Past, Present, and Future Perspectives on Computer-Aided Drug Design Methodologies.

The application of computational approaches in drug discovery has been consolidated in the last decades. These families of techniques are usually grouped under the common name of "computer-aided drug design" (CADD), and they now constitute one of the pillars in the pharmaceutical discovery pipelines in many academic and industrial environments. Their implementation has been demonstrated to tremendously improve the speed of the early discovery steps, allowing for the proficient and rational choice of proper compounds for a desired therapeutic need among the extreme vastness of the drug-like chemical space. Moreover, the application of CADD approaches allows the rationalization of biochemical and interactive processes of pharmaceutical interest at the molecular level. Because of this, computational tools are now extensively used also in the field of rational 3D design and optimization of chemical entities starting from the structural information of the targets, which can be experimentally resolved or can also be obtained with other computer-based techniques. In this work, we revised the state-of-the-art computer-aided drug design methods, focusing on their application in different scenarios of pharmaceutical and biological interest, not only highlighting their great potential and their benefits, but also discussing their actual limitations and eventual weaknesses. This work can be considered a brief overview of computational methods for drug discovery.

An engineering perspective of ceramics applied in dental reconstructions.

The demands for dental materials continue to grow, driven by the desire to reach a better performance than currently achieved by the available materials. In the dental restorative ceramic field, the structures evolved from the metal-ceramic systems to highly translucent multilayered zirconia, aiming not only for tailored mechanical properties but also for the aesthetics to mimic natural teeth. Ceramics are widely used in prosthetic dentistry due to their attractive clinical properties, including high strength, biocompatibility, chemical stability, and a good combination of optical properties. Metal-ceramics type has always been the golden standard of dental reconstruction. However, this system lacks aesthetic aspects. For this reason, efforts are made to develop materials that met both the mechanical features necessary for the safe performance of the restoration as well as the aesthetic aspects, aiming for a beautiful smile. In this field, glass and high-strength core ceramics have been highly investigated for applications in dental restoration due to their excellent combination of mechanical properties and translucency. However, since these are recent materials when compared with the metal-ceramic system, many studies are still required to guarantee the quality and longevity of these systems. Therefore, a background on available dental materials properties is a starting point to provoke a discussion on the development of potential alternatives to rehabilitate lost hard and soft tissue structures with ceramic-based tooth and implant-supported reconstructions. This review aims to bring the most recent materials research of the two major categories of ceramic restorations: ceramic-metal system and all-ceramic restorations. The practical aspects are herein presented regarding the evolution and development of materials, technologies applications, strength, color, and aesthetics. A trend was observed to use high-strength core ceramics type due to their ability to be manufactured by CAD/CAM technology. In addition, the impacts of COVID-19 on the market of dental restorative ceramics are presented.

Surely you are joking, Mr Docking!

In the wake of recent COVID-19 pandemics scientists around the world rushed to deliver numerous CADD (Computer-Aided Drug Discovery) methods and tools that could be reliably used to discover novel drug candidates against the SARS-CoV-2 virus. With that, there emerged a trend of a significant democratization of CADD that contributed to the rapid development of various COVID-19 drug candidates currently undergoing different stages of validation. On the other hand, this democratization also inadvertently led to the surge rapidly performed molecular docking studies to nominate multiple scores of novel drug candidates supported by computational arguments only. Albeit driven by best intentions, most of such studies also did not follow best practices in the field that require experience and expertise learned through multiple rigorously designed benchmarking studies and rigorous experimental validation. In this Viewpoint we reflect on recent disbalance between small number of rigorous and comprehensive studies and the proliferation of purely computational studies enabled by the ease of docking software availability. We further elaborate on the hyped oversale of CADD methods' ability to rapidly yield viable drug candidates and reiterate the critical importance of rigor and adherence to the best practices of CADD in view of recent emergence of AI and Big Data in the field.

The development of digital dentistry in the UK: An overview.

The COVID-19 pandemic has highlighted the benefits which digital technology offers to all aspects of dental practice and education. This paper provides an overview of how digital technology has enhanced clinical and administrative procedures within dental practice, including computer-aided design/computer-aided manufacture (CAD/CAM), digital radiography, 3D printing, patient records, electronic patient referrals and electronic communications from dental practices. It then considers the development of teledentistry (mHealth) and its benefits in enabling distant consultations with patients, who for one reason or another are unable to visit dental practices easily. It then goes on to consider how and why digital dental distance learning materials were provided to general dental practitioners in England by the Department of Health (DoH) (England) and how they evolved. Finally, this paper considers the use of digital technology in dental education by dental schools.

Pros and Cons of CAD/CAM Technology for Infection Prevention in Dental Settings during COVID-19 Outbreak.

The purpose of this commentary is to update the evidence reported in our previous review on the advantages and limitations of computer-aided design/computer-aided manufacturing technology in the promotion of dental business, as well as to guarantee patient and occupational safety. The COVID-19 pandemic led to an unprecedented focus on infection prevention; however, waves of COVID-19 follow one another, asymptomatic cases are nearly impossible to identify by triage in a dental setting, and the effectiveness of long-lasting immune protection through vaccination remains largely unknown. Different national laws and international guidelines (mainly USA-CDC, ECDC) have often brought about dissimilar awareness and operational choices, and in general, there has been very limited attention to this technology. Here, we discuss its advantages and limitations in light of: (a) presence of SARS-CoV-2 in the oral cavity, saliva, and dental biofilm and activation of dormant microbial infections; (b) the prevention of SARS-CoV-2 transmission by aerosol and fomite contamination; (c) the detection of various oral manifestations of COVID-19; (d) specific information for the reprocessing of the scanner tip and the ward from the manufacturers.

A feasible route for the design and manufacture of customised respiratory protection through digital facial capture.

The World Health Organisation has called for a 40% increase in personal protective equipment manufacturing worldwide, recognising that frontline workers need effective protection during the COVID-19 pandemic. Current devices suffer from high fit-failure rates leaving significant proportions of users exposed to risk of viral infection. Driven by non-contact, portable, and widely available 3D scanning technologies, a workflow is presented whereby a user's face is rapidly categorised using relevant facial parameters. Device design is then directed down either a semi-customised or fully-customised route. Semi-customised designs use the extracted eye-to-chin distance to categorise users in to pre-determined size brackets established via a cohort of 200 participants encompassing 87.5% of the cohort. The user's nasal profile is approximated to a Gaussian curve to further refine the selection in to one of three subsets. Flexible silicone provides the facial interface accommodating minor mismatches between true nasal profile and the approximation, maintaining a good seal in this challenging region. Critically, users with outlying facial parameters are flagged for the fully-customised route whereby the silicone interface is mapped to 3D scan data. These two approaches allow for large scale manufacture of a limited number of design variations, currently nine through the semi-customised approach, whilst ensuring effective device fit. Furthermore, labour-intensive fully-customised designs are targeted as those users who will most greatly benefit. By encompassing both approaches, the presented workflow balances manufacturing scale-up feasibility with the diverse range of users to provide well-fitting devices as widely as possible. Novel flow visualisation on a model face is presented alongside qualitative fit-testing of prototype devices to support the workflow methodology.

Hispidin and Lepidine E: Two Natural Compounds and Folic Acid as Potential Inhibitors of 2019-novel Coronavirus Main Protease (2019- nCoVMpro), Molecular Docking and SAR Study.

BACKGROUND: 2019-nCoVis, a novel coronavirus was isolated and identified in 2019 in the city of Wuhan, China. On February 17, 2020 and according to the World Health Organization, 71, 429 confirmed cases worldwide were identified, among them 2162 new cases were recorded in the last 24 hours. One month later, the confirmed cases jumped to 179111, with 11525 new cases in the last 24 hours, with 7426 total deaths. No drug or vaccine is present at the moment for human and animal coronavirus. METHODS: The inhibition of 3CL hydrolase enzyme provides a promising therapeutic principle for developing treatments against CoViD-19. The 3CLpro (Mpro) is known for involving in counteracting the host innate immune response. RESULTS: This work presents the inhibitory effect of some natural compounds against 3CL hydrolase enzyme, and explains the main interactions in inhibitor-enzyme complex. Molecular docking study was carried out using Autodock Vina. By screening several molecules, we identified three candidate agents that inhibit the main protease of coronavirus. Hispidin, lepidine E, and folic acid are bound tightly in the enzyme, therefore strong hydrogen bonds have been formed (1.69-1.80Å) with the active site residues. CONCLUSION: This study provides a possible therapeutic strategy for CoViD-19.

Cyanorona-20: The first potent anti-SARS-CoV-2 agent.

Explicit hindrance and blockade of the viral RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 is considered one of the most promising and efficient approaches for developing highly potent remedies for COVID-19. However, almost all of the reported viral RdRp inhibitors (either repurposed or new antiviral drugs) lack specific selectivity against the novel coronaviral RdRp and still at a beginning phase of advancement. Herein, I discovered and introduce a new pyrazine derivative, (E)-N-(4-cyanobenzylidene)-6-fluoro-3-hydroxypyrazine-2-carboxamide (cyanorona-20), as the first potent SARS-CoV-2 RdRp inhibitor with very high selectivity (209- and 45-fold more potent than favipiravir and remdesivir, respectively). This promising selective specific anti-COVID-19 compound is also deemed to be the first distinctive derivative of favipiravir. Cyanorona-20, the unprecedented nucleoside/nucleotide analog, was designed, synthesized, characterized, computationally studied, and biologically evaluated for its anti-COVID-19 actions (through a precise in vitro anti-COVID-19 assay). The results of the biological assay displayed that cyanorona-20 surprisingly exhibited very high and largely significant anti-COVID-19 activities (anti-SARS-CoV-2 EC50 = 0.45 µM), and, in addition, it could be also a very promising guide and lead compound for the design and synthesis of new anti-SARS-CoV-2 and anti-COVID-19 agents through structural modifications and further computational studies. Further appraisal for the improvement of cyanorona-20 medication is a prerequisite requirement in the coming days. In a word, the ascent of the second member (cyanorona-20 "Corona Antidote") of the novel and promising class of anti-COVID-19 pyrazine derivatives would drastically make a medical uprising in the pharmacotherapeutic treatment regimens and protocols of the recently-emerged SARS-CoV-2 infection and its accompanying COVID-19.

Indian contribution toward biomedical research and development in COVID-19: A systematic review.

COVID-19 pandemic led to an unprecedented collaborative effort among industry, academia, regulatory bodies, and governments with huge financial investments. Scientists and researchers from India also left no stone unturned to find therapeutic and preventive measures against COVID-19. Indian pharmaceutical companies are one of the leading manufacturers of vaccine in the world, are utilizing its capacity to its maximum, and are one among the forerunners in vaccine research against COVID-19 across the globe. In this systematic review, the information regarding contribution of Indian scientists toward COVID-19 research has been gathered from various news articles across Google platform apart from searching PubMed, WHO site, COVID-19 vaccine tracker, CTRI, clinicaltrials.gov, and websites of pharmaceutical companies. The article summarizes and highlights the various therapeutic and vaccine candidates, diagnostic kits, treatment agents, and technology being developed and tested by Indian researcher community against COVID-19.

COVID-19 in the Age of Artificial Intelligence: A Comprehensive Review.

The recent COVID-19 pandemic, which broke at the end of the year 2019 in Wuhan, China, has infected more than 98.52 million people by today (January 23, 2021) with over 2.11 million deaths across the globe. To combat the growing pandemic on urgent basis, there is need to design effective solutions using new techniques that could exploit recent technology, such as machine learning, deep learning, big data, artificial intelligence, Internet of Things, for identification and tracking of COVID-19 cases in near real time. These technologies have offered inexpensive and rapid solution for proper screening, analyzing, prediction and tracking of COVID-19 positive cases. In this paper, a detailed review of the role of AI as a decisive tool for prognosis, analyze, and tracking the COVID-19 cases is performed. We searched various databases including Google Scholar, IEEE Library, Scopus and Web of Science using a combination of different keywords consisting of COVID-19 and AI. We have identified various applications, where AI can help healthcare practitioners in the process of identification and monitoring of COVID-19 cases. A compact summary of the corona virus cases are first highlighted, followed by the application of AI. Finally, we conclude the paper by highlighting new research directions and discuss the research challenges. Even though scientists and researchers have gathered and exchanged sufficient knowledge over last couple of months, but this structured review also examined technological perspectives while encompassing the medical aspect to help the healthcare practitioners, policymakers, decision makers, policymakers, AI scientists and virologists to quell this infectious COVID-19 pandemic outbreak.

In silico approach: docking study of oxindole derivatives against the main protease of COVID-19 and its comparison with existing therapeutic agents.

OBJECTIVES: Presently, the pandemic of COVID-19 has worsened the situation worldwide and received global attention. The United States of America have the highest numbers of a patient infected by this disease followed by Brazil, Russia, India and many other countries. Moreover, lots of research is going on to find out effective vaccines or medicine, but still, no potent vaccine or drug is discovered to cure COVID-19. As a consequence, many types of research have designated that computer-based studies, such as protein-ligand interactions, structural dynamics, and chembio modeling are the finest choice due to its low cost and time-saving features. Here, oxindole derivatives have been chosen for docking because of their immense pharmacological applications like antiviral, antidiabetic, anti-inflammatory, and so on. Molecular docking of 30 oxindole derivatives done on the crystallized structure of the protein (COVID-19 Mpro). METHODS: The process of docking, interaction, and binding the structure of ligand with protein has executed using Molegro Virtual Docker v.7.0.0 (MVD) and visualized the usage by Molegro Molecular Viewer v.7.0.0 (MMV). RESULTS: Among the 30 derivatives, the outcomes depicted better steric interaction and hydrogen bonding amongst OD-22 ligand, OD-16 ligand, OD-4 ligand, and OD-9 ligand (oxindole derivatives) with COVID-19. In addition to this, the comparative study of these four compounds with existing drugs that are under clinical trials shows comparatively good results in terms of its MolDock scores, H-bonding and steric interactions. CONCLUSIONS: Hence, It is proposed that these four oxindole derivatives have good potential as a new drug against coronavirus as possible therapeutic agents.

A novel fully automatic design approach of a 3D printed face specific mask: Proof of concept.

The use of high quality facemasks is indispensable in the light of the current COVID pandemic. This study proposes a fully automatic technique to design a face specific mask. Through the use of stereophotogrammetry, computer-assisted design and three-dimensional (3D) printing, we describe a protocol for manufacturing facemasks perfectly adapted to the individual face characteristics. The face specific mask was compared to a universal design of facemask and different filter container's designs were merged with the mask body. Subjective assessment of the face specific mask demonstrated tight closure at the nose, mouth and chin area, and permits the normal wearing of glasses. A screw-drive locking system is advised for easy assembly of the filter components. Automation of the process enables high volume production but still allows sufficient designer interaction to answer specific requirements. The suggested protocol can be used to provide more comfortable, effective and sustainable solution compared to a single use, standardized mask. Subsequent research on printing materials, sterilization technique and compliance with international regulations will facilitate the introduction of the face specific mask in clinical practice as well as for general use.

A Computer-Aided Drug Design Approach to Predict Marine Drug-Like Leads for SARS-CoV-2 Main Protease Inhibition.

The investigation of marine natural products (MNPs) as key resources for the discovery of drugs to mitigate the COVID-19 pandemic is a developing field. In this work, computer-aided drug design (CADD) approaches comprising ligand- and structure-based methods were explored for predicting SARS-CoV-2 main protease (Mpro) inhibitors. The CADD ligand-based method used a quantitative structure-activity relationship (QSAR) classification model that was built using 5276 organic molecules extracted from the ChEMBL database with SARS-CoV-2 screening data. The best model achieved an overall predictive accuracy of up to 67% for an external and internal validation using test and training sets. Moreover, based on the best QSAR model, a virtual screening campaign was carried out using 11,162 MNPs retrieved from the Reaxys® database, 7 in-house MNPs obtained from marine-derived actinomycetes by the team, and 14 MNPs that are currently in the clinical pipeline. All the MNPs from the virtual screening libraries that were predicted as belonging to class A were selected for the CADD structure-based method. In the CADD structure-based approach, the 494 MNPs selected by the QSAR approach were screened by molecular docking against Mpro enzyme. A list of virtual screening hits comprising fifteen MNPs was assented by establishing several limits in this CADD approach, and five MNPs were proposed as the most promising marine drug-like leads as SARS-CoV-2 Mpro inhibitors, a benzo[f]pyrano[4,3-b]chromene, notoamide I, emindole SB beta-mannoside, and two bromoindole derivatives.

Development of humanized tri-specific nanobodies with potent neutralization for SARS-CoV-2.

SARS-CoV-2 is a newly emergent coronavirus, which has adversely impacted human health and has led to the COVID-19 pandemic. There is an unmet need to develop therapies against SARS-CoV-2 due to its severity and lack of treatment options. A promising approach to combat COVID-19 is through the neutralization of SARS-CoV-2 by therapeutic antibodies. Previously, we described a strategy to rapidly identify and generate llama nanobodies (VHH) from naïve and synthetic humanized VHH phage libraries that specifically bind the S1 SARS-CoV-2 spike protein, and block the interaction with the human ACE2 receptor. In this study we used computer-aided design to construct multi-specific VHH antibodies fused to human IgG1 Fc domains based on the epitope predictions for leading VHHs. The resulting tri-specific VHH-Fc antibodies show more potent S1 binding, S1/ACE2 blocking, and SARS-CoV-2 pseudovirus neutralization than the bi-specific VHH-Fcs or combination of individual monoclonal VHH-Fcs. Furthermore, protein stability analysis of the VHH-Fcs shows favorable developability features, which enable them to be quickly and successfully developed into therapeutics against COVID-19.

Design of 3D-Printed Nasopharyngeal Swabs for Children is Enabled by Radiologic Imaging.

3D-printed nasopharyngeal swabs for COVID-19 molecular diagnostic testing address the national shortage of swabs. Swab designs for adult use were placed in the public domain in March 2020. Swabs for pediatric use, however, need to be smaller and more flexible to navigate delicate pediatric nasopharyngeal cavities. We describe a novel use of maxillofacial CT scans to aid in the design of pediatric nasopharyngeal swabs.

Finding Alternate Resources for Completing Senior Design Projects During the Current COVID-19 Pandemic.

At this time many (if not all) colleges and universities are on lockdown, students have returned home, and classes have transitioned to online instruction. Students in capstone design courses around the country have no access to their school's maker spaces and test equipment. Their prototype parts may be stored in a locked maker space, making it difficult to build, test, and deliver prototypes to sponsors or clients at the end of the semester.z.

Custom-made 3D-printed face masks in case of pandemic crisis situations with a lack of commercially available FFP2/3 masks.

In the case of pandemic crisis situations, a crucial lack of protective material such as protective face masks for healthcare professionals can occur. A proof of concept (PoC) and prototype are presented, demonstrating a reusable custom-made three-dimensionally (3D) printed face mask based on materials and techniques (3D imaging and 3D printing) with global availability. The individualized 3D protective face mask consists of two 3D-printed reusable polyamide composite components (a face mask and a filter membrane support) and two disposable components (a head fixation band and a filter membrane). Computer-aided design (CAD) was used to produce the reusable components of the 3D face mask based on individual facial scans, which were acquired using a new-generation smartphone with two cameras and a face scanning application. 3D modelling can easily be done by CAD designers worldwide with free download software. The disposable non-woven melt-blown filter membrane is globally available from industrial manufacturers producing FFP2/3 protective masks for painting, construction, agriculture, and the textile industry. Easily available Velcro fasteners were used as a disposable head fixation band. A cleaning and disinfection protocol is proposed. Leakage and virological testing of the reusable components of the 3D face mask, following one or several disinfection cycles, has not yet been performed and is essential prior to its use in real-life situations. This PoC should allow the reader to consider making and/or virologically testing the described custom-made 3D-printed face masks worldwide. The surface tessellation language (STL) format of the original virtual templates of the two reusable components described in this paper can be downloaded free of charge using the hyperlink (Supplementary Material online).