Predictable Pharmacokinetics Research Articles

Synthesis, Molecular Docking, and Biological Evaluation of Novel Indole-triazole Conjugates.

Indole-triazole conjugates have emerged as promising candidates for new drug development. Their distinctive structural characteristics, coupled with a wide array of biological activities, render them a captivating and promising field of research for the creation of novel pharmaceutical agents. This study aimed to synthesize indole-triazole conjugates to investigate the influence of various substituents on the functional characteristics of indole-triazole hybrids. It also aimed to study the binding modes of new hybrids with the DNA Gyrase using molecular docking studies. A new set of indole-triazole hybrids was synthesized and characterized using various physicochemical and spectral analyses. All hybrids underwent in-silico pharmacokinetic prediction studies. The antimicrobial efficacy of the hybrids was assessed using tube dilution and agar diffusion methods. Additionally, the in-vitro antioxidant activity of synthesized compounds was determined using the 1,1-diphenyl-2-picryl-hydrazyl free radical scavenging assay. Furthermore, in silico molecular docking studies were performed to enhance our comprehension of how the synthesized compounds interact at the molecular level with DNA gyrase. Pharmacokinetic predictions of synthesized hybrids indicated favourable pharmacokinetic profiles, and none of the compounds violated the Lipinski rule of five. Notably, compound 6, featuring a cyclohexanol substituent, demonstrated superior antimicrobial and antioxidant activity (EC50 value = 14.23 μmol). Molecular docking studies further supported the in vitro antioxidant and antimicrobial findings, revealing that all compounds adeptly fit into the binding pocket of DNA Gyrase and engaged in interactions with crucial amino acid residues. In summary, our research underscores the efficacy of molecular hybridization in shaping the physicochemical, pharmacokinetic, and biological characteristics of novel indole-triazole derivatives.

First-in-human study to evaluate the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of RBD4059, a GalNAc-siRNA drug targeting coagulation factor XI (FXI), in healthy subjects

Abstract Background Patients at risk of thrombosis/thromboembolism, require effective and safe anti-coagulation with high compliance. Inhibiting FXI has emerged as a promising strategy with potential for lower bleeding risk compared to currently approved anti-coagulants. Here we report on the safety, PK and PD effects of the GalNAc-conjugated siRNA RBD4059, specifically targeting and repressing FXI protein synthesis in the liver. Purpose Investigate safety, PK, and PD of first-in-human dosing of RBD4059 in healthy subjects. Methods A randomized, single-blind, placebo-controlled, single ascending dose (SAD) phase I study in healthy subjects (NCT05653037), in cohorts of eight randomized 3:1 to receive escalating doses of RBD4059 (50, 150, and 400 mg) or placebo administered subcutaneously. Results As of January 25, 2024, 24 subjects (with follow-up to week 24) with demographics and baseline clinical characteristics shown in Table 1 were enrolled. RBD4059 was well tolerated (Table 2), all related AEs were grade 1. There was no evidence of any clinically relevant bleeding events. Plasma exposure of RBD4059 tended to increase in proportion to the dose. Maximum concentration in plasma (Cmax) was reached in 2 to 4 h and then declined in line with one-compartment kinetics. The mean plasma half-life (t1/2) ranged from 3.2 to 7.0 h. RBD4059 treatment resulted in dose dependent and sustained reductions in FXI activity and FXI antigen (Figure 1A, B, D). Observed mean maximum percentage change from baseline in FXI activity from the 50 mg, 150 mg, and 400 mg SAD cohorts were 67.5%, 81.0%, and 85.8%, respectively, recovering with a maintained effect observed on D141 (50mg: 50.6% inhibition; 150mg: 68.2% inhibition). The reduction in FXI antigen showed a very similar pattern as the reduction in FXI activity, and reductions were accompanied by a concomitant increase in APTT. (Figure 1C, D). PKPD modelling supports that RBD4059 may be dosed every 3 months or less frequent with a >90% FXI reduction throughout the dosing interval, and will be tested in the upcoming phase 2 study. Conclusion(s) RBD4059 demonstrated favorable safety, predictable PK, and pronounced durable PD effect in the dose range of 50 mg - 400 mg. This first-in-human SAD study supports the further development of RBD4059 as an anticoagulant that can maintain a high level of PD effect with a once every 3 month or less frequent dosing regimen, with potential for enhanced compliance in chronic anti-coagulant therapy.Table 1 & Table 2Figure 1.Panels A-D

In Silico Design of Novel Piperazine-Based mTORC1 Inhibitors Through DFT, QSAR and ADME Investigations

Mammalian target of rapamycin complex 1 (mTORC1) is an important and promising alternative biological target for the treatment of different types of cancer including breast, lung and renal cell carcinoma. This study contributed to the development of mathematical models highlighting the quantitative structure-activity relationship of a series of piperazine derivatives reported as mTORC1 inhibitors. Various molecular descriptors were calculated using Gaussian 09, Chemsketch, and ChemOffice software. The density funcional theory (DFT) method at the level B3LYP/6-31G+(d, p) was applied to determine the structural, electronic and energetic parameters associated with the studied molecules. The predictive ability of the built models, which is obtained by two methods (MLR and MNLR), showed that the built models are statistically significant. The QSAR modeling results revealed that the six molecular descriptors of lowest unoccupied molecular orbital energy (ELUMO), electrophilicity index (ω), molar refractivity (MR), aqueous solubility (Log S), topological polar surface area (PSA), and refractive index (n) significantly correlated to the biological inhibitory activity of piperazine derivatives. Using QSAR models and in silico pharmacokinetic profiles predictions, five new candidate compounds are selected as potential inhibitors against cancer.

In silico molecular targets, docking, dynamics simulation and physiologically based pharmacokinetics modeling of oritavancin

IntroductionOritavancin is a semi-synthetic lipoglycopeptide antibiotic primarily used to treat serious infections caused by Gram-positive bacteria. The aim of this study was to elucidate possible molecular targets of oritavancin in human and microbes in relevance to its mechanism of action and model its pharmacokinetics for optimal dose selection in clinical practice.MethodsComputational methods were used in this study which include target prediction, molecular docking, molecular dynamics simulation, pharmacokinetics prediction, and physiological-based pharmacokinetics (PBPK) modeling.ResultsOritavancin was moderately soluble in water and did not permeate the blood-brain barrier. Seven molecular targets were identified in humans. Molecular docking results showed highest binding affinity of oritavancin with PI3-kinase p110-gamma subunit (−10.34 kcal/mol), followed by Acyl-CoA desaturase (−10.07 kcal/mol) and Cytochrome P450 2C19 (−8.384 kcal/mol). Oritavancin PBPK modelling in adult human showed that infusion has lower peak concentrations (Cmax) compared to bolus administration, with 1200 mg dose yielded Cmax of 16.559 mg/L, 800 mg dose yielded Cmax of 11.258 mg/L, and 200 mg over 3 days dose yielded Cmax of 7.526 mg/L. Notably, infusion gave extended half-life (t1/2) for all doses and slightly higher clearance rates compared to bolus, particularly for the 1200 mg and 800 mg doses. The results corroborated existing clinical pharmacokinetic data, and confirmed the model’s accuracy and predictive capability.ConclusionThis comprehensive computational study has provided invaluable insights into the pharmacological profile of Oritavancin, aiding its further development and optimization for clinical use.

Uncovering the interleukin-12 pharmacokinetic desensitization mechanism and its consequences with mathematical modeling.

The cytokine interleukin-12 (IL-12) is a potential immunotherapy because of its ability to induce a Th1 immune response. However, success in the clinic has been limited due to a phenomenon called IL-12 desensitization - the trend where repeated exposure to IL-12 leads to reduced IL-12 concentrations (pharmacokinetics) and biological effects (pharmacodynamics). Here, we investigated IL-12 pharmacokinetic desensitization via a modeling approach to (i) validate proposed mechanisms in literature and (ii) develop a mathematical model capable of predicting IL-12 pharmacokinetic desensitization. Two potential causes of IL-12 pharmacokinetic desensitization were identified: increased clearance or reduced bioavailability of IL-12 following repeated doses. Increased IL-12 clearance was previously proposed to occur due to the upregulation of IL-12 receptor on T cells that causes increased receptor-mediated clearance in the serum. However, our model with this mechanism, the accelerated-clearance model, failed to capture trends in clinical trial data. Alternatively, our novel reduced-bioavailability model assumed that upregulation of IL-12 receptor on T cells in the lymphatic system leads to IL-12 sequestration, inhibiting the transport to the blood. This model accurately fits IL-12 pharmacokinetic data from three clinical trials, supporting its biological relevance. Using this model, we analyzed the model parameter space to illustrate that IL-12 desensitization occurs over a robust range of parameter values and to identify the conditions required for desensitization. We next simulated local, continuous IL-12 delivery and identified several methods to mitigate systemic IL-12 exposure. Ultimately, our results provide quantitative validation of our proposed mechanism and allow for accurate prediction of IL-12 pharmacokinetics over repeated doses.

Study of Molecular Docking, Molecular Dynamics, Pharmacokinetics and Toxicity Prediction: Compounds from Nigella sativa Linn, Andrographis paniculata Nees, and Propolis as Inhibitors of Mycobacterium tuberculosis Growth

Background: Tuberculosis (TB) is caused by *Mycobacterium tuberculosis*, and Multiple Drug-Resistant Tuberculosis (MDR-TB) arises from resistance to first-line treatments like Rifampicin and Isoniazid. Since current TB medications have been used for over four decades, discovering new drug candidates is critical. This research focuses on herbal compounds—Black cumin (*Nigella sativa*), Sambiloto (*Andrographis paniculata*), and propolis—as potential inhibitors of *M. tuberculosis* by targeting DHFR. The objective of the study is to predict the activity of these herbal compounds prior to in vitro and in vivo testing. Methods: This study employed computational tools, including Molegro Virtual Docking (MVD) and Molecular Dynamics (MD), to assess the interactions of the herbal compounds with DHFR (PDB ID: 2CIG). Pharmacokinetic predictions were also conducted to evaluate the absorption and toxicity of the compounds. Results: Molecular docking and MD simulations indicated that Andrographolide, Thymoquinone, and Caffeic Acid Phenethyl Ester effectively inhibited the growth of *M. tuberculosis*. The analysis revealed favorable binding interactions and conformational changes in DHFR, with significant activity observed for Thymoquinone. Conclusion: This study suggests that Andrographolide, Thymoquinone, and Caffeic Acid Phenethyl Ester may serve as promising candidates for further development as anti-tuberculosis drugs. Subsequent in vitro and in vivo studies are warranted to validate their therapeutic potential.

Pharmacokinetic predictions of ROS-mediated targets and genotoxin combinations via multiple ligand simultaneous docking and ROS evaluation in vitro using HepG2 cell lines.

Although combination therapy is known for its high efficacy, reduced side effects and drug resistance, toxicity remains a major drawback. Some of the genes are likely to induce hepatotoxicity through ROS-mediated mechanisms when a drug is metabolized alone or in combination in the liver. To address this, we have developed a scientific approach to predict the toxicity of different genotoxin combinations and validate their interactions with various targets. The current study is an extensive study of our previous set of in vivo rat liver microarray data processed using R studio for their functional analysis. About five combinations of genotoxins such as CPT/ETP, CPT/CPL, ETP/CPL, CP/CPT and EES/CP along with their differential gene expression targeting Chemical carcinogenesis-ROS are chosen for this study. We aim to examine the binding affinity of different genotoxin combinations using in silico multiple ligand simultaneous docking (MLSD) and are then bio-evaluated for cytotoxicity in vitro using human hepatocellular carcinoma cell lines (HepG2) with the MTT assay. As a result, dose-response cytotoxicity with its strength of interactions and a significant variance in ROS levels in the treated cells is observed compared to their IC50 values. Out of 5 combinations such as CPT/CPL, ETP/CPL and EES/CP are found not only to be significantly cytotoxic but also induce oxidative stress specifically above their IC50 values with good and moderate binding interactions ensuring their toxicity. On the contrary, the safe combinations are found to be CTP/ETP and CP/CPT possibly with no and tolerable adverse effects standing as preliminary information for researchers in drug design and development.

Impacts of age and BMI on vancomycin model choice in a Bayesian software: Lessons from a very large multi-site retrospective study.

Model-informed precision dosing (MIPD) optimizes drug doses based on pharmacokinetic (PK) model predictions, necessitating careful selection of models tailored to patient characteristics. This study evaluates the predictive performance of various vancomycin PK models across diverse age and BMI categories, drawing insights from a large multi-site database. Adults receiving vancomycin intravenous therapy at United States health systems between January 1, 2022, and December 31, 2023, were included. Patient demographics, vancomycin administration records, and therapeutic drug monitoring levels (TDMs) were collected from the InsightRX database. Age and body mass index (BMI)-based subgroups were formed to assess model performance, with predictions made iteratively. The optimal model for each age-BMI subgroup was chosen based on predefined criteria: models were filtered for mean percentage error (MPE) ≤ 20% and normalized root mean squared error (RMSE) < 8 mg/L, and then the most accurate among them was selected. A total of 384,876 treatment courses across 155 US health systems were analyzed, contributing 841,604 TDMs. Eleven models were compared, showing varying accuracy across age-BMI categories (41%-73%), with higher accuracy observed once TDMs were available for Bayesian estimates of individual PK parameters. Models performed more poorly in younger adults compared to older adults, and the optimal model differed depending on age-BMI categories and prediction methods. Notably, in the a priori period, the Colin model performed best in adults aged 18-64 years across most BMI categories; the Goti/Tong model performed best in the older, non-obese adults; and the Hughes model performed best in many of the obese categories. Our study identifies specific vancomycin PK models that demonstrate superior predictions across age-BMI categories in MIPD applications. Our findings underscore the importance of tailored model selection for vancomycin management, especially highlighting the need for improved models in younger adult patients. Further research into the clinical implications of model performance is warranted to enhance patient care outcomes.

Intercalating compounds alongside DNA helicase Q1 Plasmodium falciparum 3D7: Assessments of the Pharmacokinetic Properties Prediction of ADME.

Quantum chemical & molecular docking practices to deliver new perceptions into how etoposide, novobiocin, nogalamycin and netropsin interact with the biological targets PF3D7_0918600 (Plasmodium falciparum 3D7). Further the pharmacokinetics of a drug candidate which influenced by a variety of factors, including P- glycoprotein (Pgp) transport, PBB (Plasma protein binding), & BBB (Blood-brain barrier) permeation help to forecast the pharmacological characteristics of acetyl-CoA reductase inhibitors (ADMEs) and their metabolites. At this point, we have elevated four compounds such as etoposide, novobiocin, nogalamycin & netropsin. We have also studied molecular docking against the target protein of the Plasmodium falciparum (PF3D7_0918600) through exhausting the AutoDock Vina platform and AutoDock-Tools (ADT) and pharmacokinetic properties were carried out using the ADMET 2.0. The relative results of molecular docking recommended a greater binding affinity of novobiocin with the selected receptors among other compounds. In-silico ADME screening is a computational approach utilised to forecast the pharmacological characteristics of acetyl- CoA reductase inhibitors (ADMEs) and their metabolites. The ADMEs are based on the adsorption-desorption kinetics and pharmacopoeia. Adsorption and distribution analysis are used to assess the potential of the drug candidate. In vitro ADME is exploited to expect the effect of Pgp transport on the drug candidates. ADME has been used to predict CYP1A2 inhibitors and to predict PPB and BBB penetration. This paper summarizes the current knowledge on molecular docking, ADME and identifies potential drug candidates for ADME in vitro and in vivo.

Oleanolic acid derivatives against drug-resistant bacteria and fungi by multi-targets to avoid drug resistance

Mixed infections caused by drug-resistant bacteria and fungi pose a severe threat to human health, and multi-target drugs may provide an effective approach to combat drug-resistant pathogens. Therefore, this study aimed to investigate the efficacies of some oleanolic acid (OA) derivatives against multidrug-resistant (MDR) bacteria and fungi using in vitro and in vivo experiments. Novel amphiphilic OA derivatives were designed and optimised, in which compounds G1 and J1 exhibited effective antimicrobial activity (MICs = 1–2 μg/mL), high selectivity against MDR strains, rapid bactericidal activity, and good predictive pharmacokinetics. Mechanistically, both compounds prevented drug resistance by disrupting the bacterial cell membrane, inserting into the DNA, and binding to DNA gyrase. Additionally, J1 reduced microbial count in a mouse MRSA skin infection model and accelerated wound healing much better than vancomycin. Conclusively, this study presents a new class of potential drugs for resistant bacteria and fungi.

FTIR, 1H-/13C-NMR spectral characterization, antimicrobial, anticancer, antioxidant, anti-inflammatory, PASS, SAR, and in silico properties of methyl α-D-glucopyranoside derivatives

A novel series of biologically active derivatives based on methyl α-D-glucopyranoside (MGP) has been developed, comprising 6-O-monosubstituted MGP derivatives obtained from methyl α-D-glucopyranoside. These derivatives were transformed into 2,3,4-tri-O-acyl MGP derivatives, incorporating diverse functionalities within a single molecular framework, aimed at producing new products for antimicrobial studies. All synthesized compounds were identified through spectral analyses (FTIR, 1H-NMR, and 13C-NMR) and elemental analysis. Antimicrobial in vitro testing revealed that these MGP derivatives have notable efficacy against various pathogenic microorganisms, along with the prediction of activity spectra for substances (PASS). Compounds 2 and 7 exhibited the highest inhibitory activity against Bacillus subtilis and Escherichia coli, with minimum inhibitory concentration (MIC) values ranging from 0.25 to 64.0 µg/mL and minimum bactericidal concentration (MBC) values ranging from 8.0 to 128.0 µg/mL. Moreover, these compounds demonstrated significant antioxidant properties compared with those of standard antioxidants according to the results of the DPPH free radical scavenging assay. An evaluation of the growth and proliferation of Ehrlich ascites carcinoma (EAC) cells revealed moderate cell growth inhibition by compounds 5 and 6, with IC50 values of 5958.54 and 5437.17 µg/mL, respectively, as determined via an MTT colorimetric assay. An analysis of the structure-activity relationship (SAR) revealed that the combination of the (p-CH3.C6H4CO-) and halo-aromatic [3-Cl.C6H4CO-] chains with sugar had the highest efficiency in pathogens. Molecular docking studies using AutoDock Vina highlighted compound 7 as a promising inhibitor of the carbapenemase, OmpF, and HmoB proteins, with binding energies of -11.53 kcal/mol, -2.26 kcal/mol, and -30.75 kcal/mol, respectively. A 100-ns molecular dynamics simulation study demonstrated the validity of stable conformation and binding patterns in a stimulating environment. Pharmacokinetic characterization and ADMET predictions indicated favorable drug-like properties. These substantial in vitro and in silico studies demonstrate the importance of additional investigations to confirm the efficacy of MGP derivatives as antimicrobial agents.

Overcoming methicillin resistance by methicillin-resistant Staphylococcus aureus: Computational evaluation of napthyridine and oxadiazoles compounds for potential dual inhibition of PBP-2a and FemA proteins

Abstract The treatment of the various infections caused by Staphylococcus aureus has become challenging due to the evolving resistance against current therapeutics. In this study, the potentials of napthyridine and oxadiazole derivatives to serve as dual inhibitors of penicillin-binding protein 2a (PBP-2a) and FemA protein, which are crucial to resistance to methicillin-based drugs by S. aureus, were evaluated using molecular modeling techniques. Seventy-two compounds were subjected to molecular docking against the proteins, and the hit compounds were subjected to drug-likeness evaluation and in silico pharmacokinetics prediction. The compounds with good safety profiles were subjected to a 250-ns molecular dynamics (MD) simulation and other relevant analyses based on the MD trajectories. Five hit compounds were selected based on their high affinity for the targets as evidenced by their docking scores ranging from −8.6 to −10.1 kcal/mol for PBP-2a and −9.6 to −9.9 kcal/mol for FemA. These compounds also passed Lipinski’s rule of five evaluation with no violation and possessed high human intestinal absorption potential, showcasing their potential as orally administered therapeutic agents. However, three of the compounds were potential mutagens. MD simulation revealed that the final two compounds maintained stable interactions with the target proteins over 250 ns, with minimal deviations and fluctuations. Hydrogen bond stability and energy decomposition analysis further confirmed the strong binding affinity of the hit compounds compared to the control drug, methicillin. Conclusively, the compounds with the CID “135964525” and “44130718” are worthy of further experimental validation in the development of potential inhibitors of PBP-2a and FemA.

Molecular Docking, Molecular Dynamics, pkCSM Drug‐Likeness Profiles, Toxicity, and DFT Study of the Antioxidant and Anticancer Activities of Three Flavonoid Derivatives

AbstractThis work presents a theoretical study of the antioxidant and anticancer properties of three flavonoid derivatives Isoquercitin, Ophioglonol, and Quercetin. DFT calculations were performed to analyze their electronic properties, providing insights into their reactivity and mechanism of action. Molecular docking and molecular dynamics simulations were conducted to examine the stability behavior of the protein‐ligand complexes, providing a detailed mechanism of the interactions at the atomic level. Additionally, some physicochemical and pharmacokinetic predictions were examined by using several web servers. Quercetin and isoquercetin show therapeutic properties, with MESP plots revealing interaction regions with SOD and hAPN targets. However, isoquercetin raises concerns related to AMES toxicity and hERG inhibition. The results of Molecular docking and MD simulations provide theoretical guidance for developing effective inhibitors to treat cancer, but further experimental validation is needed to optimize therapeutic efficacy. The MM/GBSA show that Ophioglonol has the strongest binding affinity with the protein, driven by many interactions. The Actionon also demonstrates strong binding, while Isoquercitin and Quercetin have moderate to weaker affinities. The PCA revealed distinct conformational changes in the protein upon binding with the ligand, highlighting specific regions of flexibility, which could be crucial for understanding their binding mechanisms and potential therapeutic effects.

Development and Evaluation of Ontogeny Functions of the Major UDP-Glucuronosyltransferase Enzymes to Underwrite Physiologically Based Pharmacokinetic Modeling in Pediatric Populations.

Uridine 5'-diphospho-glucuronosyltransferases (UGTs) demonstrate variable expression in the pediatric population. Thus, understanding of age-dependent maturation of UGTs is critical for accurate pediatric pharmacokinetics (PK) prediction of drugs that are susceptible for glucuronidation. Ontogeny functions of major UGTs have been previously developed and reported. However, those ontogeny functions are based on in vitro data (i.e., enzyme abundance, in vitro substrate activity, and so on) and therefore, may not translate to in vivo maturation of UGTs in the clinical setting. This report describes meta-analysis of the literature to develop and compare ontogeny functions for 8 primary UGTs (UGT1A1, UGT1A4, UGT1A6, UGT1A9, UGT2B7, UGT2B10, UGT2B15, and UGT2B17) based on published in vitro and in vivo studies. Once integrated with physiologically based pharmacokinetics modeling models, in vivo activity-based ontogeny functions demonstrated somewhat greater prediction accuracy (mean squared error, MSE: 0.05) compared to in vitro activity (MSE: 0.104) and in vitro abundance-based ontogeny functions (MSE: 0.129).

Design and In-silico Study of ¹³¹Iodium Radiolabeled of Thiourea derivatives for Breast Cancer Treatment

Breast cancer is a serious challenge in both developed and developing countries, with current therapies still limited and potentially producing adverse side effects. To optimize breast cancer drug development, this study adopted an in-silico design approach. The aim is to develop radiopharmaceutical drugs with minimal side effects. Methods involved molecular docking analysis, molecular dynamics, drug scan, and pharmacokinetic profile prediction of the original ligan as well as the radioligand. Results showed that the radioligand had better binding energy and inhibition constant than tamoxifen as a comparator drug which is -11.31 kcal/mol and 0.00511 µM. Molecular dynamics analysis revealed that the radioligand compound exhibits comparable RMSD, RMSF, and stability metrics to the native ligand at the GRPR receptor with average RMSD and RMSF of 5.263 Å and 2.285 Å, respectively. By considering the results of these various methods, the radioligand compound shows potential as an effective radiopharmaceutical drug in breast cancer therapy.

Determination of Potential Lead Compound from Magnolia officinalis for Alzheimer’s Disease through Pharmacokinetic Prediction, Molecular Docking, Dynamic Simulation, and Experimental Validation

Amyloid β protein (Aβ) deposition has been implicated as the molecular driver of Alzheimer’s disease (AD) progression. The modulation of the formation of abnormal aggregates and their post-translational modification is strongly suggested as the most effective approach to anti-AD. Beta-site APP-cleaving enzyme 1 (BACE1) acts upstream in amyloidogenic processing to generate Aβ, which rapidly aggregates alone or in combination with acetylcholinesterase (AChE) to form fibrils. Accumulated Aβ promotes BACE1 activation via glycogen synthase kinase-3β (GSK-3β) and is post-translationally modified by glutaminyl cyclase (QC), resulting in increased neurotoxicity. A novel multi-target inhibitor as a potential AD agent was identified using an in silico approach and experimental validation. Magnolia officinalis, which showed the best anti-AD activity in our preliminary study, was subjected to analysis, and 82 compounds were studied. Among 23 compounds with drug-likeness, blood–brain barrier penetration, and safety, honokiol emerged as a lead structure for the inhibition of BACE1, AChE, QC, and GSK-3β in docking and molecular dynamics (MD) simulations. Furthermore, honokiol was found to be an excellent multi-target inhibitor of these enzymes with an IC50 of 6–90 μM, even when compared to other natural single-target inhibitors. Taken together, the present study is the first to demonstrate that honokiol acts as a multiple enzyme inhibitor with an excellent pharmacokinetic and safety profile which may provide inhibitory effects in broad-range areas including the overproduction, aggregation, and post-translational modification of Aβ. It also provides insight into novel structural features for the design and discovery of multi-target inhibitors for anti-AD.

Pharmacokinetic and pharmacodynamic data from the NEOLEV1 and NEOLEV2 studies

ObjectivesTo confirm that levetiracetam (LEV) demonstrates predictable pharmacokinetics(PK) at higher doses and to study the pharmacodynamics(PD) of LEV.DesignPharmacokinetic data from the NEOLEV1 and NEOLEV2 trials were analysed using a non-linear...

Emicizumab revolution in treating Hemophilia

HemophiliaA (H.A.) has beenanuncommon hereditary X-linked bleeding disorder indicated by clotting factorVIII (FVIII)deficiency, leading to impaired hemostasis. H.A. affects approximately one in 5,000male births in the U.S., often resulting in spontaneous joint bleeding, chronic pain, and an increased risk of cerebral hemorrhage. Prophylactic treatment with FVIII replacement or the bispecific antibody emicizumab has become a crucial strategy to prevent bleeding episodes and long-term tissue damage. Emicizumab, approved by the FDA &amp; EMA in2018, mimics FVIII activity by binding to activated factorIX (FIXa) &amp; factorX (F.X.), facilitating blood clotting regardless of FVIII inhibitors. The development of emicizumab involved extensive bioengineering to optimize its safety, stability, and efficacy, leading to its successful application in clinical trials. These trials demonstrated that emicizumab significantly decreases the annualized bleeding rate in studied cases with or without inhibitors, including severe H.A. cases, with a favorable safety profile and minimal adverse events. Emicizumab's subcutaneous administration, high bioavailability, and predictable pharmacokinetics make it a practical option for H.A. prophylaxis. Despite its benefits, emicizumab can interfere with specific coagulation assays and may develop anti-drug antibodies (ADAs) in rare cases, potentially reducing its efficacy. Ongoing research and post-marketing surveillance continue to assess its long-term safety and effectiveness, making emicizumab a transformative treatment in managing hemophilia A.

Neuroprotective Properties of Coriander-Derived Compounds on Neuronal Cell Damage under Oxidative Stress-Induced SH-SY5Y Neuroblastoma and in Silico ADMET Analysis.

An imbalance between reactive oxygen species (ROS) production and antioxidant defense driven by oxidative stress and inflammation is a critical factor in the progression of neurodegenerative diseases such as Alzheimer's and Parkinson's. Coriander (Coriandrum sativum L.), a culinary plant in the Apiaceae family, displays various biological activities, including anticancer, antimicrobial, and antioxidant effects. Herein, neuroprotective properties of three major bioactive compounds derived from coriander (i.e., linalool, linalyl acetate, and geranyl acetate) were investigated on hydrogen peroxide-induced SH-SY5Y neuroblastoma cell death by examining cell viability, ROS production, mitochondrial membrane potential, and apoptotic profiles. Moreover, underlying mechanisms of the compounds were determined by measuring intracellular sirtuin 1 (SIRT1) enzyme activity incorporated with molecular docking. The results showed that linalool, linalyl acetate, and geranyl acetate elicited their neuroprotection against oxidative stress via protecting cell death, reducing ROS production, preventing cell apoptosis, and modulating SIRT1 longevity. Additionally, in silico pharmacokinetic predictions indicated that these three compounds are drug-like agents with a high probability of absorption and distribution, as well as minimal potential toxicities. These findings highlighted the potential neuroprotective linalool, linalyl acetate, and geranyl acetate for developing alternative natural compound-based neurodegenerative therapeutics and prevention.

Microwave-Assisted Synthesis and Characterization of Novel 1,3,4-Oxadiazole Derivatives and Evaluation of In Vitro Antimycobacterial Activity.

Objective The study's goal was to come up with and make a new group of 1,3,4-oxadiazole derivatives (3a-3e) and test how well they could kill Mycobacterium tuberculosis (Mtb) H37Rv strain. Additionally, molecular docking and pharmacokinetic properties were analyzed using computational software to identify potential inhibitors, followed by in vitro antimycobacterial assays. Methods A group of 1,3,4-oxadiazoles was prepared by reacting acyl hydrazides with alanine, an N-protected α-amino acid, and a small amount of POCl3. This was carried out under microwave treatment. The structural characterization of the newly synthesized compounds was performed using infrared (IR) spectroscopy, nuclear magnetic resonance (NMR) spectroscopy, and mass spectrometry. The in vitro antimycobacterial activity of the 1,3,4-oxadiazole derivatives (3a-3e) was assessed using the microplate Alamar Blue assay against the Mtb H37Rv strain. The synthesized compounds were subjected to molecular docking investigations in order to gain insights into their interaction mechanisms with the mycobacterial enzyme InhA (enoyl-acyl carrier protein reductase). Computational analysis of pharmacokinetic properties was performed to predict the oral bioavailability and drug-likeness of the compounds. Results All synthesized compounds inhibited the growth of Mtbat concentrations of 50 and 100 μg/mL. At a concentration of 50 μg/mL, compounds 3c and 3d exhibited the most prominent antimycobacterial action. Molecular docking results revealed that compound 3d exhibited the highest binding energy interaction with the InhA enzyme (-9.1 kcal/mol). Pharmacokinetic predictions indicated that all compounds possess favorable drug-like properties suitable for oral administration. Conclusion This study successfully synthesized a novel series of oxadiazole derivatives (3a-3e) using a microwave-assisted method with high yields. The synthesized compounds demonstrated significant antimycobacterial activity, particularly compounds 3c and 3d. Molecular docking and pharmacokinetic analyses further confirmed the potential of these compounds as promising leads for the development of anti-tubercular agents.