Complex Pharmacology Research Articles

QSP modeling of a transiently inactivating antibody-drug conjugate highlights benefit of short antibody half life

Antibody drug conjugates (ADC) are a promising class of oncology therapeutics consisting of an antibody conjugated to a payload via a linker. DYP688 is a novel ADC comprising of a signaling protein inhibitor payload (FR900359) that undergoes unique on-antibody inactivation in plasma, resulting in complex pharmacology. To assess the impact of FR inactivation on DYP688 pharmacology and clinical developability, we performed translational modeling of preclinical PK and tumor growth inhibition (TGI) data, accompanied by mechanistic Krogh cylinder tumor modeling. Using a PK-TGI model, we identified a composite exposure-above-tumorostatic concentration (AUCTSC) metric as the PK-driver of efficacy. To underpin the mechanisms behind AUCTSC as the driver of efficacy, we performed quantitative systems pharmacology (QSP) modeling of DYP688 intratumoral pharmacokinetics and pharmacodynamics. Through exploratory simulations, we show that by deviating from canonical ADC design dogma, DYP688 has optimal FR900359 activity despite its transient inactivation. Finally, we performed the successful preclinical to clinical translation of DYP688 PK, including the payload inactivation kinetics, evidenced by good agreement of the predicted PK to the observed interim clinical PK. Overall, this work highlights early quantitative pharmacokinetics as a missing link in the ADC design-developability chasm.

Acute Behavioral and Neurochemical Effects of Sulpiride in Adult Zebrafish.

Affective and psychotic disorders are highly prevalent and severely debilitating mental illnesses that often remain untreated or treatment-resistant. Sulpiride is a common antipsychotic (neuroleptic) drug whose well-established additional (e.g., antidepressant) therapeutic effects call for further studies of a wider spectrum of its CNS effects. Here, we examined effects of acute 20-min exposure to sulpiride (50-200mg/L) on anxiety- and depression-like behaviors, as well as on brain monoamines, in adult zebrafish (Danio rerio). Overall, sulpiride exerted overt anxiolytic-like effects in the novel tank test and showed tranquilizing-like effects in the zebrafish tail immobilization test, accompanied by lowered whole-brain dopamine and its elevated turnover, without affecting serotonin or norepinephrine levels and their turnover. Taken together, these findings support complex behavioral pharmacology of sulpiride in vivo and reconfirm high sensitivity of zebrafish-based screens to this and, likely, other related clinically active neuroleptics.

Abstract 4147627: A Pharmacovigilance Study of Bempedoic Acid: Balancing Risks and Benefits

Introduction: Bempedoic acid has been approved by FDA since Feb 2020 as an adjunct to maximally tolerated statin therapy for the reduction of LDL-C, specifically in individuals afflicted by atherosclerotic cardiovascular disease (ASCVD) and heterozygous familial hypercholesterolemia (HeFH). Bempedoic acid is also a viable alternative for patients intolerant to statins. Most recently, it has been approved to use for primary prevention of hyperlipidemia, alone or in combination with a statin. It is important to study its side effect profile as it is anticipated to be used more frequentlynin the future. Methods: We explored reported adverse events (AEs) of bempedoic acid using FDA Adverse Event Reporting System (FAERS). A total of 1202 adverse effects were reported until March 31, 2024. 69.97% AEs were reported by healthcare professionals (HCPs), which were further analyzed. AEs were analyzed in men (32.53%) vs women (53.24%) and in three age groups of 18-64, 65-85, and >85 years. Results: A total of 586 (48.7%) events were serious adverse effects. Most common side effects were myalgia which included muscle pain, extremity pain and muscle spasm (25.04%), arthralgia including back pain and bone pain (18.47%), nausea (6.6%), headache(5.5%), gout (4.4%). Among the patients with adverse effects, 4.75% had cardiac side effects which included atrial fibrillation (12%), palpitation (29%), angina pectoris (18%), Myocardial Infarction (5%). Discussion: A thorough understanding of bempedoic acid's complex pharmacology empowers healthcare professionals to tailor treatment plans based on individual patient requirements. This enables informed decision-making in prescribing, optimizing dosage regimens, and mitigating potential adverse reactions. Most studies have been relatively short term in order to confirm the long term side effect profile. It would be beneficial to be cautious in using this medication for patients with above mentioned clinical conditions like myalgia, arthralgia, gout, rhabdomyolysis, atrial fibrillation, angina pectoris. Conclusion: Long term pharmacovigilance is needed to assess the safety profile of bempedoic acid over extended use. With the current increasing use of bempedoic acid, there is a need for more data on safety profiles. In future, further randomized trials are required to better assess the safety profile.

Integrating real-world data and machine learning: A framework to assess covariate importance in real-world use of alternative intravenous dosing regimens for atezolizumab.

The increase in the availability of real-world data (RWD), in combination with advances in machine learning (ML) methods, provides a unique opportunity for the integration of the two to explore complex clinical pharmacology questions. Here we present a recently developed RWD/ML framework that utilizes ML algorithms to understand the influence and importance of various covariates on the use of a given dose and schedule for drugs that have multiple approved dosing regimens. To demonstrate the application of this framework, we present atezolizumab as a use case on account of its three approved alternative intravenous (IV) dosing regimens. As expected, the real-world use of atezolizumab has generally been increasing since 2016 for the 1200 mg every 3 weeks regimen and since 2019 for the 1680 mg every 4 weeks regimen. Out of the ML algorithms evaluated, XGBoost performed the best, as measured by the area under the precision-recall curve, with an emphasis on the under-sampled class given the imbalance in the data. The importance of features was measured by Shapley Additive exPlanations (SHAP) values and showed metastatic breast cancer and use of protein-bound paclitaxel as the most correlated with the use of 840 mg every 2 weeks. Although patient usage data for alternative IV dosing regimens are still maturing, these analyses provide initial insights on the use of atezolizumab and set up a framework for the re-analysis of atezolizumab (at a future data cut) as well as application to other molecules with approved alternative dosing regimens.

Combining mathematical modeling, in vitro data and clinical target expression to support bispecific antibody binding affinity selection: a case example with FAP-4-1BBL.

The majority of bispecific costimulatory antibodies in cancer immunotherapy are capable of exerting tumor-specific T-cell activation by simultaneously engaging both tumor-associated targets and costimulatory receptors expressed by T cells. The amount of trimeric complex formed when the bispecific antibody is bound simultaneously to the T cell receptor and the tumor-associated target follows a bell-shaped curve with increasing bispecific antibody exposure/dose. The shape of the curve is determined by the binding affinities of the bispecific antibody to its two targets and target expression. Here, using the case example of FAP-4-1BBL, a fibroblast activation protein alpha (FAP)-directed 4-1BB (CD137) costimulator, the impact of FAP-binding affinity on trimeric complex formation and pharmacology was explored using mathematical modeling and simulation. We quantified (1) the minimum number of target receptors per cell required to achieve pharmacological effect, (2) the expected coverage of the patient population for 19 different solid tumor indications, and (3) the range of pharmacologically active exposures as a function of FAP-binding affinity. A 10-fold increase in FAP-binding affinity (from a dissociation constant [KD] of 0.7 nM-0.07nM) was predicted to reduce the number of FAP receptors needed to achieve 90% of the maximum pharmacological effect from 13,400 to 4,000. Also, the number of patients with colon cancer that would achieve 90% of the maximum effect would increase from 6% to 39%. In this work, a workflow to select binding affinities for bispecific antibodies that integrates preclinical in vitro data, mathematical modeling and simulation, and knowledge on target expression in the patient population, is provided. The early implementation of this approach can increase the probability of success with cancer immunotherapy in clinical development.

Molecular imaging supports the development of multispecific cancer antibodies.

Multispecific antibodies are engineered antibody derivatives that can bind to two or more distinct epitopes or antigens. Unlike mixtures of monospecific antibodies, the binding properties of multispecific antibodies enable two specific molecules to be physically linked, a characteristic with important applications in cancer therapy. The field of multispecific antibodies is highly dynamic and expanding rapidly; to date, 15 multispecific antibodies have been approved for clinical use, of which 11 were approved for oncological indications, and more than 100 new antibodies are currently in clinical development. Nevertheless, substantial challenges limit the applications of multispecific antibodies in cancer therapy, particularly inefficient targeting of solid tumours and substantial adverse effects. Both PET and single photon emission CT imaging can reveal the biodistribution and complex pharmacology of radiolabelled multispecific antibodies. This Review summarizes the insights obtained from preclinical and clinical molecular imaging studies of multispecific antibodies, focusing on their structural properties, such as molecular weight, shape, target specificity, affinity and avidity. The opportunities associated with use of molecular imaging studies to support the clinical development of multispecific antibody therapies are also highlighted.

The Mitragyna speciosa (kratom) alkaloid mitragynine: Analysis of adrenergic α2 receptor activity in vitro and in vivo

Mitragynine, an alkaloid present in the leaves of Mitragyna speciosa (kratom), has a complex pharmacology that includes low efficacy agonism at μ-opioid receptors (MORs). This study examined the activity of mitragynine at adrenergic α2 receptors (Aα2Rs) in vitro and in vivo. Mitragynine displaced a radiolabeled Aα2R antagonist ([3H]RX821002) from human Aα2ARs in vitro with lower affinity (Ki = 1260 nM) than the agonists (−)-epinephrine (Ki = 263 nM) or lofexidine (Ki = 7.42 nM). Mitragynine did not significantly stimulate [35S]GTPγS binding at Aα2ARs in vitro, but in rats trained to discriminate 32 mg/kg mitragynine from vehicle (intraperitoneally administered; i.p.), mitragynine exerted an Aα2R agonist-like effect. Both α2R antagonists (atipamezole and yohimbine) and MOR antagonists (naloxone and naltrexone) produced rightward shifts in mitragynine discrimination dose-effect function and Aα2R agonists lofexidine and clonidine produced leftward shifts. In the mitragynine trained rats, Aα2R agonists also produced leftward shifts in discrimination dose-effect functions for morphine and fentanyl. In a separate rat cohort trained to discriminate 3.2 mg/kg i.p. morphine from vehicle, naltrexone produced a rightward shift, but neither an Aα2R agonist or antagonist affected morphine discrimination. In a hypothermia assay, both lofexidine and clonidine produced marked effects antagonized by yohimbine. Mitragynine did not produce hypothermia. Together, these data demonstrate that mitragynine acts in vivo like an Aα2R agonist, although its failure to induce hypothermia or stimulate [35S]GTPγS binding in vitro, suggests that mitragynine maybe a low efficacy Aα2R agonist.

Kratom safety and toxicology in the public health context: research needs to better inform regulation.

Although kratom use has been part of life for centuries in Southeast Asia, the availability and use of kratom in the United States (US) increased substantially since the early 2000s when there was little information on kratom pharmacology, use patterns, and effects, all critical to guiding regulation and policy. Here we provide a synthesis of research with several hundred English-language papers published in the past 5years drawing from basic research, epidemiological and surveillance data, and recent clinical research. This review of available literature aims to provide an integrated update regarding our current understanding of kratom's benefits, risks, pharmacology, and epidemiology, which may inform United States-based kratom regulation. Recent surveillance indicates there are likely several million past-year kratom consumers, though estimates vary widely. Even without precise prevalence data, kratom use is no longer a niche, with millions of United States adults using it for myriad reasons. Despite its botanical origins in the coffee tree family and its polypharmacy, kratom is popularly characterized as an opioid with presumed opioid-system-based risks for addiction or overdose. Neuropharmacology, toxicology, and epidemiology studies show that kratom is more accurately characterized as a substance with diverse and complex pharmacology. Taken together the work reviewed here provides a foundation for future scientific studies, as well as a guide for ongoing efforts to regulate kratom. This work also informs much-needed federal oversight, including by the United States Food and Drug Administration. We conclude with recommendations for kratom regulation and research priorities needed to address current policy and knowledge gaps around this increasingly used botanical product.

Comparative safety of tramadol and other opioids following total hip and knee arthroplasty

BackgroundTramadol is increasingly used to treat acute postoperative pain among older adults following total hip and knee arthroplasty (THA/TKA). However, tramadol has a complex pharmacology and may be no safer than full opioid agonists. We compared the safety of tramadol, oxycodone, and hydrocodone among opioid-naïve older adults following elective THA/TKA.MethodsThis retrospective cohort included Medicare Fee-for-Service beneficiaries ≥ 65 years with elective THA/TKA between January 1, 2010 and September 30, 2015, 12 months of continuous Parts A and B enrollment, 6 months of continuous Part D enrollment, and no opioid use in the 6 months prior to THA/TKA. Participants initiated single-opioid therapy with tramadol, oxycodone, or hydrocodone within 7 days of discharge from THA/TKA hospitalization, regardless of concurrently administered nonopioid analgesics. Outcomes of interest included all-cause hospitalizations or emergency department visits (serious adverse events (SAEs)) and a composite of 10 surgical- and opioid-related SAEs within 90-days of THA/TKA. The intention-to-treat (ITT) and per-protocol (PP) hazard ratios (HRs) for tramadol versus other opioids were estimated using inverse-probability-of-treatment-weighted pooled logistic regression models.ResultsThe study population included 2,697 tramadol, 11,407 oxycodone, and 14,665 hydrocodone initiators. Compared to oxycodone, tramadol increased the rate of all-cause SAEs in ITT analyses only (ITT HR 1.19, 95%CLs, 1.02, 1.41; PP HR 1.05, 95%CLs, 0.86, 1.29). Rates of composite SAEs were not significant across comparisons. Compared to hydrocodone, tramadol increased the rate of all-cause SAEs in the ITT and PP analyses (ITT HR 1.40, 95%CLs, 1.10, 1.76; PP HR 1.34, 95%CLs, 1.03, 1.75), but rates of composite SAEs were not significant across comparisons.ConclusionsPostoperative tramadol was associated with increased rates of all-cause SAEs, but not composite SAEs, compared to oxycodone and hydrocodone. Tramadol does not appear to have a superior safety profile and should not be preferentially prescribed to opioid-naïve older adults following THA/TKA.

Cannabidiol and positive effects on object recognition memory in an in vivo model of Fragile X Syndrome: Obligatory role of hippocampal GPR55 receptors

Cannabidiol (CBD), a non-psychotomimetic constituent of Cannabis sativa, has been recently approved for epileptic syndromes often associated with Autism spectrum disorder (ASD). However, the putative efficacy and mechanism of action of CBD in patients suffering from ASD and related comorbidities remain debated, especially because of the complex pharmacology of CBD. We used pharmacological, immunohistochemical and biochemical approaches to investigate the effects and mechanisms of action of CBD in the recently validated Fmr1-Δexon 8 rat model of ASD, that is also a model of Fragile X Syndrome (FXS), the leading monogenic cause of autism. CBD rescued the cognitive deficits displayed by juvenile Fmr1-Δexon 8 animals, without inducing tolerance after repeated administration. Blockade of CA1 hippocampal GPR55 receptors prevented the beneficial effect of both CBD and the fatty acid amide hydrolase (FAAH) inhibitor URB597 in the short-term recognition memory deficits displayed by Fmr1-Δexon 8 rats. Thus, CBD may exert its beneficial effects through CA1 hippocampal GPR55 receptors. Docking analysis further confirmed that the mechanism of action of CBD might involve competition for brain fatty acid binding proteins (FABPs) that deliver anandamide and related bioactive lipids to their catabolic enzyme FAAH. These findings demonstrate that CBD reduced cognitive deficits in a rat model of FXS and provide initial mechanistic insights into its therapeutic potential in neurodevelopmental disorders.

The funnel-web spider venom derived single knot peptide Hc3a modulates acid-sensing ion channel 1a desensitisation

Acid-sensing ion channel 1a (ASIC1a) is a proton-gated channel involved in synaptic transmission, pain signalling, and several ischemia-associated pathological conditions. The spider venom-derived peptides PcTx1 and Hi1a are two of the most potent ASIC1a inhibitors known and have been instrumental in furthering our understanding of the structure, function, and biological roles of ASICs. To date, homologous spider peptides with different pharmacological profiles at ASIC1a have yet to be discovered. Here we report the characterisation of Hc3a, a single inhibitor cystine knot peptide from the Australian funnel-web spider Hadronyche cerberea with sequence similarity to PcTx1. We show that Hc3a has complex pharmacology and binds different ASIC1a conformational states (closed, open, and desensitised) with different affinities, with the most prominent effect on desensitisation. Hc3a slows the desensitisation kinetics of proton-activated ASIC1a currents across multiple application pHs, and when bound directly to ASIC1a in the desensitised conformation promotes current inhibition. The solution structure of Hc3a was solved, and the peptide-channel interaction examined via mutagenesis studies to highlight how small differences in sequence between Hc3a and PcTx1 can lead to peptides with distinct pharmacology. The discovery of Hc3a expands the pharmacological diversity of spider venom peptides targeting ASIC1a and adds to the toolbox of compounds to study the intricacies of ASIC1 gating.

The Pre-Operative Evaluation Clinic: An Underutilized Service in Optimizing Analgesic Outcomes in Patients on Buprenorphine, Methadone, and Naltrexone for Substance Use Disorder or Chronic Pain.

Patients receiving methadone, buprenorphine, and naltrexone for either chronic pain or substance use disorder (SUD) pose perioperative challenges. Due to their complex pharmacology, perioperative recommendations continue to evolve. Deviations from these recommendations may result in worse perioperative outcomes. A formal preoperative evaluation (POE) and optimization of patients on these medications are recommended to address these concerns. A single-center retrospective electronic health record review was performed with adult patients on methadone, buprenorphine, and naltrexone undergoing elective surgery between January 1, 2010 and December 31, 2020. The primary outcome of interest was the percentage of patients referred to the POE clinic for evaluation prior to the scheduled elective surgery. In addition, we assessed differences in variables (perioperative opioid, hospital length of stay, perioperative multimodal analgesics, perioperative complications, inpatient pain service consult, readmission within 30 days, cancellation of surgery, addiction medicine consult) based on POE clinic evaluation. This analysis was performed separately for patients prescribed these medications for SUD versus chronic pain. Continuous outcomes were analyzed using linear regression with generalized estimating equations (GEE) and robust variance estimates. A total of 714 patients were included in the final analysis, of which 572 (80%) took buprenorphine, methadone, or naltrexone for chronic pain and 142 (20%) took these medications for SUD. Within the chronic pain and SUD subpopulations, 193 (34%) and 35 (25%) patients had formal POE clinic assessments, respectively. Among those taking these medications for chronic pain, POE clinic evaluation was associated with a higher likelihood for receiving non-opioid multimodal analgesics perioperatively (p = 0.016). Formal preoperative evaluations are currently underutilized in patients who take buprenorphine, methadone, or naltrexone for chronic pain or SUD. These patients may benefit from POE clinic assessment to optimize perioperative outcomes.

Possibilities of complex pharmacology protection of neurons and vessels of the brain in conditions of polymorbidity

Cerebrovascular pathology is currently one of the leading medical and social problems of our time, and the vast majority of vascular diseases of the brain belong to chronic disorders of cerebral blood circulation – cerebral atherosclerosis, stratification and aneurysms of cerebral arteries, progressive vascular leukoencephalopathy, hypertensive encephalopathy, non-purulent thrombosis of cerebral veins or venous sinuses, etc. The main link in the pathogenesis of these diseases is chronic ischemia of the brain. The prerequisite for safe pharmacotherapy of these conditions is the use of drugs containing biologically active substances of natural origin. It is advisable to use combined medicines as much as possible, which significantly reduces the main risks of polypharmacy, simplifies therapy regimens, increases compliance and significantly increases the economic availability of treatment. Combined means are the most successful and convenient. The modern pharmaceutical market of Ukraine offers a fairly small number of combined medicines, among which Vazavital Neuro and Graciven deserve special attention, the combined use of which is the most appropriate

DEEPENING THEORETICAL KNOWLEDGE AND EXPLORING THE PROPERTIES OF LOCAL ANESTHETICS

Local anesthetics are indispensable agents in medical practice, offering targeted pain relief while maintaining patient consciousness. Their applications span a wide range of medical fields, including anesthesiology, surgery, and dentistry. Despite their widespread use, the complex pharmacology and potential for adverse effects necessitate a comprehensive understanding of these agents. This narrative review aims to provide an in-depth analysis of the physiology, pharmacology, and clinical applications of local anesthetics. A systematic search was conducted on PubMed, focusing on articles published in English between 2018 and 2023. Local anesthetics have evolved significantly since the first use of cocaine in the late 19th century, with newer derivatives like Lidocaine and Bupivacaine offering improved safety and efficacy. These agents are categorized into aminoesters and aminoamides based on their molecular structure, which also influences their pharmacokinetics and pharmacodynamics. The primary mechanism of action involves the modulation of voltage-gated sodium channels, although the complete mechanism remains an area of active research. Various factors, including lipid solubility, plasma pH, and pKa, influence the drug's onset, duration, and potential for toxicity. Adjuvants like adrenaline can enhance the drug's properties. Local anesthetics are a cornerstone in modern medicine, offering targeted anesthesia with a relatively favorable safety profile. Understanding their complex pharmacology is crucial for optimizing their clinical use. Future research should focus on elucidating the complete mechanisms of action and exploring the potential for new adjuvants to improve efficacy and safety.

Xanomeline displays concomitant orthosteric and allosteric binding modes at the M4 mAChR

The M4 muscarinic acetylcholine receptor (M4 mAChR) has emerged as a drug target of high therapeutic interest due to its expression in regions of the brain involved in the regulation of psychosis, cognition, and addiction. The mAChR agonist, xanomeline, has provided significant improvement in the Positive and Negative Symptom Scale (PANSS) scores in a Phase II clinical trial for the treatment of patients suffering from schizophrenia. Here we report the active state cryo-EM structure of xanomeline bound to the human M4 mAChR in complex with the heterotrimeric Gi1 transducer protein. Unexpectedly, two molecules of xanomeline were found to concomitantly bind to the monomeric M4 mAChR, with one molecule bound in the orthosteric (acetylcholine-binding) site and a second molecule in an extracellular vestibular allosteric site. Molecular dynamic simulations supports the structural findings, and pharmacological validation confirmed that xanomeline acts as a dual orthosteric and allosteric ligand at the human M4 mAChR. These findings provide a basis for further understanding xanomeline’s complex pharmacology and highlight the myriad of ways through which clinically relevant ligands can bind to and regulate GPCRs.

Impact of Virtual Reality on Pharmacology Education: A Pilot Study.

Introduction Virtual reality (VR) is a powerful tool in health professional education. It has been successfully implemented in various domains of education with positive learning outcomes. The three-dimensional (3D) visualization offered by VR can potentially be applied to learn complex pharmacology topics. This study aims to investigate whether VR technology can improve the learning of complex pharmacological concepts. Methods A VR learning module on cardiovascular drugs was developed using Kern's six-step framework. 32 medical students participated in the pilot study. Their pharmacology knowledge was assessed using pre- and post-intervention tests. Additionally, feedback from the participants were collected through a post-intervention survey that assessed learner satisfaction, ease of use, perceived usefulness, quality of visual elements, intention to use, and comfort level during the VR experience. Results Participants scored significantly higher in the post-intervention test than in the pre-intervention test (p <0.05). A majority of the participants (90%) were satisfied with the VR module, finding it easy to use, and time efficient. A minority of participants (15%) preferred a traditional learning format while some participants (20%) experienced discomfort in VR. Conclusion Our findings suggest that VR enhances pharmacology knowledge in medical students and is well-received as an innovative educational tool. By providing immersive 3D visualization of complex drug actions, VR has the potential to transform pharmacology education into an engaging and effective learning experience.

Metabotropic Glutamate Receptor Subtype 5 Positron-Emission-Tomography Radioligands as a Tool for Central Nervous System Drug Development: Between Progress and Setbacks.

The metabotropic glutamate receptor subtype 5 (mGluR5) is a class C G-protein-coupled receptor (GPCR) that has been implicated in various neuronal processes and, consequently, in several neuropsychiatric or neurodevelopmental disorders. Over the past few decades, mGluR5 has become a major focus for pharmaceutical companies, as an attractive target for drug development, particularly through the therapeutic potential of its modulators. In particular, allosteric binding sites have been targeted for better specificity and efficacy. In this context, Positron Emission Tomography (PET) appears as a useful tool for making decisions along a drug candidate's development process, saving time and money. Thus, PET provides quantitative information about a potential drug candidate and its target at the molecular level. However, in this area, particular attention has to be given to the interpretation of the PET signal and its conclusions. Indeed, the complex pharmacology of both mGluR5 and radioligands, allosterism, the influence of endogenous glutamate and the choice of pharmacokinetic model are all factors that may influence the PET signal. This review focuses on mGluR5 PET radioligands used at several stages of central nervous system drug development, highlighting advances and setbacks related to the complex pharmacology of these radiotracers.

Prediction of drug sensitivity based on multi-omics data using deep learning and similarity network fusion approaches.

With the rapid development of multi-omics technologies and accumulation of large-scale bio-datasets, many studies have conducted a more comprehensive understanding of human diseases and drug sensitivity from multiple biomolecules, such as DNA, RNA, proteins and metabolites. Using single omics data is difficult to systematically and comprehensively analyze the complex disease pathology and drug pharmacology. The molecularly targeted therapy-based approaches face some challenges, such as insufficient target gene labeling ability, and no clear targets for non-specific chemotherapeutic drugs. Consequently, the integrated analysis of multi-omics data has become a new direction for scientists to explore the mechanism of disease and drug. However, the available drug sensitivity prediction models based on multi-omics data still have problems such as overfitting, lack of interpretability, difficulties in integrating heterogeneous data, and the prediction accuracy needs to be improved. In this paper, we proposed a novel drug sensitivity prediction (NDSP) model based on deep learning and similarity network fusion approaches, which extracts drug targets using an improved sparse principal component analysis (SPCA) method for each omics data, and construct sample similarity networks based on the sparse feature matrices. Furthermore, the fused similarity networks are put into a deep neural network for training, which greatly reduces the data dimensionality and weakens the risk of overfitting problem. We use three omics of data, RNA sequence, copy number aberration and methylation, and select 35 drugs from Genomics of Drug Sensitivity in Cancer (GDSC) for experiments, including Food and Drug Administration (FDA)-approved targeted drugs, FDA-unapproved targeted drugs and non-specific therapies. Compared with some current deep learning methods, our proposed method can extract highly interpretable biological features to achieve highly accurate sensitivity prediction of targeted and non-specific cancer drugs, which is beneficial for the development of precision oncology beyond targeted therapy.

Sub-millisecond conformational dynamics of the A2A adenosine receptor revealed by single-molecule FRET

The complex pharmacology of G-protein-coupled receptors (GPCRs) is defined by their multi-state conformational dynamics. Single-molecule Förster Resonance Energy Transfer (smFRET) is well suited to quantify dynamics for individual protein molecules; however, its application to GPCRs is challenging. Therefore, smFRET has been limited to studies of inter-receptor interactions in cellular membranes and receptors in detergent environments. Here, we performed smFRET experiments on functionally active human A2A adenosine receptor (A2AAR) molecules embedded in freely diffusing lipid nanodiscs to study their intramolecular conformational dynamics. We propose a dynamic model of A2AAR activation that involves a slow (>2 ms) exchange between the active-like and inactive-like conformations in both apo and antagonist-bound A2AAR, explaining the receptor’s constitutive activity. For the agonist-bound A2AAR, we detected faster (390 ± 80 µs) ligand efficacy-dependent dynamics. Our work establishes a general smFRET platform for GPCR investigations that can potentially be used for drug screening and/or mechanism-of-action studies.

Botulinum neurotoxin: A therapeutic powerhouse with broad clinical implications.

Clostridium botulinum is a Gram-positive bacterium that produces one of the most deadly chemodenervating toxins in the world. To date, six distinct neurotoxins are available for prescription use in the United States. Decades of data across aesthetic therapeutic areas and therapeutic disease states support the safety and efficacy of C. botulinum, providing good symptom management and improved quality of life in appropriately chosen patients. Unfortunately, many clinicians are slow to progress patients to toxin therapy from more conservative measures, and others wrongly interchange the products despite characteristics unique to each. Commensurate with an improved understanding of the complex pharmacology and clinical implications of botulinum neurotoxins is the importance for clinicians to appropriately identify, educate, refer, and/or treat candidate patients. This article provides an overview of the history, mechanism of action, differentiation, indications, and uses for botulinum neurotoxins.