A Graph Convolutional Network-based screening strategy for rapid identification of SARS-CoV-2 cell-entry inhibitors

The cell entry of SARS-CoV-2 has emerged as an attractive drug development target. We previously reported that the entry of SARS-CoV-2 depends on the cell surface heparan sulfate proteoglycan (HSPG) and the cortex actin, which can be targeted by therapeutic agents identified by conventional drug repurposing screens. However, this drug identification strategy requires laborious library screening, which is time-consuming and often limited number of compounds can be screened. As an alternative approach, we developed and trained a graph convolutional network (GCN)-based classification model using information extracted from experimentally identified HSPG and actin inhibitors. This method allowed us to virtually screen 170,000 compounds, resulting in ~2000 potential hits. A hit confirmation assay with the uptake of a fluorescently labeled HSPG cargo further shortlisted 256 active compounds. Among them, 16 compounds had modest to strong inhibitory activities against the entry of SARS-CoV-2 pseudotyped particles into Vero E6 cells. These results establish a GCN-based virtual screen workflow for rapid identification of new small molecule inhibitors against validated drug targets.

Methods for Identifying Culprit Drugs in Cutaneous Drug Eruptions: A Scoping Review

Background Cutaneous drug eruptions are a significant source of morbidity, mortality, and cost to the healthcare system. Identifying the culprit drug is essential; however, despite numerous methods being published, there are no consensus guidelines. Objectives Conduct a scoping review to identify all published methods of culprit drug identification for cutaneous drug eruptions, compare the methods, and generate hypotheses for future causality assessment studies. Eligibility criteria Peer-reviewed publications involving culprit drug identification methods. Sources of evidence Medline, Embase, and Cochrane Central Register of Controlled Trials. Charting methods Registered PRISMA-ScR format protocol on Open Science Forum. Results In total, 109 studies and 26 reviews were included comprising 656,635 adverse drug events, most of which were cutaneous. There were 54 methods of culprit drug identification published, categorized as algorithms, probabilistic approaches, and expert judgment. Algorithms had higher sensitivity and positive predictive value, but lower specificity and negative predictive value. Probabilistic approaches had lower sensitivity and positive predictive value, but higher specificity and negative predictive value. Expert judgment was subjective, less reproducible, but the most frequently used to validate other methods. Studies suggest that greater accuracy may be achieved by specifically assessing cutaneous drug eruptions and using combinations of causality assessment categories. Conclusions Culprit drug identification for adverse drug reactions remains a challenge. Many methods have been published, but there are no consensus guidelines. Using causality assessment methods specifically for cutaneous drug eruptions and combining aspects of the different causality assessment categories may improve efficacy. Further studies are needed to validate this hypothesis.

An Insight into Antioxidant and Antimicrobial Activities of Ethnotherapeutically Important Trans Himalayan Medicinal Plants: A Review

The high altitude of the Himalayan cold desert represents a valuable habitat of natural resources. The extreme climatic condition manifested by intense mutagenic UV-radiation, physiological drought, desiccation and strong winds, makes the survival of plants really difficult. As a consequence of this atmospheric stressor, the plants produce unique metabolites which play a preventive role in intrinsic mechanism of sustenance. Many plant species of this region have been investigated in search of novel antioxidants and antimicrobials. Plants synthesize several antioxidants that aid in antioxidant defense system, thereby protecting plants against damage caused by active ROS. These compounds include chlorophyll derivatives, alkaloids, essential oils, phytosterols, phenolics and polyphenolics. Some of the antioxidants that have been isolated from plants include curcumin, quercetin, ascorbic acid, resveratrol amongst many other compounds. Additionally, the emergence of resistance to multiple antimicrobial agents has become a major threat to public health. Hence, fresh efforts towards new drug identification and development are greatly needed. Plants have long been used in traditional Indian medicine for numerous therapeutic benefits and low toxicity. Considering the growing interest in quest for search of plant based antimicrobials and antioxidants; an effort has been carried to systematically record the antioxidants and antimicrobial potential of plants of Himalayan region.

Loss or Theft of Controlled Substances Declared to Health Canada From 2014 to 2018: A Retrospective Study

Theft of prescription drugs is nothing new for Canadian pharmacists. Recently, an increasing body of literature has covered the diversion of controlled substances from Canadian hospitals. However, little has been published in the scientific literature concerning the data collected by Health Canada’s Loss or Theft Report Program regulated under the Controlled Drugs and Substances Act. Data from January 1, 2014, to December 31, 2018, were obtained from Health Canada’s Office of Controlled Substances (OCS). Reports to the OCS are mostly provided by pharmacies and hospitals, by veterinarian, dental, and physician clinics, pharmaceutical distributors and producers, and federal establishments and organizations. Entries include information related to the date, province, and location type; type of loss or theft; and generic name of the product, its strength, dosage form, quantity, and drug identification number. During the studied period, 45,379 submissions to the OCS provided information to create 213,895 entries to the database. After exclusions, 212,317 reports were retained for analysis. Opioids count for 45% of reports, benzodiazepines for 29%, and psychostimulants for 21%. Approximately, 29 million individual doses were lost or stolen of which 7.7 million were opioids (26%), totalizing approximately 178 million oral morphine milligram equivalents with 95% having been lost or stolen in community pharmacies. Moreover, approximately four out of 10 individual doses lost in community pharmacies are unexplained losses, which represent about 4.6 million individual doses. Reporting lost or stolen controlled substances and precursors is essential to tracking the diversion of Canada’s prescription drugs. Pharmacists therefore have an important role to play when it comes to minimizing their potential diversion. A better understanding of the situation across Canada may help to increase health care professionals’ awareness, improve practices, enhance the quality of collected data, and prevent further losses and thefts.

A COVID-19 Drug Repurposing Strategy Through Quantitative Homological Similarities by using a Topological Data Analysis Based Formalism

Since its emergence in March 2020, the SARS-CoV-2 global pandemic has produced more than 65 million cases and one point five million deaths worldwide. Despite the enormous efforts carried out by the scientific community, no effective treatments have been developed to date. We created a novel computational pipeline aimed to speed up the process of repurposable candidate drug identification. Compared with current drug repurposing methodologies, our strategy is centered on filtering the best candidate among all selected targets focused on the introduction of a mathematical formalism motivated by recent advances in the fields of algebraic topology and topological data analysis (TDA). This formalism allows us to compare three-dimensional protein structures. Its use in conjunction with two in silico validation strategies (molecular docking and transcriptomic analyses) allowed us to identify a set of potential drug repurposing candidates targeting three viral proteins (3CL viral protease, NSP15 endoribonuclease, and NSP12 RNA-dependent RNA polymerase), which included rutin, dexamethasone, and vemurafenib among others. To our knowledge, it is the first time that a TDA based strategy has been used to compare a massive amount of protein structures with the final objective of performing drug repurposing