Drug Design against Covid-19: A Remote Teaching Experience in Pharmaceutical Chemistry

Infront of with the difficulties faced in making a new drug available to the population, it is essential to seek ways to simplify the process. In silico methodologies are alternatives to benchtop experiments, being frequently used due to their speed and low cost. The present study aimed to formulate a theoretical-practical activity in the Pharmaceutical Chemistry course, where students applied their knowledge of structural modeling and molecular docking to propose bioactive compounds against molecular targets of the SARS-CoV-2 virus. The class was divided, and each group presented a drug candidate, the precursors being natural molecules. In total, seven derivatives were designed and tested against different macromolecules, and then an in silico prediction of their physicochemical characteristics was performed. The docking results were positive for all derivatives, in terms of binding energy, mainly GEND with -9.0 kcal mol-1. In addition, the prototypes exhibited good interactions with the amino acids of the respective targets, mainly KAED, QUED and GEND, in addition to presenting adequate physicochemical properties for meeting the Lipinski restrictions. Therefore, this study presented at least three potential inhibitors of SARS-CoV-2, showing the importance of using computational tools in drug design and development, as well as in teaching practice.

Technologies for Direct Detection of Covalent Protein-Drug Adducts.

In the past two decades, drug candidates with a covalent binding mode have gained the interest of medicinal chemists, as several covalent anticancer drugs have successfully reached the clinic. As a covalent binding mode changes the relevant parameters to rank inhibitor potency and investigate structure-activity relationship (SAR), it is important to gather experimental evidence on the existence of a covalent protein-drug adduct. In this work, we review established methods and technologies for the direct detection of a covalent protein-drug adduct, illustrated with examples from (recent) drug development endeavors. These technologies include subjecting covalent drug candidates to mass spectrometric (MS) analysis, protein crystallography, or monitoring intrinsic spectroscopic properties of the ligand upon covalent adduct formation. Alternatively, chemical modification of the covalent ligand is required to detect covalent adducts by NMR analysis or activity-based protein profiling (ABPP). Some techniques are more informative than others and can also elucidate the modified amino acid residue or bond layout. We will discuss the compatibility of these techniques with reversible covalent binding modes and the possibilities to evaluate reversibility or obtain kinetic parameters. Finally, we expand upon current challenges and future applications. Overall, these analytical techniques present an integral part of covalent drug development in this exciting new era of drug discovery.

Team-based learning-adopted strategy in pharmacy education: pharmacology and medicinal chemistry students' perceptions.

Background: Team-based learning (TBL) provides an advanced teaching method for healthcare education; it is characterised by being an interactive teaching session that allows groups of learners to work together in teams to discuss and apply what they have learnt to certain clinical scenarios. The following study aims to evaluate the impact of TBL strategy on the students' comprehension and acquired knowledge, to allow better application and integration of knowledge. The aim of the study was to improve pharmacy students' skills in achieving learning outcomes by adapting TBL pedagogy in the lectures. Students' feedbacks were collected via post-lecture survey. Results: The study was applied to pharmacy students covering two courses: Pharmacology III (Level 4) and Medicinal Chemistry I (Level 3) in a period of two-week lectures through the first semester of the academic year 2021/2022 in Future University in Egypt. The selected topics-related preparation materials were previously available on each course moodle page prior to the actual lecture, for the students to get prepared including growth hormone, sex hormones and their associated diseases for the pharmacology course and COVID-19 management for the Medicinal Chemistry course. The TBL lecture was started by dividing the students into teams and then readiness assurance tests were given, as individual readiness assurance test and then team readiness assurance test conceptual test were applied. The assessment of the students' decision-making skills and problem solving was evaluated through solving-related clinical cases. All the learning outcomes were achieved with maximum participation and interaction via an open discussion between the lecturer and the students during the lecture. A total of 116 students answered the survey and confirmed their satisfaction, better understanding and more participation in TBL lectures compared to other topics taught with the ordinary methods. More than half of the students recommended the TBL method for better perception and participation. Conclusion: The students felt great appreciation for the team-based lecturing. Also, recommendations and suggestions were directed towards increasing the percentage of TBL lectures in the curriculum, as it helped them to concentrate more with high participation levels.

Natural Products as Potential Therapeutic Agents for SARS-CoV-2: A Medicinal Chemistry Perspective.

Coronavirus is a single-stranded RNA virus discovered by virologist David Tyrrell in 1960. Till now seven human corona viruses have been identified including HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV, MERS-CoV and SARS-CoV-2. In the present scenario, the SARS-CoV-2 outbreak causing SARS-CoV-2 pandemic, became the most serious public health emergency of the century worldwide. Natural products have long history and advantages for the drug discovery process. Almost 80% of drugs present in market are evolved from the natural resources. With the outbreak of SARS-CoV-2 pandemic, natural product chemists have made significant efforts for the identification of natural molecules which can be effective against the SARS-CoV-2. In current compilation we have discussed in vitro and in vivo anti-viral potential of natural product-based leads for the treatment of SARS-CoV-2. We have classified these leads in different classes of natural products such as alkaloids, terpenoids, flavonoids, polyphenols, quinones, cannabinoids, steroids, glucosinolates, diarylheptanoids, etc. and discussed the efficacy and mode of action of these natural molecules. The present review will surely opens new direction in future for the development of promising drug candidates particularly from the natural origin against coronaviruses and other viral diseases.

Computational tools for aptamer identification and optimization

Aptamers are single-stranded DNA or RNA oligonucleotides that can selectively bind to a specific target. They are generally obtained by SELEX, but the procedure is challenging and time-consuming. Moreover, the identified aptamers tend to be insufficient in stability, specificity, and affinity. Thus, only a handful of aptamers have entered the practical use stage. Recently, computational approaches have demonstrated a significant capacity to assist in the discovery of high-performance aptamers. This review discusses the advances achieved in several aspects of computational tools in this field, as well as the new progress in machine learning and deep learning, which are used in aptamer identification and optimization. To illustrate these computationally aided processes, aptamer selections against SARS-CoV-2 are discussed in detail as a case study. We hope that this review will aid and motivate researchers to develop and utilize more computational techniques to discover ideal aptamers effectively. Copyright © 2022 Elsevier B.V.

CASE STUDY: Innovation in teaching delivery or learning technology Distant learning challenges and solutions: Incorporation of 3D protein visualisation in an undergraduate pharmacy medicinal chemistry course

The COVID-19 pandemic made distance learning an essential medium for teaching worldwide. The use of three-dimensional protein visualisation in teaching undergraduate medicinal chemistry courses was shown to be highly effective in increasing the students' understanding and interest in the topic. The course was designed to use the visualisation tools in lectures, and students would then use them to study drug-target interactions and present their work as a part of the course assessment. With the pandemic induced-lockdown imposed early in the term, the faculty were faced with many challenges to keep the use of tools as part of the course. The lack of direct contact, differences in students' computer literacy and availability of internet connections, in addition to the need for appropriate mediums for assignment presentations and assessment, were major concerns. In this case study the author presents the Faculty of Pharmacy and Medical Sciences at the University of Petra's approaches to overcome the challenges faced in the course delivery and assessment. Copyright © 2020 FIP.

Structures of mycobacterial ATP synthase bound to inhibitors

Tuberculosis is the second leading cause of death by infectious disease worldwide after COVID-19. Mycobacterium tuberculosis, which causes tuberculosis, is showing alarming levels of resistance to first-line antibiotics, jeopardizing efforts to eradicate the disease. Research is underway to develop new, safer drugs to treat drug resistant tuberculosis. One of these breakthrough drugs is bedaquiline, which targets the mycobacterial ATP synthase, an essential enzyme in mycobacteria. The success of bedaquiline, which has become a cornerstone of treatment for multidrug-resistant and extensively drug-resistant tuberculosis, demonstrates the importance of the mycobacterial ATP synthase as a key drug target against M. tuberculosis. Since the discovery of bedaquiline in 2005, there has been a renewed interest in developing new and improved mycobacterial ATP synthase inhibitors. We have determined electron cryomicroscopy structures of M. smegmatis ATP synthase in complex with inhibitors. We provide detailed mechanistic and structural insights into the mode of action of these compounds, which will support medicinal chemistry efforts to design new tuberculosis drugs. Our work reveals new inhibitor binding sites in the enzyme, opening the route for development of new classes of compounds and improved inhibitors. Copyright © 2022

Computational demonstration of cheminformatics and machine learning in coronavirus drug discovery

Computational tools in drug discovery involve the use of algorithms in predicting properties of potential drugs as ligands as well as biological targets in structural forms. This dates back to more than 30 years ago and have been perfected with time and advancement of technology. They are reliable to varying extents depending on the nature of the study, complexity among other factors. Computational tools help medicinal chemists, computational chemists, and structural biologists to design and optimize potential drugs as early as possible and reduce or completely avoid attrition in the drug discovery pipeline. The search for drugs to cure or manage COVID-19 is made relatively easier and more efficient by the use of computational tools to help understand the ADMET properties of possible drugs under development. This chapter demonstrates how computational tools in cheminformatics and machine learning can be used in the fight against COVID-19 from a medicinal chemistry perspective using selected parameters. © 2022 Elsevier Inc. All rights reserved.

Chapter 10 - Challenges in designing antiviral agents

Among the microorganisms, viruses have the simplest of structures. Despite this, they are the cause of a number of diseases, wherein the discovery of new antivirals is one of the most difficult tasks in medicinal chemistry. There are several approved drugs for numerous pathological conditions caused by viral agents. At the same time, there is a significant lack of effective treatments. Furthermore, many diseases remain without any specific treatment, due to several factors that make it difficult. In this context, this chapter addresses the main difficulties encountered in the discovery of antiviral agents, as well as some analogs that could overcome such limitations, which can be useful against herpes, influenza, coronavirus, human immunodeficiency virus, hepatitis B, dengue, Ebola, and Lassa. In fact, one of the main limitations for designing new antivirals is related to the rapid emergence of virus resistance to drugs. Thus, there is considerable need for new scaffolds that can overcome this enormous challenge. Furthermore, low bioavailability of nucleoside analogs and low quality in vitro assays are among the major limitations found currently. Finally, we hope that this chapter encourages medicinal chemists around the world to find possibilities to overcome these limitations by developing new methodologies for testing compounds and designing new chemical agents that could represent future treatments for these diseases.

Beyond the vaccines: a glance at the small molecule and peptide-based anti-COVID19 arsenal.

Unprecedented efforts of the researchers have been witnessed in the recent past towards the development of vaccine platforms for the control of the COVID-19 pandemic. Albeit, vaccination stands as a practical strategy to prevent SARS-CoV-2 infection, supplementing the anti-COVID19 arsenal with therapeutic options such as small molecules/peptides and antibodies is being conceived as a prudent strategy to tackle the emerging SARS-CoV-2 variants. Noteworthy to mention that collective efforts from numerous teams have led to the generation of a voluminous library composed of chemically and mechanistically diverse small molecules as anti-COVID19 scaffolds. This review article presents an overview of medicinal chemistry campaigns and drug repurposing programs that culminated in the identification of a plethora of small molecule-based anti-COVID19 drugs mediating their antiviral effects through inhibition of proteases, S protein, RdRp, ACE2, TMPRSS2, cathepsin and other targets. In light of the evidence ascertaining the potential of small molecule drugs to approach conserved proteins required for the viral replication of all coronaviruses, accelerated FDA approvals are anticipated for small molecules for the treatment of COVID19 shortly. Though the recent attempts invested in this direction in pursuit of enrichment of the anti-COVID-19 armoury (chemical tools) are praiseworthy, some strategies need to be implemented to extract conclusive benefits of the recently reported small molecule viz. (i) detailed preclinical investigation of the generated anti-COVID19 scaffolds (ii) in-vitro profiling of the inhibitors against the emerging SARS-CoV-2 variants (iii) development of assays enabling rapid screening of the libraries of anti-COVID19 scaffold (iv) leveraging the applications of machine learning based predictive models to expedite the anti-COVID19 drug discovery campaign (v) design of antibody-drug conjugates.

Development and patent synthesis of nirmatrelvir - the main component of the first oral drug against SARS-CoV-2 Paxlovid (R)

Nirmatrelvir is the main component of the first oral drug against SARS-CoV-2 called Paxlovid (R). Its development from an orally unavailable predecessor through hydrogen bond donors (HBD) replacement is highlighted, followed by an examination of the synthetic routes described in the original PCT application WO2021/250648. Based on its attributes, nirmatrelvir shows the potential to be a game changer in SARS-CoV-2 treatment.

Bibliometric Analysis: Nanotechnology and COVID-19

Background: COVID-19 pandemic information is critical to study it further, but the virus has still not been confined. In addition, even if there is no longer any threat, more knowledge may be gathered from these resources. Methods: The data used in this study was gathered from several scientific areas and the links between them. Since the COVID-19 pandemic has not been fully contained, and additional information can be gleaned from these references, bibliometric analysis of it is important. Results: A total of 155 publications on the topic of "COVID-19" and the keyword "nanotechnology" was identified in the Scopus database between 2020 and 2021 in a network visualization map. Conclusion: As a result, our analysis was conducted appropriately to provide a comprehensive understanding of COVID-19 and nanotechnology and prospective research directions for medicinal chemistry.

Plant Metabolites as SARS-CoV-2 Inhibitors Candidates: In Silico and In Vitro Studies.

Since it acquired pandemic status, SARS-CoV-2 has been causing all kinds of damage all over the world. More than 6.3 million people have died, and many cases of sequelae are in survivors. Currently, the only products available to most of the world's population to fight the pandemic are vaccines, which still need improvement since the number of new cases, admissions into intensive care units, and deaths are again reaching worrying rates, which makes it essential to compounds that can be used during infection, reducing the impacts of the disease. Plant metabolites are recognized sources of diverse biological activities and are the safest way to research anti-SARS-CoV-2 compounds. The present study computationally evaluated 55 plant compounds in five SARS-CoV-2 targets such Main Protease (Mpro or 3CL or MainPro), RNA-dependent RNA polymerase (RdRp), Papain-Like Protease (PLpro), NSP15 Endoribonuclease, Spike Protein (Protein S or Spro) and human Angiotensin-converting enzyme 2 (ACE-2) followed by in vitro evaluation of their potential for the inhibition of the interaction of the SARS-CoV-2 Spro with human ACE-2. The in silico results indicated that, in general, amentoflavone, 7-O-galloylquercetin, kaempferitrin, and gallagic acid were the compounds with the strongest electronic interaction parameters with the selected targets. Through the data obtained, we can demonstrate that although the indication of individual interaction of plant metabolites with both Spro and ACE-2, the metabolites evaluated were not able to inhibit the interaction between these two structures in the in vitro test. Despite this, these molecules still must be considered in the research of therapeutic agents for treatment of patients affected by COVID-19 since the activity on other targets and influence on the dynamics of viral infection during the interaction Spro x ACE-2 should be investigated.

From crystallographic fragment screen to preclinical candidate: Open science discovery of SARS-CoV-2 antivirals

The development of novel, low cost and globally available antiviral therapeutics remains an essential goal for the current SARS-CoV-2 pandemic. Furthermore, future pandemics could be prevented with easily deployable broad-spectrum oral antivirals and open knowledge bases that de-risk and accelerate novel antiviral discovery and development. To identify starting points for the development of such therapeutics, the XChem team at Diamond Light Source, in collaboration with various international colleagues, performed large crystallographic fragment screens against 8 key SARS-CoV-2 protein targets including the Main protease1, the Nsp3 macrodomain2 and the helicase Nsp133. The expeditious collection and open dissemination of the data from these fragment screening campaigns was enabled by the well-established platform at Diamond Light Source and by the implementation of various experimental and computational tools. This work identified numerous starting points for the development of potent anti-viral therapeutics as exemplified by the COVID Moonshot - a fully open-science structure-enabled drug discovery campaign targeting the SARS-CoV-2 main protease. 4 By leveraging crowdsourced medicinal chemistry design, high throughput structural biology, machine learning and exascale molecular simulations, we discovered a novel chemical scaffold that is differentiated to current clinical candidates in terms of toxicity and pharmacokinetics liabilities, and developed it into orally-bioavailable inhibitors with clinical potential within 2 years. All compound designs, structural data, assay data and synthesized molecules have been shared rapidly and openly, creating a rich, IP-free knowledgebase for future anti-coronavirus drug discovery.

21stRSC/SCI Medicinal Chemistry Symposium Cambridge/Virtual - September 13-15, 2021

The Royal Chemistry Society/Society of Chemistry Industry (RSC/SCI) Medicinal Chemistry Symposium is a key symposium in the field of medicinal chemistry that takes place every 2 years at the University of Cambridge, U.K., under the auspices of the RSC and the SCI. This year, in its 21st edition, it was run as a hybrid event, simultaneously attended by both in-person and virtual attendees. Its theme was 'Improving Success', and 25 orals and 30 posters were presented. The scientific program covered recent medicinal chemistry achievements in major therapeutic areas, with a few first-time structure disclosure presentations and particular emphasis on emerging early-stage drug discovery and lead optimization strategies, including reports of successful case studies illustrating fragment-based screening and phenotypic target engagement approaches. Applications of artificial intelligence (AI), mass spectrometry and photochemistry in drug design and discovery were also highlighted. This report will cover some of the medicinal chemistry presentations delivered at the meeting.

Inhibitors of SARS-CoV-2 PLpro.

The emergence of SARS-CoV-2 causing the COVID-19 pandemic, has highlighted how a combination of urgency, collaboration and building on existing research can enable rapid vaccine development to fight disease outbreaks. However, even countries with high vaccination rates still see surges in case numbers and high numbers of hospitalized patients. The development of antiviral treatments hence remains a top priority in preventing hospitalization and death of COVID-19 patients, and eventually bringing an end to the SARS-CoV-2 pandemic. The SARS-CoV-2 proteome contains several essential enzymatic activities embedded within its non-structural proteins (nsps). We here focus on nsp3, that harbours an essential papain-like protease (PLpro) domain responsible for cleaving the viral polyprotein as part of viral processing. Moreover, nsp3/PLpro also cleaves ubiquitin and ISG15 modifications within the host cell, derailing innate immune responses. Small molecule inhibition of the PLpro protease domain significantly reduces viral loads in SARS-CoV-2 infection models, suggesting that PLpro is an excellent drug target for next generation antivirals. In this review we discuss the conserved structure and function of PLpro and the ongoing efforts to design small molecule PLpro inhibitors that exploit this knowledge. We first discuss the many drug repurposing attempts, concluding that it is unlikely that PLpro-targeting drugs already exist. We next discuss the wealth of structural information on SARS-CoV-2 PLpro inhibition, for which there are now ∼30 distinct crystal structures with small molecule inhibitors bound in a surprising number of distinct crystallographic settings. We focus on optimisation of an existing compound class, based on SARS-CoV PLpro inhibitor GRL-0617, and recapitulate how new GRL-0617 derivatives exploit different features of PLpro, to overcome some compound liabilities.

Critical Thinking through Literature Review in Organic Chemistry Laboratory Course

The development of the skills to read and understand scientific literature is crucial to the future success of students. A literature review project was introduced into an organic chemistry laboratory course, in which undergraduate students were asked to acquire the skills of scientific literature searching, reading, and summarizing. The course project was improved during the COVID-19 pandemic, and a step-by-step study schedule in 7 weeks was carried out. The students wrote and handed in their reviews successfully through the training process. The literature review helped the undergraduate students to get a further comprehensive understanding of the relationship between organic chemistry and medical science.

Ultrasonic energy for construction of bioactive heterocycles

The ultrasonicenergy has been revisited and applied for the synthesis of bioactive molecules in a short time and green method. These compoundscan exhibit anticancer, antioxidant, antibacterial, antimalarial, and cytotoxic properties. Some of them are organofluorines, that are widely used as potential pharmacological agents. Significantly, the synthesis of a compound having activity against SARS-CoV-2has also been studied in this review. The complete ultrasound-assisted synthesis is catalyzedby different chemical catalysts. Ultrasonication is a promising technique for the green synthesis, rapid approach, quantitative yield of the desired molecules and brief biological importance. Among the unconventional methods, ultrasonication has drawn attention as a promising approach for the green and rapid synthesis of biological sensitive moleculesin a considerable quantity.

?COVID-19 between Myth and Science??Innovative Experimentsfor Analyzing Fake News Inside and Outside the Chemistry Classroom br

While the COVID-19 pandemic continues, theacceptance of numerous measures, such as mandatory wearing offace masks or social distancing, is declining. At the same time, thespread of fake news related to these measures is on the rise. Theacceptance of and compliance with the measures depends to alarge extent on knowledge about these very measures. For thisreason, there is a need for adequate formats inside and outside thechemistry classroom that examine the mitigation measures andrelated fake news more closely. The practical and problem-orientedapproach of the natural sciences provides a good basis forevaluating mitigation measures and fake news. Here, the focus isprimarily on the knowledge gained by conducting and evaluatingexperiments. For this reason, experiments related to measures andfake news on the COVID-19 pandemic were developed that can be carried out with household objects and chemicals. Allexperiments can be performed without much effort and are therefore intentionally designed to appeal to students and adults withlittle background in science. This paper presents a total of four experiments on the dispersion of aerosols and droplets, theeffectiveness of face masks, and the importance and mode of action of disinfectant and soap.KEYWORDS:General Public, High School/Introductory Chemistry, Public Understanding/Outreach, Distance Learning/Self Instruction,Hands-On Learning/Manipulatives, Misconceptions/Discrepant Events, Enrichment/Review Materials, Medicinal Chemistry,Nonmajor Courses, Student-Centered Learning