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One of the major virulence factors of SARS-CoV-2, NSP1, is a vital drug target due to its role in host immune evasion through multiple pathways. NSP1 protein is associated with inhibiting host mRNA translation by binding to the small subunit of ribosome through its C-terminal region. Previously, we have shown the structural dynamics of NSP1 C-terminal region (NSP1-CTR) in different physiological environments. So, it would be very interesting to investigate the druggable compounds that could bind with NSP1-CTR. Here, in this article, we have performed the different spectroscopic technique-based binding assays of an anticancer drug Mitoxantrone dihydrochloride (MTX) against the NSP1-CTR. We have also performed molecular docking followed by computational simulations with two different forcefields up to one microsecond. Overall, our results have suggested good binding between NSP1-CTR and MTX and may have implications in developing therapeutic strategies targeting NSP1 protein of SARS-CoV-2.

Several challenges are associated with rare disease drug development in neurology. In this article, we summarize the U.S. Food and Drug Administration's experience with clinical drug development for rare neurological diseases and discuss clinical pharmacology's critical contributions to drug development for rare diseases. We used publicly available information to identify and screen drug products approved for rare neurological indications between 1983 and 2019. We highlighted cases in which clinical pharmacology contributed to the evidence of drug efficacy, dose selection for pivotal clinical trials, dose optimization based on intrinsic and extrinsic factors, pharmacokinetic bridging for formulations, and efficacy bridging across different racial groups. Fifty-one approved drug products were identified since the introduction of Orphan Drug Act in 1983. Interestingly, the number of approvals in the last few years increased significantly, probably due to advances in genomic research and targeted drug modalities. Evaluation of dose selection in patient populations showed that in 52% of cases, the sponsors did not evaluate efficacy for more than one or two dose levels throughout the development program. Clinical pharmacology studies to evaluate the effect of intrinsic or extrinsic factors were adequately characterized in most of the applications. With the expansion of model informed drug development (MIDD) applications, (e.g., quantitative systems pharmacology and deep learning neural network models), the role and impact of clinical pharmacology is expected to grow exponentially in the next decade and enhance the development of novel treatment modalities for neurological rare diseases.

Amid a global pandemic, the US Food and Drug Administration (FDA) remained relatively active, approving 55novel molecular entities (NMEs) in 2020, the third highest annual rate recorded. Orphan approvals also surged, capturing 60% of NMEs introduced during 2020, as did the number of NMEs approved using a priority review. The pandemic did appear to impact one recent trend, and in a paradoxically encouraging way. Escalating rates of consolidation slowed in 2020, with only 102 companies lost, down by two-thirds over the rate in 2019. This leaves 2000 extant clinical-stage pharmaceutical companies. When limiting this analysis to companies contributing to the research and development (R&D) of an approved drug, eight were lost, leaving 144 extant.

Recent decades have been marked by a wave drug treatment research in autism spectrum disorder (ASD). This work has resulted in improved ability to treat commonly occurring behavioral challenges associated with ASD including most prominently irritability marked by aggression, self-injurious behavior, and severe tantrums. While treatment of interfering behavior has progressed in our field, there remain several areas of unmet medical need including most prominently a lack of any approved drug therapies for the core, defining symptoms of autism. We outline the progress to date in the field of autism drug treatment while taking a future look forward into how decades of work can inform better future steps in this field.

A significant proportion of recently approved drug molecules possess poor aqueous solubility which further restrains their desired bioavailability. Poor aqueous solubility of these drugs poses significant hurdles in development of novel drug delivery systems and achieving target response. Self-emulsifying drug delivery systems (SEDDS) emerged as an insightful approach for delivering highly hydrophobic entities to enhance their bioavailability. Conventional SEDDS were developed in a liquid form which owned numerous shortcomings like low stability and drug loading efficiency, fewer choices of dosage forms and irreversible precipitation of drug or excipients. To address these curbs solid-SEDDS (S-SEDDS) was introduced as an efficient strategy that combined advantages of solid dosage forms such as increased stability, portability and patient compliance along with substantial improvement in the bioavailability. S-SEDDS are isotropic mixtures of oil, surfactant, solvent and co-solvents generated by solidification of liquid or semisolid self-emulsifying ingredients onto powders. The present review highlights components of S-SEDDS, their peculiarities to be considered while designing solid dosage forms and various methods of fabrication. Lastly, key challenges faced during development, applications and future directions for the research in this area are thoroughly summarized.

Introduction: Levonadifloxacin is a novel antibiotic belonging to the benzoquinolizine subclass of fluoroquinolone with potent activity against Methicillin Resistant Staphylococcus aureus (MRSA) and Quinolone Resistant Staphylococcus aureus (QRSA). Both intravenous levonadifloxacin and its oral formulation have recently been approved in India for the treatment of acute bacterial skin related infections. Aim: To assess the activity of levonadifloxacin against gram positive clinical isolates collected from Intensive Care Units (ICUs) using the disk-diffusion method. Materials and Methods: The present descriptive study where non duplicate isolates of Staphylococcus aureus (S. aureus) and other gram positive isolates from various clinical samples from all Intensive Care Units (ICUs) were collected from June to December 2020 and subjected to levonadifloxacin susceptibility testing (disk diffusion method) as per the Clinical and Laboratory Standards Institute (CLSI) guidelines, 2020. Data analysis was performed using Statistical Package for the Social Sciences (SPSS) software, version 25.0. Results: A total of 142 gram positive clinical isolates collected from all ICUs of the hospital were analysed. These isolates included coagulase negative S. aureus 109 (76.8%), S. aureus 21 (14.8%) and Enterococcus faecalis 12 (8.4%). All the gram positive isolates of the study were susceptible to levonadifloxacin as per the prespecified interpretive criteria identified based on population pharmacokinetic model and Monte Carlo simulation enabled probability of pharmacodynamic target attainment analysis. Conclusion: Results of this in vitro study shows good activity of levonadifloxacin against gram positive isolates including difficult to-treat methicillin resistant staphylococcal isolates collected from ICU patients.

On a worldwide scale, the outbreak of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has led to extensive damage to the health system as well as the global economy. Hitherto, there has been no approved drug or vaccine for this disease. Therefore, the use of general antiviral drugs is at the first line of treatment, though complicated with limited effectiveness and systemic side effects. Given the pathophysiology of the disease, researchers have proposed various strategies not only to find a more specific therapeutic way but also to reduce the side effects. One strategy to accomplish these goals is to use CRISPR/Cas13 system. Recently, a group of scientists has used the CRISPR/Cas13 system, which is highly effective in eliminating the genome of RNA viruses. Due to the RNA nature of the coronavirus genome, it seems that this system can be effective against the disease. The main challenge regarding the application of this system is to deliver it to the target cells efficiently. To solve this challenge, it seems that using virosomes with protein S on their membrane surface can be helpful. Studies have shown that protein S interacts with its specific receptor in target cells named Angiotensin-Converting Enzyme 2 (ACE2). Here, we propose if CRISPR/Cas13 gene constructs reach the infected cells efficiently using a virosomal delivery system, the virus genome will be cleaved and inactivated. Considering the pathophysiology of the disease, an important step to implement this hypothesis is to embed protein S on the membrane surface of virosomes to facilitate the delivery of gene constructs to the target cells.

Medical management of epilepsy seeks to eliminate or to reduce the frequency of seizures, help patients maintain a normal lifestyle, and maintain psychosocial and occupational activities, while avoiding the negative side effects of long-term treatment. Current FDA approved drugs have been shown to have similar efficacy; however, they all share a commonality of having side effects that have the potential to significantly reduce a patient’s quality of life. Cenobamate, a newly-FDA approved drug used to treat partial-onset seizures in adult patients, has demonstrated promise in that it works on two proposed mechanisms that are commonly associated with epilepsy. Cenobamate acts as a positive allosteric modulator of the GABAA ion channels and is effective in reducing repetitive neuronal firing by inhibition of voltage-gated sodium channels, although the complete mechanism of action is currently unknown. The efficacy of Cenobamate with its low toxicity and adverse drug reaction profile emphasizes the need to further evaluate antiepileptic therapies containing sulfamoylphenyl and/or carbamate moieties in their chemical structure. Recent studies have found more patients to be seizure free during the maintenance period when compared to placebo. The most common side effects reported in with Cenobamate are somnolence, dizziness, headache, nausea, and fatigue. There are currently ongoing phase III studies looking to further evaluate the long-term benefits of Cenobamate and investigate adverse events.

In view of many European countries and the USA leading to the second wave of COVID-19 pandemic, winter season, the evolution of new mutations in the spike protein, and no registered drugs and vaccines for COVID-19 treatment, the discovery of effective and novel therapeutic agents is urgently required. The degrees and frequencies of COVID-19 clinical complications are related to uncontrolled immune responses, secondary bacterial infections, diabetes, cardiovascular disease, hypertension, and chronic pulmonary diseases. It is essential to recognize that the drug repurposing strategy so far remains the only means to manage the disease burden of COVID-19. Despite some success of using single-target drugs in treating the disease, it is beyond suspicion that the virus will acquire drug resistance by acquiring mutations in the drug target. The possible synergistic inhibition of drug efficacy due to drug-drug interaction cannot be avoided while treating COVID-19 and allied clinical complications. Hence, to avoid the unintended development drug resistance and loss of efficacy due to drug-drug interaction, multi-target drugs can be promising tools for the most challenging disease. In the present work, we have carried out molecular docking studies of compounds from the FDA approved drug library, and the FDA approved and passed phase −1 drug libraries with ten therapeutic targets of COVID-19. Results showed that known drugs, including nine anti-inflammatory compounds, four antibiotics, six antidiabetic compounds, and one cardioprotective compound, could effectively inhibit multiple therapeutic targets of COVID-19. Further in-vitro, in vivo, and clinical studies will guide these drugs' proper allocation to treat COVID-19. Communicated by Ramaswamy H. Sarma

Background: COVID-19 is a life-threatening novel corona viral infection to our civilization and spreading rapidly. Tremendousefforts have been made by the researchers to search for a drug to control SARS-CoV-2. Methods: Here, a series of arsenical derivatives were optimized and analyzed with in silico study to search the inhibitor of RNA dependent RNA polymerase (RdRp), the major replication factor of SARS-CoV-2. All the optimized derivatives were blindly docked with RdRp of SARS-CoV-2 using iGEMDOCK v2.1. Results: Based on the lower idock score in the catalytic pocket of RdRp, darinaparsin (-82.52 kcal/- mol) was revealed to be the most effective among them. Darinaparsin strongly binds with both Nsp9 replicase protein (-8.77 kcal/mol) and Nsp15 endoribonuclease (-8.3 kcal/mol) of SARS-- CoV-2 as confirmed from the AutoDock analysis. During infection, the ssRNA of SARS-CoV-2 is translated into large polyproteins forming viral replication complex by specific proteases like 3CL protease and papain protease. This is also another target to control the virus infection where darinaparsin also performs the inhibitory role to proteases of 3CL protease (-7.69 kcal/mol) and papain protease (-8.43 kcal/mol). Conclusion: In the host cell, the furin protease serves as a gateway to the viral entry and darinaparsin docked with furin protease, which revealed a strong binding affinity. Thus, screening of potential arsenic drugs would help in providing the fast in-vitro to in-vivo analysis towards the development of therapeutics against SARS-CoV-2.

Molecules that bind DNA by intercalating its bases remain among the most potent cancer therapies and antimicrobials due to their interference with DNA-processing proteins. To accelerate the discovery of novel intercalating drugs, we designed a fluorescence resonance energy transfer (FRET)-based probe that reports on DNA intercalation, allowing rapid and sensitive screening of chemical libraries in a high-throughput format. We demonstrate that the method correctly identifies known DNA intercalators in approved drug libraries and discover previously unreported intercalating compounds. When introduced in cells, the oligonucleotide-based probe rapidly distributes in the nucleus, allowing direct imaging of the dynamics of drug entry and its interaction with DNA in its native environment. This enabled us to directly correlate the potency of intercalators in killing cultured cancer cells with the ability of the drug to penetrate the cell membrane. The combined capability of the single probe to identify intercalators in vitro and follow their function in vivo can play a valuable role in accelerating the discovery of novel DNA-intercalating drugs or repurposing approved ones.

The novel corona virus (Covid-19) has become a great challenge worldwide since 2019, as no drug has been reported yet. Different clinical trials are still under way. Among them is Ivermectin (IVM), an FDA approved drug which was recently reported as a successful candidate to reduce SARS-CoV-2 viral load by inhibiting Importin-α1 (IMP-α1) protein which subsequently affects nuclear transport of viral proteins but its basic binding mode and inhibitory mechanism is unknown. Therefore, we aimed to explore the inhibitory mechanism and binding mode of IVM with IMP-α1 via different computational methods. Initially, comparative docking of IVM was performed against two different binding sites (Nuclear Localization Signal (NLS) major and minor sites) of IMP-α1 to predict the probable binding mode of IVM. Then, classical MD simulation was performed (IVM/NLS-Major site and IVM/NLS-Minor site), to predict its comparative stability dynamics and probable inhibitory mechanism. The stability dynamics and biophysical analysis of both sites highlighted the stable binding of IVM within NLS-Minor site by establishing and maintaining more hydrophobic contacts with crucial residues, required for IMP-α1 inhibition which were not observed in NLS-major site. Altogether, these results recommended the worth of IVM as a possible drug to limit the SARS-CoV-2 viral load and consequently reduces its progression. Communicated by Ramaswamy H. Sarma

Background: A newer trend has been seen recently to reuse the conventional drugs with distinct indications for the newer applications to speed up the drug discovery and development based on earlier records and safety data. Most of the non-cancerous agents could afford a little or tolerable side effects in individuals. However, the repositioning of these non-cancerous agents for successful anticancer therapy is an outstanding strategy for future anti-cancer drug development. Since more diverse and selective cancer drug targets are being discovered and developed, the approved drug collections are particularly useful to quickly identify clinically advanced anticancer drugs against those targets. Objective: Antihelminthic drugs such as Mebendazole and Albendazole (Benzimidazole class) have been reported to exhibit cytotoxicity (or anticancer activities) against several types of cancer. Therefore, this study aims to repurpose the benzimidazole scaffold for breast cancer treatment. Methods: In the present study, three hydrazone analogs having a benzimidazole motif in their structural frame were synthesized. Their in-silico binding studies against HER2 receptor (PDB ID: 4LQM) and ADMET studies were carried out using Accelrys drug discovery studio 4.1. Cytotoxicity of the synthesized compounds against HER2 overexpressed MCF-7 cell lines was determined by MTT assay. Results: One of the compounds 2-[2-(2,4-dinitrophenyl)hydrazinylidene]-2,3-dihydro-1H-benzimidazole (U1) has shown good cytotoxicity when compared to the standard Lapatinib, which is a well known HER2 inhibitor. Conclusion: Thus, the designed benzimidazole scaffold might serve as the best leads for treating breast cancer, which is additionally confirmed by performing their docking study via Accelrys discovery studio.

The FDA conducts independent reviews of scientific data obtained with investigational drug products to ensure that they are safe and effective. As a result of this process, FDA-approved product labeling is generated that is considered one of the most trusted sources of information for use of an approved drug. But FDA approval is only the beginning of the life cycle of a new drug; the first oncology drugs now have more than 7 decades of clinical experience in the postmarketing setting. Due, in part, to lack of incentives, some companies may not seek inclusion of new data, other than new safety information, in FDA-approved product labeling. Ensuring that product labeling provides adequate directions for use is important for all drugs, including older therapies that may form the backbone of many standard combination regimens for pediatric and adult cancers. Project Renewal is an FDA Oncology Center of Excellence pilot program that leverages expertise from the clinical and scientific oncology communities to review published literature and generate a drug-specific product report summarizing data that may support updates to FDA-approved product labeling. This article provides a broad overview of Project Renewal's collaborative pilot process for identifying and assessing literature supporting potential labeling updates, while engaging the oncology community to increase awareness of FDA's evidentiary standards and deliberative processes used when considering the addition of new indications and dosing regimens to product labeling.

Introduction Guidelines for treatment of multidrug-resistant (MDR) bacteria rely on newly approved antibiotics, with limited evidence of their effectiveness for treating these infections. Data regarding cost of such an approach are lacking. We aimed to evaluate estimated cost of using newly approved antibiotic drugs compared to older antibiotics for the treatment of difficult-to-treat pathogens. Methods MDR bacteria of interest included those defined by the World Health Organization as critical or of high priority for research. Old and newly approved antibiotics for these bacteria, defined as approved before or after January 2010, respectively, were evaluated for treatment cost and for 14-day treatment course. Estimated annual costs were calculated based on the Centers for Disease Control and Prevention’s' report on MDR bacteria prevalence in US hospitalized patients. Old and new drugs costs were compared. Results The cost of a 14-day treatment course for methicillin-resistant Staphylococcus aureus bacteremia with a newly approved drug was found to be 6 to 60 times higher than that of older drugs. Similarly, the cost of a 14-day course for carbapenem-resistant Enterobacterales or MDR Pseudomonas aeruginosa was doubled with new drugs; and for carbapenem-resistant Acinetobacter baumannii, ~ 20 times higher with newer drugs. Annual incremental costs of treating difficult-to-treat Gram-negative bacteria with new drugs ranged from 30 million to over 500 million USD. Conclusions Using newly approved antibiotic drugs for MDR infections carries a large incremental cost. Additional data to support survival benefit of these drugs are required to justify the price differences. Subgroups of patients who would benefit most from treatment should be defined. Supplementary Information The online version contains supplementary material available at 10.1007/s40121-021-00412-y.

In recent years, new treatment options for both common and rare bone diseases have become available. The sclerostin antibody romosozumab is the most recently approved drug for the therapy of postmenopausal osteoporosis. Its anabolic capacity makes it a promising treatment option for severe osteoporosis. Other sclerostin antibodies for the treatment of rare bone diseases such as osteogenesis imperfecta are currently being investigated. For rare bone diseases such as X‑linked hypophosphatemia (XLH) and hypophosphatasia (HPP), specific therapies are now also available, showing promising data in children and adults with a severe disease course. However, long-term data are needed to assess a sustained benefit for patients.Neue therapeutische Möglichkeiten zur Therapie der Osteoporose, aber auch seltener Knochenerkrankungen stehen neuerdings zu Verfügung. Der Sclerostin-Antikörper Romosozumab wurde unlängst zur Behandlung der postmenopausalen Osteoporose zugelassen. Durch seine osteoanabole Wirkung scheint Romosozumab eine vielversprechende Therapieoption der schweren Osteoporose zu sein. Andere Sclerostin-Antikörper werden derzeit bei seltenen Knochenerkrankungen wie der Osteogenesis imperfecta untersucht. Für den Phosphatdiabetes („X-linked hypophosphatemia“, XLH) und die Hypophosphatasie (HPP) stehen nun spezifische Therapien zur Verfügung, die in den bisherigen Studien überzeugende Ergebnisse zeigten. Langzeitdaten sind jedoch erforderlich, um das Risiko-Nutzen-Profil abschätzen zu können.

Objectives The study sought to learn if it were possible to develop an ontology that would allow the Food and Drug Administration approved indications to be expressed in a manner computable and comparable to what is expressed in an electronic health record. Materials and Methods A random sample of 1177 of the 3000+ extant, distinct medical products (identified by unique new drug application numbers) was selected for investigation. Close manual examination of the indication portion of the labels for these drugs led to the development of a formal model of indications. Results The model represents each narrative indication as a disjunct of conjuncts of assertions about an individual. A desirable attribute is that each assertion about an individual should be testable without reference to other contextual information about the situation. The logical primitives are chosen from 2 categories (context and conditions) and are linked to an enumeration of uses, such as prevention. We found that more than 99% of approved label indications for treatment or prevention could be so represented. Discussion While some indications are straightforward to represent, difficulties stem from the need to represent temporal or sequential references. In addition, there is a mismatch of terminologies between what is present in an electronic health record and in the label narrative. Conclusions A workable model for formalizing drug indications is possible. Remaining challenges include designing workflow to model narrative label indications for all approved drug products and incorporation of standard vocabularies.

Introduction: Perception of illness varies among individuals and psoriasis of the same severity can be perceived in different ways by patients, making it essential to evaluate quality of life (QoL) since it can provide information on the impact of the disease on the patient's overall well-being. The use of patient-reported outcomes in clinical trials provides the ability to integrate objective clinical assessment with the patient's perception of their own state of health. Areas covered: The introduction of anti-IL17 agents in clinical practice has given patients the possibility to achieve a PASI90 response (almost clear skin) or even higher (complete clear skin) in the majority of patients. There is accumulating evidence in support of PASI90 response as the new standard goal for therapy based on its greater correlation with health-related QoL. The present review summarizes current knowledge of the effects of secukinumab on the QoL of patients with psoriasis using patient-reported outcome measures. Expert Opinion: Secukinumab, the first approved drug of this new class, has fully reached a new therapeutic paradigm not only in terms of clinical efficacy, but also in terms of patient satisfaction and self-rated health.

Some of the most prominent and promising catalysts in organic synthesis for the requisite construction of C–C and C–N bonds are palladium (Pd) catalysts, which play a pivotal role in pharmaceutical and medicinal chemistry. Their wide range of selectivities, mild reaction conditions, and simple, efficient, and economical protocols make them desirable for the synthesis of highly functionalized molecules, medicinally important intermediates, pharmaceuticals, and agro-products. Researchers from academia and the pharmaceutical industry have also utilized a wide variety of Pd-catalysts for the synthesis of pharmaceuticals on a small and large scale. This review describes pharmaceuticals approved by the United States Food and Drug Administration (the U.S. FDA) between 2015 and 2020, which were synthesized via Pd-catalyzed cross-coupling reactions for the construction of carbon–carbon (C–C) and carbon–nitrogen (C–N) bonds. The review includes both medicinal chemistry routes and patented routes on a bulk scale. Along with details of the synthetic protocols of coupling reactions, the medicinal properties of each approved drug are discussed.

The mTOR (mammalian or mechanistic Target of Rapamycin) is linked with oral cancer. Therefore, it is of interest to study the molecular docking-based binding of paclitaxel (a FDA approved drug for oral cancer) and its analogues with mTOR. Hence, we report the binding features of 10-Deacetyltaxol, 7-Epi-10-deacetyltaxol, 7-Epi-Taxol and 6alpha-Hydroxypaclitaxel with mTOR for further consideration.

In the last few years, several studies emerged for the treatment of interstitial lung disease (ILD) associated with systemic sclerosis (SSc). Some of the studied drugs showed efficacy compared to placebo or to a control group. Since early 2020, nintedanib has been approved for the treatment of SSc-ILD. Although several drugs are used to treat SSc-LD, it is now the first approved drug for SSc-ILD. Here, we aim to provide an overview about our current therapy algorithm and strategy as well as our interpretation of study results as an experienced SSc-ILD center.

Given the COVID-19 pandemic, currently, there are many drugs in clinical trials against this virus. Among the excellent drug targets of SARS-CoV-2 are its proteases (Nsp3 and Nsp5) that plays vital role in polyprotein processing giving rise to functional nonstructural proteins, essential for viral replication and survival. Nsp5 (also known as Mpro) hydrolyzes replicase polyprotein (1ab) at eleven different sites. For targeting Mpro, we have employed drug repurposing approach to identify potential inhibitors of SARS-CoV-2 in a shorter time span. Screening of approved drugs through docking reveals Hyaluronic acid and Acarbose among the top hits which are showing strong interactions with catalytic site residues of Mpro. We have also performed docking of drugs Lopinavir, Ribavirin, and Azithromycin on SARS-CoV-2 Mpro. Further, binding of these compounds (Hyaluronic acid, Acarbose, and Lopinavir) is validated by extensive molecular dynamics simulation of 500 ns where these drugs show stable binding with Mpro. We believe that the high-affinity binding of these compounds will help in designing novel strategies for structure-based drug discovery against SARS-CoV-2. Communicated by Ramaswamy H. Sarma

In the last thirty years, obesity has reached epidemic proportions and is now regarded as a major health issue in contemporary society trending to serious economic and social burdens. The latest projections of the World Health Organization are alarming. By 2030, nearly 60% of the worldwide population could be either obese or overweight, highlighting the needs to find innovative treatments. Currently, bariatric surgery is the most effective way to efficiently lower body mass. Although great improvements in terms of recovery and patient care were made in these surgical procedures, bariatric surgery remains an option for extreme forms of obesity and seems unable to tackle obesity pandemic expansion. Throughout the last century, numerous pharmacological strategies targeting either peripheral or central components of the energy balance regulatory system were designed to reduce body mass, some of them reaching sufficient levels of efficiency and safety. Nevertheless, obesity drug therapy remains quite limited on its effectiveness to actually overcome the obesogenic environment. Thus, innovative unimolecular polypharmacology strategies, able to simultaneously target multiple actors involved in the obesity initiation and expansion, were developed during the last ten years opening a new promising avenue in the pharmacological management of obesity. In this review, we first describe the clinical features of obesity-associated conditions and then focus on the outcomes of currently approved drug therapies for obesity as well as new ones expecting to reach the clinic in the near future.

Background One of the major challenges in pediatric treatment is the lack of suitable drug preparations specifically designed and marketed for children. Most of the FDA approved drug formulations for adults have not been approved for use in pediatric patients. Shortage of suitable pediatric dosage information often leads health professionals to use adult formulations in an off-label manner. The aim of this work was to review the safety and biopharmaceutical challenges of commonly found excipients in off-label pediatric formulations as well as to show the current progress to alleviate pediatric toxicity related to excipients. Methods Research findings and medical case reports were searched from credible sources including Scopus, PubMed, OVID, Google Scholar, Embase, Cochrane Library, and Web of Science. Results As several studies and clinical case reports have revealed, off-label adult formulations usage causes pediatric patients to become exposed to potentially harmful excipients, which are essential components of drug products. In addition to their toxicities, some of the excipients affect the biopharmaceutical property of different drugs. Immature organ and body composition, large body surface area and slower metabolism and elimination capabilities of pediatrics are the main causes of toxicities associated with different excipients. Recent studies have also shown that good progress is being made to develop safe and suitable excipients for pediatric use. Conclusion A risk and benefit assessment should be done before using off-label formulation as excipients cause mild to severe toxicities and biopharmaceutical problems to pediatric patients.

Remdesivir is presently been considered as ‘molecule of hope’ to curb the menace of COVID19. Non-availability of any USFDA approved drug has led to several attempt of drug-repurposing and development of new therapeutic molecules. However, Remdesivir has been found to be effective against a broad range of virus including SARS, MERS and COVID 19 through in-vitro studies. Several clinical research attempt are presently being conducted showing promising result yet not conclusive. This review summarized all such clinical trials to critically appraise the usage of Remdesivir against COVID 19 along with the publications related to the results of the clinical studies. The present regulatory aspect i. e. Emergency Use Authorization (EYA) and information of molecule and plausible mechanism is also dealt.

One of the most prominent topics in drug discovery is efficient exploration of the vast drug-like chemical space to find synthesizable and novel chemical structures with desired biological properties. To address this challenge, we created the DrugSpaceX (https://drugspacex.simm.ac.cn/) database based on expert-defined transformations of approved drug molecules. The current version of DrugSpaceX contains >100 million transformed chemical products for virtual screening, with outstanding characteristics in terms of structural novelty, diversity and large three-dimensional chemical space coverage. To illustrate its practical application in drug discovery, we used a case study of discoidin domain receptor 1 (DDR1), a kinase target implicated in fibrosis and other diseases, to show DrugSpaceX performing a quick search of initial hit compounds. Additionally, for ligand identification and optimization purposes, DrugSpaceX also provides several subsets for download, including a 10% diversity subset, an extended drug-like subset, a drug-like subset, a lead-like subset, and a fragment-like subset. In addition to chemical properties and transformation instructions, DrugSpaceX can locate the position of transformation, which will enable medicinal chemists to easily integrate strategy planning and protection design.

Since the first case reports in Wuhan, China, the SARS-CoV-2 has caused a pandemic and took lives of > 8,35,000 people globally. This single-stranded RNA virus uses Angiotensin-converting enzyme 2 (ACE2) as a receptor for entry into the host cell. Overexpression of ACE2 is mainly observed in hypertensive, diabetic and heart patients that make them prone to SARS-CoV-2 infection. Mitigations strategies were opted globally by the governments to minimize transmission of SARS-CoV-2 via the implementation of social distancing norms, wearing the facemasks, and spreading awareness using digital platforms. The lack of an approved drug treatment regimen, and non-availability of a vaccine, collectively posed a challenge for mankind to fight against the SARS-CoV-2 pandemic. In this scenario, repurposing of existing drugs and old treatment options like convalescent plasma therapy can be one of the potential alternatives to treat the disease. The drug repurposing provides a selection of drugs based on the scientific rationale and with a shorter cycle of clinical trials, while plasma isolated from COVID-19 recovered patients can be a good source of neutralizing antibody to provide passive immunity. In this review, we provide in-depth analysis on these two approaches currently opted all around the world to treat COVID-19 patients. For this, we used “Boolean Operators” such as AND, OR & NOT to search relevant research articles/reviews from the PUBMED for the repurposed drugs and the convalescent plasma in the COVID-19 treatment. The repurposed drugs like Chloroquine and Hydroxychloroquine, Tenofovir, Remdesivir, Ribavirin, Darunavir, Oseltamivir, Arbidol (Umifenovir), Favipiravir, Anakinra, and Baricitinib are already being used in clinical trials to treat the COVID-19 patients. These drugs have been approved for a different indication and belong to a diverse category such as anti-malarial/anti-parasitic, anti-retroviral/anti-viral, anti-cancer, or against rheumatoid arthritis. Although, the vaccine would be an ideal option for providing active immunity against the SARS-CoV-2, but considering the current situation, drug repurposing and convalescent plasma therapy and repurposed drugs are the most viable option against SARS-CoV-2. Electronic supplementary material The online version of this article (10.1007/s11010-020-03924-2) contains supplementary material, which is available to authorized users.

On the basis of official Finnish Medicines Authority (Fimea)-approved drug monographs, less than half of the approved small-molecule drugs between 2007 and 2016 were substrates, inhibitors or inducers of CYP enzymes, predominantly of CYP3A4. No significant unexpected, life-threatening, CYP-associated drug-drug interactions (CYP-DDIs) of newly approved drug entities have been observed in the last 10–15 years. The present analysis seems to suggest that tools to study and predict potentially significant CYP-DDIs are working and efficient.

Antimalarial drugs Chloroquine and Hydroxychloroquine have garnered most attention recently as a successful remedy for COVID19. However, the use of these drugs is still questionable due to its undetermined efficacy and side effects. The present study utilizes in-silico high throughput screening of FDA approved antiviral compounds and secondary plant metabolites against spike protein of novel coronavirus (SARS-CoV-2). This target was chosen because it is instrumental in entry of virus into human cells. It is observed that the plant compound Tocopheryl-curcumin has more affinity for spike protein of SARS-CoV-2 in comparison to the majority of FDA approved drugs. Tocopheryl-curcumin binds with the binding site of RBD domain of spike protein (6VSB, chain A) with free energy (∆G) of binding of -11.20 kcal/mol and makes strong hydrogen bonds with amino acid residues of S366, V367, L368, S373, and K529. Among the FDA approved drugs, Pibrentasvir obtains top rank with free energy (∆G) of binding of -9.69 kcal/mol. whereas; surprisingly Chloroquine (-6.87 kcal/mol) and Hydroxychloroquine (-7.24 kcal/mol) ranked lower in our docking study. The toxicity prediction by VEGA predicts that tocopheryl-curcumin shows no toxicity as compared to FDA approved drugs. Therefore, we infer that the plant-based tocopheryl-curcumin could be considered as potential and safer drug against COVID 19 disease as compared to chemical based drugs.

An acute respiratory disease (SARS-CoV-2, also recognized as COVID-19/2019-nCoV), caused by nCoV created a worldwide emergency. The World Health Organization declared the SARS-CoV-2 as epidemic of international concern on January 2020. After SARS-CoV in 2002 and MERS-CoV in 2012, the emergence of SARS-CoV-2 is marked as third highly pathogenic coronavirus of 21st century. Till now, various researches have been conducted, highlighting SARS-CoV-2 as β-coronavirus with high phylogenetic and genomic similarity with bat-CoV, indicating bats as natural reservoir of coronaviruses. It has also been confirmed that SARS-CoV-2 uses the same (ACE2) receptor for host cellular entry as of SARS-CoV, and primarily spread through respiratory pathway. Evidences shows continuous human-to-human viral transfer, with numerous worldwide exported cases. Currently, there is no specific approved drug available for the treatment of SARS-CoV-2, but various anti-parasitic and anti-viral drugs are being investigated. In this review, we have described several possible therapeutic modalities for SARS-CoV-2 infection based on (i) host protease inhibitors to block viral entry into the cell; (ii) gene silencing using siRNA-based RNAi and (iii) type I interferons (IFN1)-based therapeutics have been discussed in detail. Background knowledge on these strategies highlight them as potential therapeutic targets, which could be evaluated on urgent basis to combat COVID-19 epidemic.

The whole world is currently facing a pandemic of an infectious disease known as novel coronavirus disease-2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) . This outbreak emerged unexpectedly and imposed a potential threat to humans, associated with the social and economic burden on the individual and federal governments. COVID-19, which initially started in Wuhan City of China and then spread to the whole world, has been declared a Public Health Emergency of International Concern. The continuous increase in the number of confirmed cases leads to high mortality across the world. Growing evidence indicates that the mortality rate is very predominant in elderly people and those with preexisting health conditions. However, the potential pathogenesis of SARS-CoV-2 infection in humans is still unknown. The dysregulated/exuberant immune response may have substantially contributed to the SARS-CoV-2-mediated pathology. Nevertheless, there is no clinically approved drug/vaccine currently available that can restrict its pathogenesis. However, several drugs are currently shown to provide some therapeutic benefits for COVID-19 patients, including antiviral drugs that might have a significant role in restricting the current pandemic of COVID-19. In this article, we highlighted the pharmacological treatment strategies for COVID-19 and purposed the therapeutic targets for the development of vaccines or anti-viral drug molecules against SARS-CoV-2 infection in humans.

Despite strict measures taken by many countries, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to be an issue of global concern. Currently, there are no clinically proven pharmacotherapies for coronavirus disease 2019, despite promising initial results obtained from drugs such as azithromycin and hydroxychloroquine. Therefore, the repurposing of clinically approved drugs for use against SARS-CoV-2 has become a viable strategy. Here, we searched for drugs that target SARS-CoV-2 3C-like protease (3CL(pro)) and viral RNA-dependent RNA polymerase (RdRp) by in silico screening of the U.S. Food and Drug Administration approved drug library. Well-tolerated and widely used drugs were selected for molecular dynamics (MD) simulations to evaluate drug-protein interactions and their persistence under physiological conditions. Tetracycline, dihydroergotamine, ergotamine, dutasteride, nelfinavir, and paliperidone formed stable interactions with 3CL(pro)based on MD simulation results. Similar analysis with RdRp showed that eltrombopag, tipranavir, ergotamine, and conivaptan bound to the enzyme with high binding free energies. Docking results suggest that ergotamine, dihydroergotamine, bromocriptine, dutasteride, conivaptan, paliperidone, and tipranavir can bind to both enzymes with high affinity. As these drugs are well tolerated, cost-effective, and widely used, our study suggests that they could potentially to be used in clinical trials for the treatment of SARS-CoV-2-infected patients., NA

The Corona virus Disease (COVID-19) is caused because of novel coronavirus (SARS-CoV-2) pathogen detected in China for the first time, and from there it spread across the globe creating a worldwide pandemic of severe respiratory complications. The virus requires structural and non-structural proteins for its multiplication that are produced from polyproteins obtained by translation of its genomic RNA. These polyproteins are converted into structural and non-structural proteins mainly by the main protease (Mpro). A systematic screening of a drug library (having drugs and diagnostic agents which are approved by FDA or other world authorities) and the Asinex BioDesign library was carried out using pharmacophore and sequential conformational precision level filters using the Schrodinger Suite. From the screening of approved drug library, three antiviral agents ritonavir, nelfinavir and saquinavir were predicted to be the most potent Mpro inhibitors. Apart from these pralmorelin, iodixanol and iotrolan were also identified from the systematic screening. As iodixanol and iotrolan carry some limitations, structural modifications in them could lead to stable and safer antiviral agents. Screenings of Asinex BioDesign library resulted in 20 molecules exhibiting promising interactions with the target protein Mpro. They can broadly be categorized into four classes based on the nature of the scaffold, viz. disubstituted pyrazoles, cyclic amides, pyrrolidine-based compounds and miscellaneous derivatives. These could be used as potential molecules or hits for further drug development to obtain clinically useful therapeutic agents for the treatment of COVID-19. Graphic abstract Electronic supplementary material The online version of this article (10.1007/s11030-020-10130-1) contains supplementary material, which is available to authorized users.

TB is the 9th leading cause of death worldwide above HIV/AIDS. Tuberculosis (TB) management remains challenging due to the emergence of drug-resistant tuberculosis such as MDR-TB and XDR-TB. To improvise therapeutic results for MDR/XDR-TB, 89 nations had started utilizing bedaquiline and 54 had utilized delamanid by June 2017. Unfortunately, cardiac arrhythmia was found to be the most serious side effect associated with the both drugs restricting their use for the management of MDR- and XDR-TB. The current review discussed the clinically trialed and approved drug for the treatment of XDR-TB, recently reported compounds against XDR-TB, their synthesis and activity spectrum. This information could be helpful to the medicinal chemist in synthesizing the best XDR-TB inhibitors free from resistance and toxicity.

In the last thirty years, obesity has reached epidemic proportions and is now regarded as a major health issue in contemporary society trending to serious economic and social burdens. The latest projections of the World Health Organization are alarming. By 2030, nearly 60% of the worldwide population could be either obese or overweight, highlighting the needs to find innovative treatments. Currently, bariatric surgery is the most effective way to efficiently lower body mass. Although great improvements in terms of recovery and patient care were made in these surgical procedures, bariatric surgery remains an option for extreme forms of obesity and seems unable to tackle obesity pandemic expansion. Throughout the last century, numerous pharmacological strategies targeting either peripheral or central components of the energy balance regulatory system were designed to reduce body mass, some of them reaching sufficient levels of efficiency and safety. Nevertheless, obesity drug therapy remains quite limited on its effectiveness to actually overcome the obesogenic environment. Thus, innovative unimolecular polypharmacology strategies, able to simultaneously target multiple actors involved in the obesity initiation and expansion, were developed during the last ten years opening a new promising avenue in the pharmacological management of obesity. In this review, we first describe the clinical features of obesity-associated conditions and then focus on the outcomes of currently approved drug therapies for obesity as well as new ones expecting to reach the clinic in the near future.

Introduction: During the first half of the last decade the p38 MAP kinase family was a very popular target in academic as well as industrial research programs. Many attempts to achieve marketing authorization for a p38 MAPK inhibitor for the treatment of pro-inflammatory diseases, like rheumatoid arthritis (RA), failed at the state of clinical trials, mostly due to selectivity and/or toxicity issues.Areas covered: Herein, the patents and corresponding publications of international companies, universities and other research institutions, which focus on the development, identification and optimization of new selective p38 inhibitors and their fields of use are summarized.Expert opinion: p38 MAP kinase inhibitors are a mature field with many pre-clinically validated structural classes, more than 20 candidates in clinical trials but still (except the weak and unselective p38 inhibitor pirfenidone) no approved drug. Big Pharma hasn't contributed much to the patents of the last five years but remarkable contribution have come from academic environment or small biotech companies. Three general punchlines of innovation have shown up. Tailor-made molecules with properties for local application, mainly type-II (Urea-type) inhibitors for lung- or skin diseases, isoform p38γ,δ-selective inhibitors for the treatment of cutaneous t-cell lymphoma (CTCL) and substrate-specific inhibitors (e.g. p38/MK2).

Purpose: SARS-CoV-2 first emerged in China in December 2019 and rapidly spread worldwide. No vaccine or approved drug is available to eradicate the virus, however, some drugs that are indicated for other afflictions seems to be potentially beneficial to treat the infection albeit without unequivocal evidence. The aim of this article is to review the published background on the effectiveness of these drugs against COVID-19 Methods: A thorough literature search was conducted on recently published studies which have published between January 1 to March 25, 2020. PubMed, Google Scholar and Science Direct databases were searched Results: A total 22 articles were found eligible. 8 discuss about treatment outcomes from their applied drugs during treatment of COVID-19 patients, 4 report laboratory tests, one report animal trial and other 9 articles discuss recommendations and suggestions based on the treatment process and clinical outcomes of other diseases such as malaria, ebola, severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). The data and/or recommendations are categorized in 4 classes: (a) anti-viral and anti-inflammatory drugs, (b) anti-malaria drugs, (c) traditional Chinese drugs and (d) other treatments/drugs. Conclusion: All examined treatments, although potentiality effective against COVID-19, need either appropriate drug development or clinical trial to be suitable for clinical use.

Background As real-world data resources expand and improve, there will increasingly be opportunities to study the effectiveness of interventions. There is a need to ensure that study designs explore potential sources of bias and either acknowledge or mitigate them, in order to improve the accuracy of findings. The objective of this study was to understand newly approved drug utilization patterns in real-world clinical settings over time. Methods This retrospective study included three sources of real-world data (claims, electronic health records, and recoded data from a quality care program) collected from patients diagnosed with gastric cancer who initiated therapy with either trastuzumab or ramucirumab. Linear regression was used to investigate trends in the use of these drugs for the care of patients with gastric cancer over time from Food and Drug Administration (FDA) approval. Results Eligible patients (n=1700) had consistent demographic and clinical characteristics over time. After regulatory approval, trastuzumab was used in later lines of therapy and then shifted to earlier lines (p=0.002), while ramucirumab utilization remained consistent over time after FDA approval (p=0.49). Ramucirumab augmentation, defined as the addition of the drug after initiation of a line of therapy, decreased over time (p=0.03), and trastuzumab augmentation remained consistent over time (p=0.58). Conclusion Since treatment effectiveness may change across lines of treatment, bias may arise if there are changes in the use of the drug (such as line migration) during the time period of analysis using real-world data.

The time and cost of developing new drugs have led many groups to limit their search for therapeutics to compounds that have previously been approved for human use. Many “repurposed” drugs, such as derivatives of thalidomide, antibiotics, and antivirals have had clinical success in treatment areas well beyond their original approved use. These include applications in treating antibiotic‐resistant organisms, viruses, cancers and to prevent burn scarring. The major theoretical justification for reusing approved drugs is that they have known modes of action and controllable side effects. Coadministering antibiotics with inhibitors of bacterial toxins or enzymes that mediate multidrug resistance can greatly enhance their activity. Drugs that control host cell pathways, including inflammation, tumor necrosis factor, interferons, and autophagy, can reduce the “cytokine storm” response to injury, control infection, and aid in cancer therapy. An active compound, even if previously approved for human use, will be a poor clinical candidate if it lacks specificity for the new target, has poor solubility or can cause serious side effects. Synergistic combinations can reduce the dosages of the individual components to lower reactivity. Preclinical analysis should take into account that severely ill patients with comorbidities will be more sensitive to side effects than healthy trial subjects. Once an active, approved drug has been identified, collaboration with medicinal chemists can aid in finding derivatives with better physicochemical properties, specificity, and efficacy, to provide novel therapies for cancers, emerging and rare diseases.

Cancer is a leading cause of death worldwide, and the incidence continues to increase. Despite major research aimed at discovering and developing novel and effective anticancer drugs, oncology drug development is a lengthy and costly process, with high attrition rates. Drug repositioning (DR, also referred to as drug repurposing), the process of finding new uses for approved noncancer drugs, has been gaining popularity in the past decade. DR has become a powerful alternative strategy for discovering and developing novel anticancer drug candidates from the existing approved drug space. Indeed, the availability of several large established libraries of clinical drugs and rapid advances in disease biology, genomics/transcriptomics/proteomics and bioinformatics has accelerated the pace of activity‐based, literature‐based and in silico DR, thereby improving safety and reducing costs. However, DR still faces financial obstacles in clinical trials, which could limit its practical use in the clinic. Here, we provide a brief review of DR in cancer and discuss difficulties in the development of DR for clinical use. Furthermore, we introduce some promising DR candidates for anticancer therapy in Japan., We provide a brief review of drug repositioning (DR) in cancer and discuss difficulties in the development of DR for clinical use. Furthermore, we introduce some promising DR candidates for anticancer therapy in Japan.

Pretomanid (PA-824) is the recently (2019) approved drug for the treatment of extensively drug-resistant (XDR) TB and the multidrug-resistant (MDR) TB by US FDA. The experimental data of antitubercular activity of 543 pretomanid derivatives (total 6 datasets) against replicating (active) and non-replicating (dormant) forms of Mycobacterium tuberculosis (strain H37Rv) are available in the literature. Such vast experimental data of pretomanid derivatives against both of these endpoints, and recent approval of pretomanid molecule as a drug encouraged us to utilize this existing experimental information for the development of the 3D-pharmacophore models. The developed model (Hypo-1, MABA) showed the three physicochemical features namely, the oxygen atom of nitro group (HBA_1), fused pyran ring of imidazopyran heterocycle (HYAl_2) and the 4-fluorophenyl moiety (HYAr_3) are crucial for the antitubercular activity against replicating M. tb. Subsequently, the pharmacophore model (Hypo-1, LORA) developed against the non-replicating form of M. tb also showed the contribution of three physicochemical features namely, the 4-tri-fluoromethyl group (HYAl_2) and both the phenyl groups (HYAr_3, HYAr_4) of biaryl moiety in increasing the antitubercular activity. Both the pharmacophoric classifier models showed the classification accuracies of 82.98 and 74.42% for the training set compounds, and 63.91 and 61.60% for the test set compounds respectively, for labelling the compounds into higher and lower active classes. Both the models were also found to be retaining the higher active compounds in top 1.00% of the total number of compounds (decoys and actives), after performing the decoy set screening. Communicated by Ramaswamy H. Sarma

The rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a significant worldwide health concern in recent months. The world has not dealt with such adversities since World War II. The spread has had a devastating and massive impact on global health, the economy, and people's everyday lives. With the crisis looming around the world, there is not yet any report of a clinically approved drug effective against this virus or or vaccine that can prevent people from getting infected. In this article, we describe different types of diagnostic tests currently used to detect SARS-CoV-2 infection. We also present an overview of the basic principles involved, advantages, and the pitfalls associated with each technique. This article also provides an insight into various supplementary diagnostic modalities, including recent advancements in sensing technologies and further clinical improvement and novelties to fight this pandemic.

COVID-19 has caused lockdowns all over the world in early 2020, as a global pandemic. Both theoretical and experimental efforts are seeking to find an effective treatment to suppress the virus. In silico drug design can play a vital role in identifying promising drug candidates against COVID-19. Herein, we focused on the main protease of SARS-CoV-2 that has crucial biological functions in the virus. We performed a ligand-based virtual screening followed by a docking screening for testing approved drugs and bioactive compounds listed in the DrugBank and ChEMBL databases. The top 8 docking results were advanced to all-atom MD simulations to study the relative stability of the protein-ligand interactions. MD simulations support that the catalytic residue, His41, has a neutral side chain with a protonated delta position. An absolute binding energy (ΔG) of -42 kJ mol-1 for the protein-ligand (Mpro-N3) complex has been calculated using the potential-of-mean-force (geometrical) approach. Furthermore, the relative binding energies were computed for the top docking results. Our results suggest several promising approved and bioactive inhibitors of SARS-CoV-2 Mpro as follows: a bioactive compound, ChEMBL275592, which has the best MM/GBSA binding energy; the second-best compound, montelukast, is an approved drug used in the treatment of asthma and allergic rhinitis; the third-best compound, ChEMBL288347, is a bioactive compound. Bromocriptine and saquinavir are other approved drugs that also demonstrate stability in the active site of Mpro, albeit their relative binding energies are low compared to the N3 inhibitor. This study provides useful insights into de novo protein design and novel inhibitor development, which could reduce the cost and time required for the discovery of a potent drug to combat SARS-CoV-2.