Drug Development Pathway Research Articles

Review article: The need for more efficient and patient‐oriented drug development pathways in NASH—setting the scene for platform trials

Non-alcoholic steatohepatitis (NASH) constitutes a significant unmet medical need with a burgeoning field of clinical research and drug development. Platform trials (PT) might help accelerate drug development while lowering overall costs and creating a more patient-centric environment. This review provides a comprehensive and nuanced assessment of the NASH clinical development landscape. Narrative review and expert opinion with insight gained during the EU Patient-cEntric clinicAl tRial pLatforms (EU-PEARL) project. Although NASH represents an opportunity to use adaptive trial designs, including master protocols for PT, there are barriers that might be encountered owing to distinct and sometimes opposing priorities held by these stakeholders and potential ways to overcome them. The following aspects are critical for the feasibility of a future PT in NASH: readiness of the drug pipeline, mainly from large drug companies, while there is not yet an FDA/EMA-approved treatment; the most suitable design (trial Phase and type of population, e.g., Phase 2b for non-cirrhotic NASH patients); the operational requirements such as the scope of the clinical network, the use of concurrent versus non-concurrent control arms, or the re-allocation of participants upon trial adaptations; the methodological appraisal (i.e. Bayesian vs. frequentist approach); patients' needs and patient-centred outcomes; main regulatory considerations and the funding and sustainability scenarios. PT represent a promising avenue in NASH but there are a number of conundrums that need addressing. It is likely that before a global NASH PT becomes a reality, 'proof-of-platform' at a smaller scale needs to be provided.

Outcomes of patients (pts) with metastatic colorectal cancer (mCRC) participating in phase I clinical trials: The Sarah Cannon Research Institute UK experience.

142 Background: In the last decade immunotherapy, BRAF inhibitors (inh) and trifluridine-tipiracil became new standard of care (SoC) options for selected mCRC pts through the drug development pathway. In this study we aimed to evaluate clinical characteristics and outcomes of pts with mCRC participating in phase I trials. Methods: Electronic medical records from 10/2011 to 07/2022 were reviewed; pts who received at least one dose of trial drug were included. Data were analysed with descriptive statistic. Results: 81 (100%) pts were identified; 38 (47%) female; median age: 59 (range 31-80); 31 pts (38%) - right sided; 35 (44%) - RASmut, 29 (36%) - BRAFmut, 16 (20%) - RAS/BRAFw; MSI-H status was detected in 11 pts. Eleven pts participated in >1 trial, for a total of 96 cases. Median follow-up was 7 months (m); overall response rate was 6.8%, mPFS: 2.9 m, mOS 18.8 m. Age<50 (P=0,02), low lymphocyte/monocyte ratio (LMR ≤2.8) (P=0.02), in-situ primary tumour (P<0.001), no adjuvant therapy (P=0,001), right sided tumour (P=0,02) were independently associated with shorter OS (univariate analysis); the last three variables remained significant in multivariate analysis. Outcomes according to 4 drug classes and others (chemotherapy-based +/- targeted agents) are shown. Conclusions: Phase 1 trials offer a reasonable therapeutic approach for pts with mCRC and early access to drugs with potential to become SoC in future. [Table: see text]

Overcoming structural barriers to diffusion of HIV pre-exposure prophylaxis.

HIV prevention with antiretroviral medication in the form of pre-exposure prophylaxis (PrEP) offers a critical tool to halt the HIV pandemic. Barriers to PrEP access across drug types, formulations, and delivery systems share remarkable commonalities and are likely to be generalizable to future novel PrEP strategies. Appreciation of these barriers allows for planning earlier in the drug-development pathway rather than waiting for the demonstration of efficacy. The purpose of this article is to propose a core set of considerations that should be included in the drug-development process for future PrEP interventions. A literature synthesis of key barriers to PrEP uptake in the United States was conducted to elucidate commonalities across PrEP agents and delivery methods. Based on the published literature, we divided challenges into three main categories of structural barriers: (1) provider and clinic characteristics; (2) cost considerations; and (3) disparities and social constructs, with potential solutions provided for each. Pragmatic strategies for examining and overcoming these barriers before future PrEP regulatory approval are recommended. If these strategies are considered well before the time of commercial availability, the potential for PrEP to interrupt the HIV pandemic will be greatly enhanced.

Rare missense variant (R251G) on APOE counterbalances the Alzheimer’s disease risk associated with APOE‐ε4

AbstractBackgroundDespite decades of research, the mechanisms linking APOE to Alzheimer’s disease (AD) remain poorly understood. Finding additional risk variants at the APOE locus, beyond the common APOE‐ε2 and APOE‐ε4 alleles, may help elucidate how APOE is involved in the disease.MethodAssociation with case‐control status was tested in a sequenced discovery sample (Stage 1) and followed‐up in several microarray imputed cohorts as well as the UK Biobank whole‐exome sequencing resource using a proxy‐AD phenotype (Stages 2+3) (Table 1). Stage 1 included 37,409 non‐unique participants of European or Admixed‐European ancestry, with 11,868 cases and 11,934 controls passing analysis inclusion criteria. In Stages 2+3, 475,473 participants were considered across 8 cohorts, of which 56,029 cases, 28,484 proxy‐AD cases, and 328,372 healthy‐controls passed inclusion criteria, and were of European ancestry.ResultTwo missense variants were associated with a two to three‐fold decreased AD risk: R251G (odds ratio, 0.44; 95% confidence interval [CI], 0.33‐0.59; P = 4.7×10‐8) and V236E (odds ratio, 0.37; 95% CI, 0.25‐0.56; P = 1.9×10‐6) (Table 2, Figures 1, 2). Additionally, the cumulative incidence of AD in carriers of these variants was found to grow more slowly with age compared to non‐carriers (Table 3).ConclusionWe identified a novel variant associated with AD, R251G, which mitigates the ε4 associated AD risk, and confirmed the protective effect of the V236E variant. The location of the variants confirms that the carboxyl‐terminal portion of apoE plays an important role in AD pathogenesis. The large risk reductions reported here, suggest that protein chemistry and functional assays of these variants have the potential to identify novel pathways for drug development.

Selected Articles from This Issue

Glioblastoma (GBM) is one of the most aggressive cancers and it is usually refractory to immunotherapies. EGFR variant III (EGFRvIII) is an EGFR mutation commonly present in GBM that generates a unique cell surface neoantigen in tumor cells. Here, Iurlaro and colleagues have designed and developed a novel T cell bispecific antibody (TCB) with specificity for EGFRvIII and CD3. The EGFRvIII-TCB promoted T cell activation and tumor cell killing in EGFRvIII-expressing patient-derived models, and induced tumor regression in GBM patient-derived xenografts (PDX). These results led to the clinical testing of the EGFRvIII-TCB for the treatment of EGFRvIII-expressing GBMs.Comparative oncology clinical trials, carried out in pet dogs with spontaneously occurring cancers, are increasingly recognized a valuable component of the anti-cancer drug discovery and development pathway. In this report, LeBlanc and colleagues conducted a clinical study of a novel orally bioavailable inhibitor of valosin-containing protein (VCP), CB-5339, in pet dogs with a variety of malignancies. This canine trial generated key pharmacokinetic and pharmacodynamic data, defined a tolerable dose and schedule, and discovered an efficacy signal in multiple myeloma. The data generated herein provided a foundation for future studies of this drug in humans with multiple myeloma as well as other tumor types.Glutamine metabolism has been considered an important mechanism for control of tumor growth and survival. Here, Yokoyama and colleagues describe the preclinical pharmacology and mechanism of action of the novel clinical stage glutamine antagonist, DRP-104 (sirpiglenastat). Broadly targeting all 10 glutamine metabolizing enzymes, DRP-104 leads to profound anti-tumor activity related to both direct effects on tumor metabolism as well as immune mediated activity via remodeling of the tumor microenvironment and induction of both innate and adaptive anti-tumor immunity. This unique activity shows promise for the treatment of various tumors including those resistant to immune checkpoint inhibitors.Prostate cancer is the second leading cause of cancer related deaths and most commonly diagnosed cancer in US males. Although androgen receptor-targeted therapies such as enzalutamide are initially effective for the treatment of advanced prostate cancer, resistance occurs frequently. Here, Ning and colleagues have demonstrated that Wnt5A/FZD2 signaling plays vital roles in conferring resistance to enzalutamide and the levels of their expression correlates with aggressive prostate cancer with shortened disease-free survival. Furthermore, a novel bioengineered BERA-Wnt5A siRNA construct significantly suppressed tumor growth and enhanced enzalutamide treatment, suggesting targeting Wnt5A could be developed as a potential therapy for advanced prostate cancer.

Are the Current Processes and Regulations Fit for Purpose to Deliver Novel Therapies During Pandemics? A Perspective on COVID-19 from the UK.

The COVID-19 pandemic was the first ‘stress test’ to assess whether the current regulations in the United Kingdom (UK) are fit for purpose to develop novel therapies during pandemics. It saw innovations and collaborations across the spectrum of the drug development and regulatory pathways, including extraordinary collaborations between the various stakeholders involved in the process, the repositioning of medicines, the deployment of multi-arm, multi-interventional adaptive trials, the institution of operational simplicity and flexibility across various trial activities, and regulatory innovations. The question arises whether the innovative flexibilities and the urgency that were instituted could have resulted in compromises to the integrity of the process. An assessment of the conduct of the RECOVERY trial and the speedy approval of dexamethasone by the UK Medicines and Healthcare products Regulatory Agency demonstrates that no compromises were made to the ethical and scientific integrity of the process. Lessons learnt could be applied for future pandemics and to enhance R&D productivity and contribute to global health by improving access to medicines, especially in low- and middle-income countries and for neglected or rare diseases. What is needed is not a major transformation in the process but the flexible adaptation of existing regulations to reduce bureaucracy and handover times. Arriving at an optimal balance between scientific standards, regulations and commercial conflicts of interest will pose considerable challenges but what the COVID-19 pandemic has shown is that where there is will, there is always a way.

Defining disease modification in myelofibrosis in the era of targeted therapy.

The development of targeted therapies for the treatment of myelofibrosis highlights a unique issue in a field that has historically relied on symptom relief, rather than survival benefit or modification of disease course, as key response criteria. There is, therefore, a need to understand what constitutes disease modification of myelofibrosis to advance appropriate drug development and therapeutic pathways. Here, the authors discuss recent clinical trial data of agents in development and dissect the potential for novel end points to act as disease modifying parameters. Using the rationale garnered from latest clinical and scientific evidence, the authors propose a definition of disease modification in myelofibrosis. With improved overall survival a critical outcome, alongside the normalization of hematopoiesis and improvement in bone marrow fibrosis, there will be an increasing need for surrogate measures of survival for use in the early stages of trials. As such, the design of future clinical trials will require re‐evaluation and updating to incorporate informative parameters and end points with standardized definitions and methodologies.

Re-orienting anti-malarial drug development to better serve pregnant women

Malaria is one of the most serious infectious diseases affecting predominantly low- and middle-income countries, where pregnant women are among the populations at risk. There are limited options to prevent or treat malaria in pregnancy, particularly in the first trimester, and existing ones may not work optimally in areas where the threat of drug resistance is rising. As malaria elimination is a key goal of the global health community, the inclusion of pregnant women in the adult population to protect from malaria will be key to achieving success. New, safe, and effective options are needed but it can take decades of evidence-gathering before a medicine is recommended for use in pregnancy. This is because pregnant women are typically not included in pre-registration clinical trials due to fear of causing harm. Data to support dosing and safety in pregnancy are subsequently collected in post-licensure studies. There have been growing calls in recent years that this practice needs to change, amplified by the COVID-19 pandemic and increasing public awareness that newly developed medicines generally cannot be administered to pregnant women from the onset. The development of new anti-malarials should ensure that data informing their use in pregnancy and breastfeeding are available earlier. To achieve this, a mindset change and a different approach to medications for pregnant women are needed. Changes in non-clinical, translational, and clinical approaches in the drug development pathway, in line with recent recommendations from the regulatory bodies are proposed in this Comment. The new approach applies to any malaria-endemic region, regardless of the type of Plasmodium responsible for malaria cases. By incorporating intentional and systematic data collection from pre-registration stages of development through post-licensure, it will be possible to inform on the benefit/risk balance of a new anti-malarial earlier and help ensure that the needs of pregnant individuals are addressed in a more timely and equitable manner in the future.

Leveraging Real-World Data for EMA Qualification of a Model-Based Biomarker Tool to Optimize Type-1 Diabetes Prevention Studies.

The development of therapies to prevent or delay the onset of type 1 diabetes (T1D) remains challenging, and there is a lack of qualified biomarkers to identify individuals at risk of developing T1D or to quantify the time‐varying risk of conversion to a diagnosis of T1D. To address this drug development need, the T1D Consortium (i) acquired, remapped, integrated, and curated existing patient‐level data from relevant observational studies, and (ii) used a model‐based approach to evaluate the utility of islet autoantibodies (AAs) against insulin/proinsulin autoantibody, GAD65, IA‐2, and ZnT8 as biomarkers to enrich subjects for T1D prevention. The aggregated dataset was used to construct an accelerated failure time model for predicting T1D diagnosis. The model quantifies presence of islet AA permutations as statistically significant predictors of the time‐varying probability of conversion to a diagnosis of T1D. Additional sources of variability that greatly improved the accuracy of quantifying the time‐varying probability of conversion to a T1D diagnosis included baseline age, sex, blood glucose measurements from the 120‐minute timepoints of oral glucose tolerance tests, and hemoglobin A1c. The developed models represented the underlying evidence to qualify islet AAs as enrichment biomarkers through the qualification of novel methodologies for drug development pathway at the European Medicines Agency (EMA). Additionally, the models are intended as the foundation of a fully functioning end‐user tool that will allow sponsors to optimize enrichment criteria for clinical trials in T1D prevention studies.

The development of broad-spectrum antiviral medical countermeasures to treat viral hemorrhagic fevers caused by natural or weaponized virus infections.

The Joint Program Executive Office for Chemical, Biological, Radiological, and Nuclear Defense (JPEO-CBRND) began development of a broad-spectrum antiviral countermeasure against deliberate use of high-consequence viral hemorrhagic fevers (VHFs) in 2016. The effort featured comprehensive preclinical research, including laboratory testing and rapid advancement of lead molecules into nonhuman primate (NHP) models of Ebola virus disease (EVD). Remdesivir (GS-5734, Veklury, Gilead Sciences) was the first small molecule therapeutic to successfully emerge from this effort. Remdesivir is an inhibitor of RNA-dependent RNA polymerase, a viral enzyme that is essential for viral replication. Its robust potency and broad-spectrum antiviral activity against certain RNA viruses including Ebola virus and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) led to its clinical evaluation in randomized, controlled trials (RCTs) in human patients during the 2018 EVD outbreak in the Democratic Republic of the Congo (DRC) and the ongoing Coronavirus Disease 2019 (COVID-19) pandemic today. Remdesivir was recently approved by the US Food and Drug Administration (FDA) for the treatment of COVID-19 requiring hospitalization. Substantial gaps remain in improving the outcomes of acute viral infections for patients afflicted with both EVD and COVID-19, including how to increase therapeutic breadth and strategies for the prevention and treatment of severe disease. Combination therapy that joins therapeutics with complimentary mechanisms of action appear promising, both preclinically and in RCTs. Importantly, significant programmatic challenges endure pertaining to a clear drug and biological product development pathway for therapeutics targeting biodefense and emerging pathogens when human efficacy studies are not ethical or feasible. For example, remdesivir’s clinical development was facilitated by outbreaks of Ebola and SARS-CoV-2; as such, the development pathway employed for remdesivir is likely to be the exception rather than the rule.The current regulatory licensure pathway for therapeutics targeting rare, weaponizable VHF agents is likely to require use of FDA’s established Animal Rule (21 CFR 314.600–650 for drugs; 21 CFR 601.90–95 for biologics). The FDA may grant marketing approval based on adequate and well-controlled animal efficacy studies when the results of those studies establish that the drug is safe and likely to produce clinical benefit in humans. In practical terms, this is anticipated to include a series of rigorous, well-documented, animal challenge studies, to include aerosol challenge, combined with human safety data. While small clinical studies against naturally occurring, high-consequence pathogens are typically performed where possible, approval for the therapeutics currently under development against biodefense pathogens will likely require the Animal Rule pathway utilizing studies in NHPs. We review the development of remdesivir as illustrative of the effort that will be needed to field future therapeutics against highly lethal, infectious agents.

Guidelines for Nanopharmaceutical Products for Regulatory Approval

The word 'nano' refers to a Greek prefix that means 'dwarf' or very little,' and represents a thousand millionth of a meter (10-9) in length. Nanoscience and nanotechnology are the study and application of nanoscale range materials. Initially, the term Nanotechnology was used by N. Taniguchi in 1974 at an international conference on industrial production in Tokyo to characterize the super-thin processing of materials with nanometre accuracy and the fabrication of nano-sized systems (Bayda S. et al., 2020). The usage of nanomaterials has enhanced the application of nanomedicine in various therapeutics area with challenges and limitations over the last ten years. Alteration of the physiochemical, biological, mechanical & other properties of the materials made the nanomaterials and it can be utilized in different useful activities such as drug development, drug target. Nanotechnology utilized novel nanomaterials to make useful products. This technology has been used to overcome the limitations & challenges in different drug therapies. (Harea JI et al., 2017). 
 The combination of nanotechnology with pharmaceuticals and biomedicals is termed nano pharmaceutical. Nanopharmaceuticals is a new technology in current practice. As a result, there are no widely agreed nanopharmaceuticals guidelines. The general idea of regulatory requirements for Active Pharmaceutical Ingredients (API), as stated in the CDSCO's New Drugs and Clinical Trial Rules 2019, was mandatory in drug development pathways. These criteria are also in line with the International Council for Harmonization (ICH) recommendations and international standards that other countries using such items follow. New Drugs and Clinical Trials Rules, 2019 should be followed in different drug development. (Harea JI et al., 2017). 
 Globally, there are important guidelines developed by the United States Food & Drugs Administration (USFDA), International Council for Harmonization (ICH), or Organization for Economic Co-operation and Development (OECD). (Harea JI et al., 2017). 
 Current regulatory approaches by US Food & Drug Administration (FDA), established the nanotechnology task force in August 2006. This regulatory approach encourages the development of nanoproducts. FDA has issued the guidelines in 2007 to the industry to address the benefits & risks of Drugs, medical devices, and other nanoproducts. FDA is also working with other U.S. government agencies to focus on the safety & efficacy of nanoproducts and U.S. initiates the National Nanotechnology Initiative (NNI) which is a federal research & development program to coordinate the effort of all government agencies involved in nanotechnology. The main goal of the NNI is to maintain the class of research & development program, encourage inducing the new technologies in the product, developing the supporting infrastructure & tools needed for nanotechnology (Ventola et al., 2012).

Three discipline collaborative radiation therapy (3DCRT) special debate: FLASH radiotherapy needs ongoing basic and animal research before implementing it to a large clinical scale.

Three discipline collaborative radiation therapy (3DCRT) special debate: FLASH radiotherapy needs ongoing basic and animal research before implementing it to a large clinical scale.

Activation of E6AP/UBE3A-Mediated Protein Ubiquitination and Degradation Pathways by a Cyclic γ-AA Peptide.

Manipulating the activities of E3 ubiquitin ligases with chemical ligands holds promise for correcting E3 malfunctions and repurposing the E3s for induced protein degradation in the cell. Herein, we report an alternative strategy to proteolysis-targeting chimeras (PROTACs) and molecular glues to induce protein degradation by constructing and screening a γ-AA peptide library for cyclic peptidomimetics binding to the HECT domain of E6AP, an E3 ubiquitinating p53 coerced by the human papillomavirus and regulating pathways implicated in neurodevelopmental disorders such as Angelman syndrome. We found that a γ-AA peptide P6, discovered from the affinity-based screening with the E6AP HECT domain, can significantly stimulate the ubiquitin ligase activity of E6AP to ubiquitinate its substrate proteins UbxD8, HHR23A, and β-catenin in reconstituted reactions and HEK293T cells. Furthermore, P6 can accelerate the degradation of E6AP substrates in the cell by enhancing the catalytic activities of E6AP. Our work demonstrates the feasibility of using synthetic ligands to stimulate E3 activities in the cell. The E3 stimulators could be developed alongside E3 inhibitors and substrate recruiters such as PROTACs and molecular glues to leverage the full potential of protein ubiquitination pathways for drug development.

The Chemical Composition and Health-Promoting Effects of the Grewia Species-A Systematic Review and Meta-Analysis.

Globally grown and organoleptically appreciated Grewia species are known as sources of bioactive compounds that avert the risk of communicable and non-communicable diseases. Therefore, in recent years, the genus Grewia has attracted increasing scientific attention. This is the first systematic review which focusses primarily on the nutritional composition, phytochemical profile, pharmacological properties, and disease preventative role of Grewia species. The literature published from 1975 to 2021 was searched to retrieve relevant articles from databases such as Google Scholar, Scopus, PubMed, and Web of Science. Two independent reviewers carried out the screening, selection of articles, and data extraction. Of 815 references, 56 met our inclusion criteria. G. asiatica and G. optiva were the most frequently studied species. We found 167 chemical compounds from 12 Grewia species, allocated to 21 categories. Flavonoids represented 41.31% of the reported bioactive compounds, followed by protein and amino acids (10.7%), fats and fatty acids (9.58%), ash and minerals (6.58%), and non-flavonoid polyphenols (5.96%). Crude extracts, enriched with bioactive compounds, and isolated compounds from the Grewia species show antioxidant, anticancer, anti-inflammatory, antidiabetic, hepatoprotective/radioprotective, immunomodulatory, and sedative hypnotic potential. Moreover, antimicrobial properties, improvement in learning and memory deficits, and effectiveness against neurodegenerative ailments are also described within the reviewed article. Nowadays, the side effects of some synthetic drugs and therapies, and bottlenecks in the drug development pathway have directed the attention of researchers and pharmaceutical industries towards the development of new products that are safe, cost-effective, and readily available. However, the application of the Grewia species in pharmaceutical industries is still limited.

Improving the assessment of the probability of success in late stage drug development.

There are several steps to confirming the safety and efficacy of a new medicine. A sequence of trials, each with its own objectives, is usually required. Quantitative risk metrics can be useful for informing decisions about whether a medicine should transition from one stage of development to the next. To obtain an estimate of the probability of regulatory approval, pharmaceutical companies may start with industry-wide success rates and then apply to these subjective adjustments to reflect program-specific information. However, this approach lacks transparency and fails to make full use of data from previous clinical trials. We describe a quantitative Bayesian approach for calculating the probability of success (PoS) at the end of phase II which incorporates internal clinical data from one or more phase IIb studies, industry-wide success rates, and expert opinion or external data if needed. Using an example, we illustrate how PoS can be calculated accounting for differences between the phase II data and future phase III trials, and discuss how the methods can be extended to accommodate accelerated drug development pathways.

A scoping review of the EU's impact on access to medicines in low- and middle-income countries

The European Union (EU) has a potential major influence on patients' global access to medicines. Historically, this influence most notably came through the EU's trade and aid agendas that intentionally targeted foreign markets. Now, the EU's own internal pharmaceutical policy appears to indirectly shape global access to medicines (ex. EU's large-scale Covid-19 vaccine procurement and export bans). To understand the ways the EU's internal and external policies impact on global access to medicines, this Scoping Review synthesises evidence of the EU's global regulatory influence and its impacts on access to medicines in non-EU low- and middle-income countries (LMICs). By searching 8 databases and grey literature, documents published in English, Spanish, Portuguese, or Russian between 1995-2021 that addressed an EU law, regulation, or policy in relation to access to medicines in LMICs were included. This review identifies three mechanisms through which EU action impacts on medicines in LMICs. One, the EU's external, treaty-based agreements with LMICs can affect their pharmaceutical trade, sales, and use. Two, EU's internal market regulation, standards, and methods are used as models or sources of inspiration for pharmaceutical governance in LMICs. Three, ‘soft' forms of EU influence manifest through the EU's technical assistance, its research and development (aid) funding, and its ‘capacity building' activities towards LMIC actors in the field of pharmaceuticals. Examples of impacts of EU action ranged from the development of new medicines primarily for LMICs, to changes in the availability of generics and on medicines spending in LMICs, and the potential for a more efficient yet less autonomous local market approval process. Most evidence of impact was not peer reviewed. This study raises the question of how to support resilient and efficient global pathways for drug development and regulation while still being responsive and accountable to the local public interest.Key messages There are 3 mechanisms through which EU action impacts on medicines in LMICs: treaty-based agreements, EU internal market regulation, and ‘soft' EU influence.EU decision makers need a reliable understanding of how the EU’s internal and external policies impact on pharmaceuticals globally.

Ravidasvir: equitable access through an alternative drug development pathway

The development of highly effective direct-acting antivirals has made it possible to imagine the global elimination of hepatitis C, which afflicts an estimated 58 million people and causes 290 000 deaths globally each year.1 Inspired by this possibility, in 2016, WHO established the goal of eliminating viral hepatitis globally by 2030.2

Computational Atom-based Three-Dimensional Quantitative Structure-Activity Relationship (3D QSAR) Model for Predicting Anti-Dengue Agents

Dengue fever is a viral infection spread by the female mosquito Aedes aegypti. It is a virus spread by mosquitoes found all over the tropics with risk levels varying depending on rainfall, relative humidity, temperature and urbanization. There are no specific medications that can be used to treat the condition. The development of possible bioactive ligands to combat Dengue fever before it becomes a pandemic is a global priority. Few studies on building three-dimensional quantitative structure-activity relationship (3D QSAR) models for anti-dengue agents have been reported. Thus, we aimed at building a statistically validated atom-based 3D-QSAR model using bioactive ligands reported to possess significant anti-dengue properties. In this study, the Schrodinger PhaseTM atom-based 3D QSAR model was developed and was validated using known anti-dengue properties as ligand data. This model was also tested to see if there was a link between structural characteristics and anti-dengue activity of a series of 3-acyl-indole derivatives. The established 3D QSAR model has strong predictive capacity and is statistically significant [Model: R2 Training Set = 0.93, Q2 (R2 Test Set) = 0.72]. In addition, the pharmacophore characteristics essential for the reported anti-dengue properties were explored using combined effects contour maps (coloured contour maps: blue: positive potential and red: negative potential) of the model. In the pathway of anti-dengue drug development, the model could be included as a virtual screening method to predict novel hits.

Paving a pathway for drug development in HER2-positive biliary tract cancer.

After a decade of limited success in drug development for advanced biliary tract cancers, a wave of targeted therapeutics has become available for tumours with alterations in FGFR2, IDH1, BRAF, mismatch repair proteins, and NTRK.1 HER2 (also known as ERBB2) now joins this expanding list of molecular targets with the results of the HER2-positive biliary tract cancer cohort of the MyPathway basket study.

Plant-Based Phytochemical Screening by Targeting Main Protease of SARS-CoV-2 to Design Effective Potent Inhibitors.

Simple SummaryVirtual screening schemes, including molecular docking in conjunction with molecular dynamics simulation, were accomplished, as they extend an ample opportunity to screen plausible inhibitors of the main protease from an extensive phytochemical library. The preferential phytochemicals were retrieved from Asian plants through the data mining procedure and comprehensive literature study. The three preeminent reliable phytochemical exhibited toxicity by no means during the scrutinization of ADMET prominences. Moreover, pharmacologically distinguishing characteristics and the biological activity of the lead phytochemicals were satisfying as a repurposing antiviral drug contender. Additionally, the molecular dynamics simulation exhibited thermal stability and a stable binding affinity of the protein-compound complex that refers to the appreciable efficacy of the lead optimization. Therefore, the preferable phytochemicals are worth substantial evaluation in the biological laboratory to recommend plausible antiviral drug contenders.Currently, a worldwide pandemic has been declared in response to the spread of coronavirus disease 2019 (COVID-19), a fatal and fast-spreading viral infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The low availability of efficient vaccines and treatment options has resulted in a high mortality rate, bringing the world economy to its knees. Thus, mechanistic investigations of drugs capable of counteracting this disease are in high demand. The main protease (Mpro) expressed by SARS-CoV-2 has been targeted for the development of potential drug candidates due to the crucial role played by Mpro in viral replication and transcription. We generated a phytochemical library containing 1672 phytochemicals derived from 56 plants, which have been reported as having antiviral, antibacterial, and antifungal activity. A molecular docking program was used to screen the top three candidate compounds: epicatechin-3-O-gallate, psi-taraxasterol, and catechin gallate, which had respective binding affinities of −8.4, −8.5, and −8.8 kcal/mol. Several active sites in the targeted protein, including Cys145, His41, Met49, Glu66, and Met165, were found to interact with the top three candidate compounds. The multiple simulation profile, root-mean-square deviation, root-mean-square fluctuation, radius of gyration, and solvent-accessible surface area values supported the inflexible nature of the docked protein–compound complexes. The toxicity and carcinogenicity profiles were assessed, which showed that epicatechin-3-O-gallate, psi-taraxasterol, and catechin gallate had favorable pharmacological properties with no adverse effects. These findings suggest that these compounds could be developed as part of an effective drug development pathway to treat COVID-19.