Human-Focused Multiparameter Optimization Scores for Rank Ordering Compounds during Early Drug Discovery: Validation of PBPK Models Based on Clinical PK Data.

Physiologically based pharmacokinetic (PBPK) models are increasingly used in drug discovery to prioritize compounds that meet the desired pharmacokinetic (PK) profiles. We developed a generalized PBPK model using only early discovery data and validated it across 18 Genentech compounds without compound-specific fitting. The model effectively rank-ordered compounds based on hypothetical PK drivers of pharmacodynamics, including minimum and maximum unbound concentrations ( and ) and unbound area under the curve (AUCu).

Case Report: Solitary adrenal metastasis from esophageal adenocarcinoma.

Introduction: Solitary adrenal metastasis from a primary esophageal malignancy is relatively rare. While there are case reports of aggressive treatment with esophagectomy and adrenalectomy providing long-term survival, the treatment paradigm is not well defined. Complications from esophageal adenocarcinoma and its treatment can significantly impact the patient's quality of life and prognosis.

Magnesium(II)-bicarbonate complexes catalyze the Fenton-like reaction under nearly neutral conditions: kinetics and mechanism.

The results reported herein indicate that solutions containing Mg(HO) + HCO + HO can replace Fe(HO) + HO, or the use of other transition metal complexes, as catalysts of the Fenton-like processes. The reactive oxidizing intermediate formed in this system is the CO˙ anion radical. Detailed experimental and density functional theory (DFT) calculations point out that CO˙ is formed the decomposition of [(HO)Mg(CO)(HO)].

m5C RNA Methylation Is Dysregulated by Oncogenic Herpesviruses via c-Myc Signaling to Counteract Host Antiviral Factors.

Herpesviruses are a group of double-stranded DNA viruses known to develop versatile viral strategies to escape host immune surveillance for promoting their replication and propagation. This is illustrated by Kaposi's sarcoma-associated herpesvirus (KSHV), an oncogenic gamma-herpesvirus that overcomes host immune suppression by multiple mechanisms. In this study, we reported that KSHV dysregulates 5-methylcytosine (m5C) modification and mRNA stability of host antiviral factors to benefit its lytic replication.

Plasmonic DNA-Barcoded Virion Nano-Oscillators for Multiplexed Quantification of Small-Molecule Binding Kinetics to Membrane Proteins.

A high-density nano-oscillator platform using self-assembled DNA-barcoded virion sensors is developed to address the critical need for high-throughput label-free measurement of small-molecule binding to membrane proteins. By integrating virion display technology with charge-sensitive plasmonic detection, our platform enables robust, label-free quantification of small-molecule binding kinetics to membrane proteins. Gold nanoparticle-virion conjugates are self-assembled onto a plasmonic sensor chip via a flexible molecular linker to form high-density nano-oscillators.

AI-Driven Applications in Clinical Pharmacology and Translational Science: Insights From the ASCPT 2024 AI Preconference.

Artificial intelligence (AI) is driving innovation in clinical pharmacology and translational science with tools to advance drug development, clinical trials, and patient care. This review summarizes the key takeaways from the AI preconference at the American Society for Clinical Pharmacology and Therapeutics (ASCPT) 2024 Annual Meeting in Colorado Springs, where experts from academia, industry, and regulatory bodies discussed how AI is streamlining drug discovery, dosing strategies, outcome assessment, and patient care. The theme of the preconference was centered around how AI can empower clinical pharmacologists and translational researchers to make informed decisions and translate research findings into practice.

The loss of both pUL16 and pUL21 in HSV-1-infected cells alters capsid-tegument composition, nuclear membrane architecture, cytoplasmic maturation and cell-to-cell spread.

Previously, we had developed synthetic genomics methods to assemble an infectious clone of herpes simplex virus type-1 (HSV-1) strain KOS. To do this, the genome was assembled from 11 separate cloned fragments in yeast using transformation-associated recombination. Using this method, we generated null mutations in five tegument protein-coding genes as well as different combinations of these mutants.

Multitask Deep Learning Models of Combined Industrial Absorption, Distribution, Metabolism, and Excretion Datasets to Improve Generalization.

The optimization of absorption, distribution, metabolism, and excretion (ADME) profiles of compounds is critical to the drug discovery process. As such, machine learning (ML) models for ADME are widely used for prioritizing the design and synthesis of compounds. The effectiveness of ML models for ADME depends on the availability of high-quality experimental data for a diverse set of compounds that is relevant to the emerging chemical space being explored by the drug discovery teams.

Nelfinavir inhibition of Kaposi's sarcoma-associated herpesvirus protein expression and capsid assembly.

Background: Antiviral therapies that target herpesviruses are clinically important. Nelfinavir is a protease inhibitor that targets the human immunodeficiency virus (HIV) aspartyl protease. Previous studies demonstrated that this drug could also inhibit Kaposi's sarcoma-associated herpesvirus (KSHV) production.

Expression and fusogenic activity of SARS CoV-2 Spike protein displayed in the HSV-1 Virion.

Severe acute respiratory syndrome coronavirus (SARS-CoV) is a zoonotic pathogen that can cause severe respiratory disease in humans. The new SARS-CoV-2 is the cause of the current global pandemic termed coronavirus disease 2019 (COVID-19) that has resulted in many millions of deaths world-wide. The virus is a member of the Betacoronavirus family, its genome is a positive strand RNA molecule that encodes for many genes which are required for virus genome replication as well as for structural proteins that are required for virion assembly and maturation.

Nelfinavir Inhibition of Kaposi's sarcoma-associated herpesvirus protein expression and capsid assembly.

Background: Antiviral therapies that target herpesviruses are clinically important. Nelfinavir is a protease inhibitor that targets the human immunodeficiency virus (HIV) infections aspartyl protease. Previous studies demonstrated that this drug could also inhibit Kaposi's sarcoma-associated herpesvirus (KSHV) production.

Plaquing of Herpes Simplex Viruses.

There are numerous published protocols for plaquing viruses, including references within primary literature for methodology. However, plaquing viruses can be difficult to perform, requiring focus on its specifications and refinement. It is an incredibly challenging method for new students to master, mainly because it requires meticulous attention to the most minute details.

Assembly of infectious Kaposi's sarcoma-associated herpesvirus progeny requires formation of a pORF19 pentamer.

Herpesviruses cause severe diseases particularly in immunocompromised patients. Both genome packaging and release from the capsid require a unique portal channel occupying one of the 12 capsid vertices. Here, we report the 2.

Pharmacodynamic measures within tumors expose differential activity of PD(L)-1 antibody therapeutics.

Macromolecules such as monoclonal antibodies (mAbs) are likely to experience poor tumor penetration because of their large size, and thus low drug exposure of target cells within a tumor could contribute to suboptimal responses. Given the challenge of inadequate quantitative tools to assess mAb activity within tumors, we hypothesized that measurement of accessible target levels in tumors could elucidate the pharmacologic activity of a mAb and could be used to compare the activity of different mAbs. Using positron emission tomography (PET), we measured the pharmacodynamics of immune checkpoint protein programmed-death ligand 1 (PD-L1) to evaluate pharmacologic effects of mAbs targeting PD-L1 and its receptor programmed cell death protein 1 (PD-1).

Characteristics of patients discharged and readmitted after COVID-19 hospitalisation within a large integrated health system in the United States.

Background: Limited studies have explored post-discharge outcomes following Coronavirus Disease 2019 (COVID-19) hospitalisation. We sought to characterise patients discharged following a COVID-19 hospitalisation within a large integrated health system in the United States.

Methods: We performed a retrospective study of 2180 COVID-19 patients discharged between 1 April 2020 and 31 July 2020.

Arsenicals, the Integrated Stress Response, and Epstein-Barr Virus Lytic Gene Expression.

Following our observation that clofoctol led to Epstein-Barr virus (EBV) lytic gene expression upon activation of the integrated stress response (ISR), we decided to investigate the impact of AsO on viral lytic gene expression. AsO has also been reported to activate the ISR pathway by its activation of the heme-regulated inhibitor (HRI). Our investigations show that AsO treatment leads to eIF2α phosphorylation, upregulation of ATF4 and TRB3 expression, and an increase of EBV Zta gene expression in lymphoid tumor cell lines as well as in naturally infected epithelial cancer cell lines.

The Derivation of a Matched Molecular Pairs Based ADME/Tox Knowledge Base for Compound Optimization.

Matched Molecular Pairs (MMP) analysis is a well-established technique for Structure Activity and Property Analysis (SAR and SPR). Summarizing multiple MMPs that describe the same structural change into a single chemical transform can be a powerful tool for prediction (termed Transform from here on). This is particularly useful in the area of Absorption, Distribution, Metabolism, and Elimination (ADME) analysis that is less influenced by 3D structural binding effects.

Structure-Property Relationships and Machine Learning Models for Addressing CYP3A4-Mediated Victim Drug-Drug Interaction Risk in Drug Discovery.

Among the FDA-approved small molecule drugs (2005-2016) that are primarily metabolized by cytochrome P450 (CYP), 64% are primarily metabolized by CYP3A4. As the proportion of an individual drug's fraction metabolized through CYP3A4 increases, the risk for the drug to be a victim of an interaction with CYP3A4 inhibitors or inducers increases. Therefore, it is important to assess the extent of involvement of individual CYP enzymes in the overall clearance for a scaffold early in discovery and mitigate the CYP3A4-mediated victim-drug-drug interaction (DDI) risk, if warranted by the desired clinical profile of the drug.

Plasticity of the Mycobacterium tuberculosis respiratory chain and its impact on tuberculosis drug development.

The viability of Mycobacterium tuberculosis (Mtb) depends on energy generated by its respiratory chain. Cytochrome bc1-aa3 oxidase and type-2 NADH dehydrogenase (NDH-2) are respiratory chain components predicted to be essential, and are currently targeted for drug development. Here we demonstrate that an Mtb cytochrome bc1-aa3 oxidase deletion mutant is viable and only partially attenuated in mice.

Prediction of Fraction Unbound in Microsomal and Hepatocyte Incubations: A Comparison of Methods across Industry Datasets.

The fraction unbound in the incubation, , is an important parameter to consider in the evaluation of intrinsic clearance measurements performed in hepatocytes or microsomes. Reliable estimates of based on a compound's structure have the potential to positively impact the screening timelines in drug discovery. Previous works suggested that is primarily driven by passive processes and can be described using physicochemical properties such as lipophilicity and the protonation state of the molecule.

Pharmacologic Activation of Lytic Epstein-Barr Virus Gene Expression without Virion Production.

Several therapeutic strategies targeting Epstein-Barr virus (EBV)-associated tumors involve upregulation of viral lytic gene expression. Evidence has been presented that the unfolded protein response (UPR) leads to EBV lytic gene expression. Clofoctol, an antibacterial antibiotic, has been reported to upregulate the UPR in prostate cancer cell lines and to slow their growth.