olds which may be due to missing mechanistic understanding of gut physiology and/or protein binding in very young children. Model predictions for ≧2 year olds showed that entrectinib AUC(0-t) was increased by approximately sevenfold and five to threefold by strong and high-moderate and low-moderate CYP3A4 inhibitors, respectively. Based on these victim DDI predictions, dose adjustments for entrectinib when given concomitantly with strong and moderate CYP3A4 inhibitors in pediatric subjects were recommended. These simulations informed the approved entrectinib label without the need for additional clinical pharmacology studies.

Debates Surrounding the Use of Antithrombotic Therapy in Hemophilic Patients with Cardiovascular Disease: Best Strategies to Minimize Severe Bleeding Risk.

Navigating through antithrombotic therapy in patients with both hemophilia and cardiovascular pathology presents a complex scenario with inherent challenges and opportunities. The presence of hemophilia, characterized by impaired blood clotting, adds a layer of complexity to the management of cardiovascular conditions requiring antiplatelet therapy and anticoagulation. Striking a delicate balance between the necessity for antithrombotic treatment to prevent cardiovascular events and the heightened risk of severe bleeding in individuals with hemophilia demands a nuanced and carefully considered approach. The challenges revolve around identifying an optimal therapeutic strategy that effectively mitigates cardiovascular risks without exacerbating bleeding tendencies. In hemophilic patients with cardiovascular disease, the decision to use antiplatelet therapy requires careful consideration of the individual's bleeding risk profile, considering factors such as the severity of hemophilia, history of bleeding episodes, and concurrent medications. The goal is to provide effective antithrombotic treatment while minimizing the potential for excessive bleeding complications. Conventional anticoagulants like warfarin pose difficulties due to their potential to increase the risk of bleeding. On the other hand, emerging options like novel direct oral anticoagulants (DOACs) present an opportunity, offering predictable pharmacokinetics and user-friendly administration. However, a comprehensive exploration of their safety and efficacy in hemophilic patients is imperative. Achieving the right equilibrium between preventing cardiovascular events and minimizing bleeding risk is pivotal in selecting the most effective therapeutic option for individuals with hemophilia and cardiovascular pathology. A multidisciplinary approach, integrating the expertise of hematologists and cardiologists, becomes essential to customize treatments and address the intricacies of this medical challenge.

Pharmacokinetics of isavuconazonium sulfate and its active metabolite isavuconazole in healthy dogs.

Invasive fungal infections (IFIs) are growing in importance in veterinary and human medicine. IFIs such as aspergillosis, blastomycosis, coccidioidomycosis and histoplasmosis remain challenging to treat in dogs. Isavuconazole is a novel antifungal medication that, when compared to currently used azoles, has an expanded spectrum of antifungal activity Rudramurthy (2011), Pfaller (2013), Spec (2018), has more predictable pharmacokinetics in humans Desai (2016), Cojutti (2021) and may cause fewer side effects such as liver and renal toxicity Maertens (2016), DiPippo (2018). The pharmacokinetic profile and safety of isavuconazole in dogs has not yet been characterized. The purpose of this study was to evaluate the pharmacokinetics of isavuconazole in healthy dogs that received a single dose of the prodrug isavuconazonium sulfate. Using full crossover design, six healthy beagle dogs received isavuconazonium sulfate at a mean (+/- SD) dose of 20.6 (+/- 2.8) mg/kg orally and 21.8 (+/- 4.2) mg/kg intravenously. Plasma was collected for batched pharmacokinetic analysis of prodrug and metabolite, isavuconazole, by ultra-high-pressure liquid chromatography tandem mass spectrometry (UHPLC-MS/MS). The median (Q1-Q3) maximum isavuconazole peak plasma concentration was estimated at 3,876.5 (2,811.0-4,800.0) ng/mL following oral administration, with a median (Q1-Q3) peak level at 1.3 (1.0-2.0) hours. Following intravenous administration, the median (Q1-Q3) isavuconazole peak plasma concentration was estimated at 3,221.5 (2,241.5-3,609.0) ng/mL, with a median (Q1-Q3) peak level at 0.4 (0.3-0.6) hours. The median (Q1-Q3) half-life of isavuconazole was 9.4 (7.0-12.2) hours and 14.0 (8.1-21.7) hours for oral and intravenous routes, respectively. One dog received inadvertent subcutaneous drug administration without any apparent adverse effects. Another dog experienced an anaphylactic reaction following accidental rapid drug infusion. No other drug-related adverse events were observed. At dosages used in this study, healthy dogs achieved isavuconazole plasma levels comparable to human therapeutic targets, and when properly administered the drug was well-tolerated.

Prediction method of pharmacokinetic parameters of small molecule drugs based on GCN network model.

Accurately predicting plasma protein binding rate (PPBR) and oral bioavailability (OBA) helps to better reveal the absorption and distribution of drugs in the human body and subsequent drug design. Although machine learning models have achieved good results in prediction accuracy, they often suffer from insufficient accuracy when dealing with data with irregular topological structures. In view of this, this study proposes a pharmacokinetic parameter prediction framework based on graph convolutional networks (GCN), which predicts the PPBR and OBA of small molecule drugs. In the framework, GCN is first used to extract spatial feature information on the topological structure of drug molecules, in order to better learn node features and association information between nodes. Then, based on the principle of drug similarity, this study calculates the similarity between small molecule drugs, selects different thresholds to construct datasets, and establishes a prediction model centered on the GCN algorithm. The experimental results show that compared with traditional machine learning prediction models, the prediction model constructed based on the GCN method performs best on PPBR and OBA datasets with an inter-molecular similarity threshold of 0.25, with MAE of 0.155 and 0.167, respectively. In addition, in order to further improve the accuracy of the prediction model, GCN is combined with other algorithms. Compared to using a single GCN method, the distribution of the predicted values obtained by the combined model is highly consistent with the true values. In summary, this work provides a new method for improving the rate of early drug screening in the future.

Stigmast-4-en-3-one from Euonymus alatus (Thunb.) Siebold. improves diabetic retinopathy and angiogenesis mediated by glucocorticoids receptor

Ethnopharmacological relevanceEuonymus alatus (Thunb.) Siebold. (EA), a traditional Chinese medicine, is widely used in the treatment of diabetes. Our group has previously found that EA could treat diabetic retinopathy (DR) and stigmast-4-en-3-one (Numbered E6) is the active substance responsible for inhibiting angiogenesis in vitro by EA. However, the effects and mechanisms of E6 in the treatment of DR is still unknown. Aim of the studyThe aim of this study was to investigate the effects and mechanisms of E6 in EA on DR. Additionally, a comparison was made between the effects of E6 and triamcinolone acetonide (TA), as well as the side effects of E6 and dexamethasone. Materials and methodsOcular affinity assessment and pharmacokinetic parameter prediction were conducted to evaluate the potential of E6 to treat DR. Retinal endothelial cells were used to investigate the in vitro inhibitory effect of E6 on vascular proliferation. Additionally, chicken embryos, zebrafish, and mice were used to investigate the in vivo anti-vascular proliferation effect of E6. Finally, diabetic mice were used to investigate whether E6 improves diabetic retinopathy and to compare its efficacy with that of TA. We then used network pharmacology to study the targets of E6 and performed molecular docking; followed by immunofluorescence experiments, ELISA, Western blot, and tube formation experiments to further investigate its mechanism. Finally, we compared the side effects of E6 with those of dexamethasone. ResultsE6 was found to have an affinity for the eye and to inhibit vascular proliferation both in vivo and in vitro. Moreover, E6 was found to be more efficacious than TA in the treatment of DR. Molecular docking experiments predicted that the glucocorticoid receptor (GR) is a potential target of E6, and immunofluorescence analyses confirmed that E6 upregulated the expression of the GR in the retina of hyperglycemic mice. In addition, western blotting results and tube formation experiments showed that E6 also attenuated angiogenesis by inhibiting the Hippo and VEGF pathways. Finally, by comparing the effects of E6 and dexamethasone on glucose regulation and osteoporosis, E6 was found to have fewer side effects. ConclusionsE6 is a highly effective drug for the treatment of DR, superior to TA and with fewer side effects than dexamethasone. Its mechanism involves the activation of glucocorticoid receptor and inhibition of Hippo and VEGF pathways to alleviate angiogenesis and inflammation. This study is the first to investigate the role and mechanism of E6 in improving DR. The findings suggest that E6 has unique advantages in the treatment of DR.

A Comprehensive Physiologically Based Pharmacokinetic Model for Predicting Vildagliptin Pharmacokinetics: Insights into Dosing in Renal Impairment.

Physiologically based pharmacokinetic (PBPK) modeling is of great importance in the field of medicine. This study aims to construct a PBPK model, which can provide reliable drug pharmacokinetic (PK) predictions in both healthy and chronic kidney disease (CKD) subjects. To do so, firstly a review of the literature was thoroughly conducted and the PK information of vildagliptin was collected. PBPK modeling software, PK-Sim®, was then used to build and assess the IV, oral, and drug-specific models. Next, the average fold error, visual predictive checks, and predicted/observed ratios were used for the assessment of the robustness of the model for all the essential PK parameters. This evaluation demonstrated that all PK parameters were within an acceptable limit of error, i.e., 2 fold. Also to display the influence of CKD on the total and unbound AUC (the area under the plasma concentration-time curve) and to make modifications in dose, the analysis results of the model on this aspect were further examined. This PBPK model has successfully depicted the variations of PK of vildagliptin in healthy subjects and patients with CKD, which can be useful for medical practitioners in dosage optimization in renal disease patients.

Synthesis, vibrational analysis, thermal analysis, quantum-chemical calculation, molecular docking and dynamics, DMPK and evaluation of the antichagasic potential of a fluorinated chalcone

Chagas disease affects 7 million people worldwide and is endemic in 20 Latin American countries. It is estimated to cause about 14,000 deaths annually and more than 75 million people are at risk of infection. Therefore, there is an urgent need for the development of new therapeutic agents. In this study, we describe the synthesis, characterization, and tripanocidal activity of the chalcone (E)-1-(4-aminophenyl)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)prop‑2-en-1-one (DF). The compound was characterized by spectroscopic techniques and its potential against T. cruzi was evaluated by in vitro assays against Y strain forms and in silico analyses including quantum analyses, multiparameter optimization (MPO) based pharmacokinetic prediction and molecular docking and dynamics simulations. The results of the present study show that DF has a trypanocidal effect, presents a significant reduction in toxicity compared to benznidazole, and can induce morphological changes such as cellular extravasation and the presence of pores, observed by scanning electron microscopy in addition to flow cytometry data, highlighted by staining with 7-AAD, indicative of necrosis, with better selectivity than benznidazole. Molecular docking results showed that the chalcone ligand has a higher affinity for the cruzain enzyme, calculated as -7.5 kcal/mol, forming a stable complex interacting at the benznidazole site. The pharmacokinetic study showed that chalcone has the properties of lipophilicity and polarity that favor its passive permeability (Papp), estimated in 2.1 × 10−5 cm/s in intestinal cells. These results are relevant because chalcone has been described as a molecule with the potential to inhibit growth or cause death of T. cruzi.

Exploring the Mechanism of Shen Qi Gui Oral Liquid against Chemotherapy-Induced Myelosuppression in Cancer Patients Based on Network Pharmacology and Molecular Docking.

Shen Qi Gui oral liquid (SQG) may be beneficial for chemotherapyinduced myelosuppression (CIM). However, the underlying mechanism of CIM treated with SQG is still lacking. A total of 27 blood samples from cancer patients were selected to perform RNA-seq to obtain the Differentially Expressed Genes (DEGs). Then, the active components and target genes of SQG were acquired. Next, the drug targets and DEGs were intersected to obtain the intersection genes, followed by functional enrichment analysis and construction of a drug-compoundgene- disease network. Subsequently, core genes were selected. Then, immune cell infiltration, molecular docking, pharmacokinetic and toxicity prediction, and RT-qPCR were performed. A total of 1,341 DEGs, 51 active compounds, and 264 target genes were identified. Then, 30 intersection genes were acquired. Next, a drug-compound-gene-disease network was constructed, and 7 core genes were acquired. Immune infiltration analysis exhibited that only T follicular helper cells were significantly increased in the CIM group, which was significantly negatively correlated with MAPK1, MAPK14, MCL1, PTEN, and PTGS2. The luteolin, quercetin, and beta-sitosterol showed better affinity with core genes. Luteolin and quercetin, which satisfied Lipinski's rule of five, were likely absorbed by the gastrointestinal system. Toxicity predictions showed that neither luteolin nor quercetin exhibited carcinogenicity or hepatotoxicity. PTEN, PTGS2, CCL2, FOS, MCL1, MAPK1, and MAPK14 were identified as the core genes in CIM patients, which were involved in the MAPK and PI3K-Akt signaling pathways. Luteolin and quercetin may be the promising drugs against CIM.

In silico exploration of anti-prostate cancer compounds from differential expressed genes

Prostate cancer (PCa) is a complex and biologically diverse disease with no curative treatment options at present. This study aims to utilize computational methods to explore potential anti-PCa compounds based on differentially expressed genes (DEGs), with the goal of identifying novel therapeutic indications or repurposing existing drugs. The methods employed in this study include DEGs-to-drug prediction, pharmacokinetics prediction, target prediction, network analysis, and molecular docking. The findings revealed a total of 79 upregulated DEGs and 110 downregulated DEGs in PCa, which were used to identify drug compounds capable of reversing the dysregulated conditions (dexverapamil, emetine, parthenolide, dobutamine, terfenadine, pimozide, mefloquine, ellipticine, and trifluoperazine) at a threshold probability of 20% on several molecular targets, such as serotonin receptors 2a/2b/2c, HERG protein, adrenergic receptors alpha-1a/2a, dopamine D3 receptor, inducible nitric oxide synthase (iNOS), epidermal growth factor receptor erbB1 (EGFR), tyrosine-protein kinases, and C-C chemokine receptor type 5 (CCR5). Molecular docking analysis revealed that terfenadine binding to inducible nitric oxide synthase (-7.833 kcal.mol−1) and pimozide binding to HERG (-7.636 kcal.mol−1). Overall, binding energy ΔGbind (Total) at 0 ns was lower than that of 100 ns for both the Terfenadine-iNOS complex (-101.707 to -103.302 kcal.mol−1) and Ellipticine-TOPIIα complex (-42.229 to -58.780 kcal.mol−1). In conclusion, this study provides insight on molecular targets that could possibly contribute to the molecular mechanisms underlying PCa. Further preclinical and clinical studies are required to validate the therapeutic effectiveness of these identified drugs in PCa disease.

Ceanothanes Derivatives as Peripheric Anionic Site and Catalytic Active Site Inhibitors of Acetylcholinesterase: Insights for Future Drug Design.

Alzheimer's disease (AD) is a multifactorial and fatal neurodegenerative disorder. Acetylcholinesterase (AChE) plays a key role in the regulation of the cholinergic system and particularly in the formation of amyloid plaques; therefore, the inhibition of AChE has become one of the most promising strategies for the treatment of AD, particularly concerning AChE inhibitors that interact with the peripheral anionic site (PAS). Ceanothic acid isolated from the Chilean Rhamnaceae plants is an inhibitor of AChE through its interaction with PAS. In this study, six ceanothic acid derivatives were prepared, and all showed inhibitory activity against AChE. The structural modifications were performed starting from ceanothic acid by application of simple synthetic routes: esterification, reduction, and oxidation. AChE activity was determined by the Ellmann method for all compounds. Kinetic studies indicated that its inhibition was competitive and reversible. According to the molecular coupling and displacement studies of the propidium iodide test, the inhibitory effect of compounds would be produced by interaction with the PAS of AChE. In silico predictions of physicochemical properties, pharmacokinetics, drug-likeness, and medicinal chemistry friendliness of the ceanothane derivatives were performed using the Swiss ADME tool.

Discovery and prospects of new heterocyclic Isatin-hydrazide derivative with a novel role as estrogen receptor α degrader in breast cancer cells.

Introduction: Isatin, a heterocycle scaffold, is the backbone of many anticancer drugs and has previously been reported to engage multiple cellular targets and mechanisms, including angiogenesis, cell cycle, checkpoint pathways and multiple kinases. Here, we report that a novel isatin derivative, 5i, degrades estrogen receptor alpha (ERα) in estrogen-dependent breast cancer cells. This effect of the isatin nucleus has not been previously reported. Tamoxifen and fulvestrant represent standard therapy options in estrogen-mediated disease but have their own limitations. Isatin-based triple angiokinase inhibitor BIBF1120 (Nintedanib) and multikinase inhibitor Sunitinib (Sutent) have been approved by the FDA. Methods: Keeping this in view, we synthesized a series of N'-(1-benzyl-2-oxo-1, 2-dihydro-3H-indol-3-ylidene) hydrazide derivatives and evaluated them in vitro for antiproliferative activities in MCF-7 (ER+) cell line. We further investigated the effect of the most potent compound (5i) on the Erα through Western Blot Analysis. We used in silico pharmacokinetics prediction tools, particularly pkCSM tool, to assess the activity profiles of the compounds. Results and discussion: Compound 5i showed the best antiproliferative activity (IC50 value; 9.29 ± 0.97µM) in these cells. Furthermore, 5i downregulated ERα protein levels in a dose-dependent manner in MCF-7. A multifaceted analysis of physicochemical properties through Data Warrior software revealed some prominent drug-like features of the synthesized compounds. The docking studies predicted the binding of ligands (compounds) with the target protein (ERα). Finally, molecular dynamics (MD) simulations indicated stable behavior of the protein-ligand complex between ERα and its ligand 5i. Overall, these results suggest that the new isatin derivative 5i holds promise as a new ERα degrader.

Exploring Centella asiatica-derived Compounds as Inhibitors of Chikungunya Virus nsP2 Protease: Insights into Pharmacokinetics Prediction

Exploring Centella asiatica-derived Compounds as Inhibitors of Chikungunya Virus nsP2 Protease: Insights into Pharmacokinetics Prediction

A sub-pharmacological test dose does not predict individual docetaxel exposure in prostate cancer patients.

Docetaxel is a cytotoxic drug used for first-line treatment of various malignancies. It has a narrow therapeutic index and shows wide interpatient variability in clearance and toxicity. Tools for individual dose optimization are needed to maximize efficacy and avoid toxicity. We performed a proof-of-concept study (EudraCT 2016-003785-77) to evaluate whether pharmacokinetics after a sub-pharmacological test dose of 1000µg docetaxel (millidose) could be used to predict therapeutic dose exposure. Thirty prostate cancer patients eligible for treatment with docetaxel as part of routine clinical care were included. An intravenous docetaxel millidose was administered 1-7 days prior to therapeutic docetaxel. After both doses plasma docetaxel concentrations were measured by ultra- high performance liquid chromatography-tandem mass spectrometry. The docetaxel clearance was estimated with non-linear mixed effects modeling. Geometric mean docetaxel clearance was 57.9L/h (GCV 78.6%) after admission of a millidose and 40.3L/h (GCV 60.7%) after admission of a therapeutic dose. The millidose and therapeutic dose in a single patient were not significantly correlated (Spearman's rho R = 0.02, P = 0.92). Docetaxel pharmacokinetics at milli- and therapeutic dose level showed insufficient correlation for individual dose optimization. However, the clearance of a docetaxel millidose and full dose are within the same order of magnitude. Therefore, docetaxel millidose pharmacokinetics could potentially facilitate prediction of docetaxel pharmacokinetics at a population level in situations where therapeutic dose levels are impractical, such as pharmacokinetic drug-drug interaction studies or pediatric studies.

Unveiling potent inhibitors for schistosomiasis through ligand-based drug design, molecular docking, molecular dynamics simulations and pharmacokinetics predictions.

Schistosomiasis is a neglected tropical disease which imposes a considerable and enduring impact on affected regions, leading to persistent morbidity, hindering child development, diminishing productivity, and imposing economic burdens. Due to the emergence of drug resistance and limited management options, there is need to develop additional effective inhibitors for schistosomiasis. In view of this, quantitative structure-activity relationship studies, molecular docking, molecular dynamics simulations, drug-likeness and pharmacokinetics predictions were applied to 39 Schistosoma mansoni Thioredoxin Glutathione Reductase (SmTGR) inhibitors. The chosen QSAR model demonstrated robust statistical parameters, including an R2 of 0.798, R2adj of 0.767, Q2cv of 0.681, LOF of 0.930, R2test of 0.776, and cR2p of 0.746, confirming its reliability. The most active derivative (compound 40) was identified as a lead candidate for the development of new potential non-covalent inhibitors through ligand-based design. Subsequently, 12 novel compounds (40a-40l) were designed with enhanced anti-schistosomiasis activity and binding affinity. Molecular docking studies revealed strong and stable interactions, including hydrogen bonding, between the designed compounds and the target receptor. Molecular dynamics simulations over 100 nanoseconds and MM-PBSA free binding energy (ΔGbind) calculations validated the stability of the two best-designed molecules. Furthermore, drug-likeness and pharmacokinetics prediction analyses affirmed the potential of these designed compounds, suggesting their promise as innovative agents for the treatment of schistosomiasis.

Design, synthesis and molecular modeling of pyrazoline based coumarin derivatives as tubulin polymerization inhibitors

A series of coumarin-pyrazoline hybrids was synthesized by cyclization of the coumarin chalcones with hydrazine hydrate and phenyl hydrazine through 1,4-addition on α,β-unsaturated carbonyl system. The synthesized derivatives were evaluated for their cytotoxicity against HCT116, MCF7 and BJ-1 cell lines. Among them, compounds 5d and 5f showed the best selectivity indices (IC50= 13.2 and 12.3 µM (HCT116), 5.0 and 5.5 µM (MCF7) and 26.2 and 26.5 µM (BJ-1), respectively). Derivative 5d revealed an inhibitory effect on tubulin assembly (IC50= 6.53 µM), and CDK2 activity (IC50= 0.47 µM). Induction of apoptosis was observed in MCF-7 cells after treatment with derivative 5d which was associated with a significant decrease in Bcl-2 level and 3-fold increase in Bax level. Moreover, derivative 5d revealed an anti-migration activity as detected by wound healing assay. The active compound 5d was docked within the β tubulin active site to investigate the protein-ligand interactions illustrating a unique binding mode with better score than colchicine (-8.5 kcal/mol). Those studies, along with pharmacokinetics predictions, provided a base for further optimization of compound 5d as a potential anti-tubulin agent.

A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Single Ascending Dose Trial of AWZ1066S, an Anti-Wolbachia Candidate Macrofilaricide.

AWZ1066S has been developed as a potential treatment for the neglected tropical diseases lymphatic filariasis and onchocerciasis. AWZ1066S targets the Wolbachia bacterial endosymbiont present in the causative nematode parasites. This phase 1, first-in-human study aimed to assess the safety and pharmacokinetics of AWZ1066S in healthy human participants. In a randomized double-blind, placebo-controlled, single ascending dose study, healthy adults received a single oral dose of AWZ1066S (or placebo) and were followed up for 10 days. The planned single doses of AWZ1066S ranged from 100 to 1600mg, and each dose was administered to a cohort of 8 participants (6 AWZ1066S and 2 placebo). In total 30 people participated, 18 (60%) female, median age 30.0 years (minimum 20, maximum 61). The cohorts administered 100, 200, 300, and 400mg of AWZ1066S progressed unremarkably. After single 700-mg doses all 4 participants developed symptoms of acute gastritis and transient increases in liver enzymes. The severity of these adverse events ranged from mild to severe, with 1 participant needing hospital admission. Pharmacokinetic analysis indicated that AWZ1066S is rapidly absorbed with predictable pharmacokinetics. In conclusion, safety concerns prevented this study from reaching the human exposures needed for AWZ1066S to be clinically effective against lymphatic filariasis and onchocerciasis.

&lt;i&gt;In silico&lt;/i&gt; evaluation of hypericin and pseudohypericin as candidates for monkeypox treatment

Monkeypox (Mpox) is a viral zoonotic and human-to-human disease with no specific drug or treatment protocol targeting the monkeypox virus (MPXV). In the MPXV life cycle, viral kinase phosphorylation plays a crucial role in early morphogenesis in the cytoplasm, making inhibition of MPXV kinase a potential therapeutic approach for controlling Mpox. Hypericum sampsonii contains several bioactive compounds, such as hypericin and pseudohypericin, which are known for their antiviral properties. In this study, a computational investigation of the physicochemical properties of hypericin and pseudohypericin revealed drug-like characteristics. Pharmacokinetic predictions indicated that hypericin and pseudohypericin are non-toxic to the central nervous system, hepatic system, and cardiac system. Molecular docking results indicated a strong binding affinity of hypericin/pseudohypericin with MPXV thymidylate kinase. As a result, these compounds are being considered as potential Mpox control candidates.

Development of a predictive algorithm for the efficacy of half-life extension strategies

A challenge in development of peptide and protein therapeutics is rapid elimination from the body, necessitating frequent dosing that may lead to toxicities and/or poor patient compliance. To solve this issue, there has been great investment into half-life extension of rapidly eliminated drugs using approaches such as albumin binding, fusion to albumin or Fc, or conjugation to polyethylene glycol. Despite clinical successes of half-life extension products, no clear relationship has been drawn between properties of drugs and the pharmacokinetic parameters of their half-life extended analogues. In this study, non-compartmentally derived pharmacokinetic parameters (half-life, clearance, volume of distribution) were collected for 186 half-life extended drugs and their unmodified parent molecules. Statistical testing and regression analysis was performed to evaluate relationships between pharmacokinetic parameters and a matrix of variables. Multivariate linear regression models were developed for each of the three pharmacokinetic parameters and model predictions were in good agreement with observed data with r2 values for each parameter being: half-life: 0.879, clearance: 0.820, volume of distribution: 0.937. Significant predictors for each parameter included the corresponding pharmacokinetic parameter of the parent drug and descriptors related to molecular weight. This model represents a useful tool for prediction of the potential benefits of half-life extension.