Drug Discovery Strategies Research Articles

Determination of Ligand Binding Modes in Hydrated Viral Ion Channels to Foster Drug Design and Repositioning.

Target-based design and repositioning are mainstream strategies of drug discovery. Numerous drug design and repositioning projects have been launched to fight the ongoing COVID-19 pandemic. The resulting drug candidates have often failed due to the misprediction of their target-bound structures. The determination of water positions of such structures is particularly challenging due to the large number of possible drugs and the diversity of their hydration patterns. To answer this challenge and help correct predictions, we introduce a new protocol HydroDock, which can build hydrated drug–target complexes from scratch. HydroDock requires only the dry target and drug structures and produces their complexes with appropriately positioned water molecules. As a test application of the protocol, we built the structures of amantadine derivatives in complex with the influenza M2 transmembrane ion channel. The repositioning of amantadine derivatives from this influenza target to the SARS-CoV-2 envelope protein was also investigated. Excellent agreement was observed between experiments and the structures determined by HydroDock. The atomic resolution complex structures showed that water plays a similar role in the binding of amphipathic amantadine derivatives to transmembrane ion channels of both influenza A and SARS-CoV-2. While the hydrophobic regions of the channels capture the bulky hydrocarbon group of the ligand, the surrounding waters direct its orientation parallel with the axes of the channels via bridging interactions with the ionic ligand head. As HydroDock supplied otherwise undetermined structural details, it can be recommended to improve the reliability of future design and repositioning of antiviral drug candidates and many other ligands with an influence of water structure on their mechanism of action.

Identification of TrkB Binders from Complex Matrices Using a Magnetic Drug Screening Nanoplatform.

Brain-derived neurotrophic factor (BDNF) and its receptor tyrosine receptor kinase B (TrkB) have been shown to play an important role in numerous neurological disorders, such as Alzheimer's disease. The identification of biologically active compounds interacting with TrkB serves as a drug discovery strategy to identify drug leads for neurological disorders. Here, we report effective immobilization of functional TrkB on magnetic iron oxide nanoclusters, where TrkB receptors behave as "smart baits" to bind compounds from mixtures and magnetic nanoclusters enable rapid isolation through magnetic separation. The presence of the immobilized TrkB was confirmed by specific antibody labeling. Subsequently, the activity of the TrkB on iron oxide nanoclusters was evaluated with ATP/ADP conversion experiments using a known TrkB agonist. The immobilized TrkB receptors can effectively identify binders from mixtures containing known binders, synthetic small molecule mixtures, and Gotu Kola (Centella asiatica) plant extracts. The identified compounds were analyzed by an ultrahigh-performance liquid chromatography system coupled with a quadrupole time-of-flight mass spectrometer. Importantly, some of the identified TrkB binders from Gotu Kola plant extracts matched with compounds previously linked to neuroprotective effects observed for a Gotu Kola extract approved for use in a clinical trial. Our studies suggest that the possible therapeutic effects of the Gotu Kola plant extract in dementia treatment, at least partially, might be associated with compounds interacting with TrkB. The unique feature of this approach is its ability to fast screen potential drug leads using less explored transmembrane targets. This platform works as a drug-screening funnel at early stages of the drug discovery pipeline. Therefore, our approach will not only greatly benefit drug discovery processes using transmembrane proteins as targets but also allow for evaluation and validation of cellular pathways targeted by drug leads.

Systems Pharmacology-Based Precision Therapy and Drug Combination Discovery for Breast Cancer.

Simple SummaryBreast cancer (BC) is a typical global cancer and the second leading cause of cancer-related deaths among women worldwide. BC is a heterogeneous disease with several subtypes, and it is a challenge to use multi-omic data effectively to find suitable drugs for patients. In this paper, we used the GeneRank algorithm and gene dependency network to propose a precision drug discovery strategy that can recommend drugs for individuals and screen existing drug combinations that could be used to treat different BC subtypes. Our results showed that this precision drug discovery strategy identified important disease-related genes in individuals and specific groups, supporting its efficiency, high reliability, and practical application value in drug discovery.Breast cancer (BC) is a common disease and one of the main causes of death in females worldwide. In the omics era, researchers have used various high-throughput sequencing technologies to accumulate massive amounts of biomedical data and reveal an increasing number of disease-related mutations/genes. It is a major challenge to use these data effectively to find drugs that may protect human health. In this study, we combined the GeneRank algorithm and gene dependency network to propose a precision drug discovery strategy that can recommend drugs for individuals and screen existing drugs that could be used to treat different BC subtypes. We used this strategy to screen four BC subtype-specific drug combinations and verified the potential activity of combining gefitinib and irinotecan in triple-negative breast cancer (TNBC) through in vivo and in vitro experiments. The results of cell and animal experiments demonstrated that the combination of gefitinib and irinotecan can significantly inhibit the growth of TNBC tumour cells. The results also demonstrated that this systems pharmacology-based precision drug discovery strategy effectively identified important disease-related genes in individuals and special groups, which supports its efficiency, high reliability, and practical application value in drug discovery.

Drug discovery strategies for novel leukotriene A4 hydrolase inhibitors

ABSTRACT Introduction Leukotriene A4 hydrolase (LTA4H) is the final and rate limiting enzyme regulating the biosynthesis of leukotriene B4 (LTB4), a pro-inflammatory lipid mediator implicated in a large number of inflammatory pathologies. Inhibition of LTA4H not only prevents LTB4 biosynthesis but also induces a lipid mediator class-switch within the 5-lipoxygenase pathway, elevating biosynthesis of the anti-inflammatory lipid mediator Lipoxin A4. Ample preclinical evidence advocates LTA4H as attractive drug target for the treatment of chronic inflammatory diseases. Areas covered This review covers details about the biochemistry of LTA4H and describes its role in regulating pro- and anti-inflammatory mediator generation. It summarizes recent efforts in medicinal chemistry toward novel LTA4H inhibitors, recent clinical trials testing LTA4H inhibitors in pulmonary inflammatory diseases, and potential reasons for the discontinuation of former development programs. Expert opinion Given the prominent role of LTB4 in initiating and perpetuating inflammation, LTA4H remains an appealing drug target. The reason former attempts targeting this enzyme have not met with success in the clinic can be attributed to compound-specific liabilities of first-generation inhibitors and/or choice of target indications to test this mode of action. A new generation of highly potent and selective LTA4H inhibitors is currently undergoing clinical testing in indications with a strong link to LTB4 biology.

Coronavirus, the King Who Wanted More Than a Crown: From Common to the Highly Pathogenic SARS-CoV-2, Is the Key in the Accessory Genes?

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), that emerged in late 2019, is the etiologic agent of the current “coronavirus disease 2019” (COVID-19) pandemic, which has serious health implications and a significant global economic impact. Of the seven human coronaviruses, all of which have a zoonotic origin, the pandemic SARS-CoV-2, is the third emerging coronavirus, in the 21st century, highly pathogenic to the human population. Previous human coronavirus outbreaks (SARS-CoV-1 and MERS-CoV) have already provided several valuable information on some of the common molecular and cellular mechanisms of coronavirus infections as well as their origin. However, to meet the new challenge caused by the SARS-CoV-2, a detailed understanding of the biological specificities, as well as knowledge of the origin are crucial to provide information on viral pathogenicity, transmission and epidemiology, and to enable strategies for therapeutic interventions and drug discovery. Therefore, in this review, we summarize the current advances in SARS-CoV-2 knowledges, in light of pre-existing information of other recently emerging coronaviruses. We depict the specificity of the immune response of wild bats and discuss current knowledge of the genetic diversity of bat-hosted coronaviruses that promotes viral genome expansion (accessory gene acquisition). In addition, we describe the basic virology of coronaviruses with a special focus SARS-CoV-2. Finally, we highlight, in detail, the current knowledge of genes and accessory proteins which we postulate to be the major keys to promote virus adaptation to specific hosts (bat and human), to contribute to the suppression of immune responses, as well as to pathogenicity.

Antiparasitic mebendazole (MBZ) effectively overcomes cisplatin resistance in human ovarian cancer cells by inhibiting multiple cancer-associated signaling pathways.

Ovarian cancer is the third most common cancer and the second most common cause of gynecologic cancer death in women. Its routine clinical management includes surgical resection and systemic therapy with chemotherapeutics. While the first-line systemic therapy requires the combined use of platinum-based agents and paclitaxel, many ovarian cancer patients have recurrence and eventually succumb to chemoresistance. Thus, it is imperative to develop new strategies to overcome recurrence and chemoresistance of ovarian cancer. Repurposing previously-approved drugs is a cost-effective strategy for cancer drug discovery. The antiparasitic drug mebendazole (MBZ) is one of the most promising drugs with repurposing potential. Here, we investigate whether MBZ can overcome cisplatin resistance and sensitize chemoresistant ovarian cancer cells to cisplatin. We first established and characterized two stable and robust cisplatin-resistant (CR) human ovarian cancer lines and demonstrated that MBZ markedly inhibited cell proliferation, suppressed cell wounding healing/migration, and induced apoptosis in both parental and CR cells at low micromole range. Mechanistically, MBZ was revealed to inhibit multiple cancer-related signal pathways including ELK/SRF, NFKB, MYC/MAX, and E2F/DP1 in cisplatin-resistant ovarian cancer cells. We further showed that MBZ synergized with cisplatin to suppress cell proliferation, induce cell apoptosis, and blunt tumor growth in xenograft tumor model of human cisplatin-resistant ovarian cancer cells. Collectively, our findings suggest that MBZ may be repurposed as a synergistic sensitizer of cisplatin in treating chemoresistant human ovarian cancer, which warrants further clinical studies.

Reversible Covalent PROTACs: Novel and Efficient Targeted Degradation Strategy.

The proteolysis targeting chimeras (PROTACs), which are composed of a target protein binding moiety, a linker, and an E3 ubiquitin ligase binder, have been a promising strategy for drug design and discovery. Given the advantages of potency, selectivity, and drug resistance over inhibitors, several PROTACs have been reported in literature, which mostly focus on noncovalent or irreversible covalent binding to the target proteins. However, it must be noted that noncovalent or irreversible PROTACs have several drawbacks such as weak binding affinity and unpredictable off-target effects. Reversible covalent PROTACs, with properties of enhanced potency, selectivity, and long duration of action, have attracted an increasing amount of attention. Here, we propose a comparison between these three patterns and highlight that reversible covalent PROTACs could pave the way for a wide variety of challenging target degradations.

Quadruplex Ligands in Cancer Therapy.

Simple SummaryFour-stranded nucleic acid secondary structures (quadruplexes) including DNA G-quadruplexes, RNA G-quadruplexes and i-Motifs display key regulatory functions in the human genome. Quadruplexes play an important role in telomere lengthening and the expression control of several cancer-related genes. In this context, quadruplex ligands are considered as potential strategies for anticancer drug discovery. Previous reviews are mainly focused on ligands targeting DNA G-quadruplexes, RNA G-quadruplexes and i-Motifs in a separate way, hindering a holistic study. The present review overcomes this limitation by providing a general overview of the recent research on ligands targeting the three different quadruplex structures in cancer.Nucleic acids can adopt alternative secondary conformations including four-stranded structures known as quadruplexes. To date, quadruplexes have been demonstrated to exist both in human chromatin DNA and RNA. In particular, quadruplexes are found in guanine-rich sequences constituting G-quadruplexes, and in cytosine-rich sequences forming i-Motifs as a counterpart. Quadruplexes are associated with key biological processes ranging from transcription and translation of several oncogenes and tumor suppressors to telomeres maintenance and genome instability. In this context, quadruplexes have prompted investigations on their possible role in cancer biology and the evaluation of small-molecule ligands as potential therapeutic agents. This review aims to provide an updated close-up view of the literature on quadruplex ligands in cancer therapy, by grouping together ligands for DNA and RNA G-quadruplexes and DNA i-Motifs.

Novel pyrrolo[2,1-c][1,4]benzodiazepine-3,11-dione (PBD) derivatives as selective HDAC6 inhibitors to suppress tumor metastasis and invasion in vitro and in vivo

Selective inhibition of histone deacetylase 6 (HDAC6) has been emerged as a promising approach to cancer treatment. As a pivotal strategy for drug discovery,molecular hybridization was introduced in this study and a series of pyrrolo[2,1-c][1,4] benzodiazepine-3,11-diones (PBDs) based hydroxamic acids was rationally designed and synthesizedas novel selective HDAC6 inhibitors. Preliminary in vitro enzyme inhibition assay and structure–activity relationship (SAR) discussion confirmed our design strategy and met the expectation. Several of the compounds showed high potent against HDAC6 enzyme in vitro, and compound A7 with a long aliphatic linker was revealed to have the similar activity as the positive control tubastatin A. Further in vitro characterization of A7 demonstrates the metastasis inhibitory potency in MDA-MB-231 cell line and western blotting showed that A7 could induce the upregulation of Ac-α-tubulin, but not induce the excessive acetylation of histone H3, which indicated that the compound had HDAC6 targeting effect in MDA-MB-231 cells. In vivo study revealed that compound A7 has satisfactory inhibitory effects onliver and lung metastasis of breast cancer in mice. Molecular docking released that A7 could fit well with the receptor and interact with some key residues, which lays a foundation for further structural modifications to elucidate the interaction mode between compounds and target protein. This pharmacological investigation workflow provided a reasonable and reference methodto examine the pharmacological effects of inhibiting HDAC6 with a single molecule, either in vitro or in vivo. All of these results suggested that A7 is a promising lead compound that could lead to the further development of novel selective HDAC6 inhibitors for the treatment of tumor metastasis.

In vitro evaluation of new 4-thiazolidinones on invasion and growth of Toxoplasma gondii

Treatments for toxoplasmosis such as pyrimethamine have shown numerous side effects. It has been reported that the likelihood of relapse associated with pyrimethamine-based therapy in patients with HIV and toxoplasmic encephalitis (TE) can have significant implications, even for patients who often develop new lesions in areas of the brain previously free of infection. This led us to research for new agents against Toxoplasma gondii. Recent findings have shown the potent biological activity of 4-thiazolidinones. We proposed to design and synthesize a new series of 2-hydrazono-4-thiazolidinones derivatives to evaluate the in vitro growth inhibition effect on T. gondii. The growth rates of T. gondii tachyzoites in Human Foreskin Fibroblast (HFF) cell culture were identified by two in vitro methodologies. The first one was by fluorescence in which green fluorescent RH parasites and cherry-red fluorescent ME49 parasites were used. The second one was a colorimetric methodology using β-Gal parasites of the RH strain constitutively expressing the enzyme beta-galactosidase. The 4-thiazolidinone derivatives 1B, 2B and 3B showed growth inhibition at the same level of Pyrimethamine. These compounds showed IC50 values of 1B (0.468–0.952 μM), 2B (0.204–0.349 μM) and 3B (0.661–1.015 μM) against T. gondii. As a measure of cytotoxicity the compounds showed a TD50 values of: 1B (60 μM), 2B (206 μM) and 3B (125 μM). The in vitro assays and molecular modeling results suggest that these compounds could act as possible inhibitors of the Calcium-Dependent Protein Kinase 1 of T. gondii. Further, our results support the fact that of combining appropriate detection technologies, combinatorial chemistry and computational biology is a good strategy for efficient drug discovery. These compounds merit in vivo analysis for anti-parasitic drug detection.

Cloperastine inhibits esophageal squamous cell carcinoma proliferation in vivo and in vitro by suppressing mitochondrial oxidative phosphorylation

Esophageal squamous cell carcinoma (ESCC) is a major type of esophageal cancer. The prognosis of patients with ESCC remains poor because of the high morbidity and mortality of the disease. One strategy for drug discovery for ESCC treatment or prevention is screening FDA-approved drugs. In the present study, we found that the antitussive agent cloperastine can inhibit the proliferation of ESCC cells. However, the underlying mechanism was unclear. To determine the mechanism of this inhibitory effect, we performed proteomic analysis using KYSE150 cells treated with cloperastine and DMSO. The results identified several down-regulated signaling pathways included those of three key proteins (NADH dehydrogenase [ubiquinone] 1 alpha subcomplex 1, NADH ubiquinone oxidoreductase subunit S5, and cytochrome C oxidase subunit 6B1) involved in oxidative phosphorylation. Meanwhile, we observed that oxidative phosphorylation in mitochondria was inhibited by the drug. Importantly, cloperastine suppressed ESCC growth in a xenograft mouse model in vivo. Our findings revealed that cloperastine inhibits the proliferation of ESCC in vivo and in vitro by suppressing mitochondrial oxidative phosphorylation.

Human embryo research, stem cell-derived embryo models and invitro gametogenesis: Considerations leading to the revised ISSCR guidelines.

SummaryThe ISSCR Guidelines for Stem Cell Research and Clinical Translation were last revised in 2016. Since then, rapid progress has been made in research areas related to in vitro culture of human embryos, creation of stem cell-based embryo models, and in vitro gametogenesis. Therefore, a working group of international experts was convened to review the oversight process and provide an update to the guidelines. This report captures the discussion and summarizes the major recommendations made by this working group, with a specific emphasis on updating the categories of review and engagement with the specialized scientific and ethical oversight process.

A Comprehensive Review on Strategies for New Drug Discovery and Enhanced Productivity in Research and Development: Recent Advancements and Future Prospectives

At present, due to increased costs, decreased productivity, and lack of breakthrough technologies, many pharmaceutical firms face various challenges in their research and development projects. A variety of environmental concerns have also been gradually placing pressure on the pharmaceutical industry, including substantial profit losses due to patent expiration, more expensive health care facilities, and more stringent regulatory requirements. A system-oriented approach to finding innovative solutions is essential to this complicated problem. In our opinion, the key to solving these challenges is to increase the quality and number of creative and cost-effective new pharmaceutical products without incurring excessive R&D expenses, both for the future profitability of pharmaceutical industries and developments in healthcare. Our main emphasis is to highlight the strategies and models like Quality by Design, Lean Six Sigma, Organ-on-Chip, Chorus, AI, and so on in delivering innovations, which can be a good positive change for industries as to increase productivity in terms of time efficiency and innovation as well. These models focus on the creation and diffusion of knowledge internal to the firms. The major focus points should include critical investigation in innovations where the risk is high, as this can lead to the safer side of the development. We then propose specific strategies that could have the most substantial impact on improving R&D productivity. Besides this, the selection of strategy and models at the same point is as important as its implementation and its accurate selection can assist pharmaceutical companies to improve R&D organizations and their productivity.

Targeting γ-Secretase for Familial Alzheimer's Disease.

Familial Alzheimer's disease (FAD) is a rare early-onset genetic form of a common dementia of old age. Striking in middle age, FAD is caused by missense mutations in three genes: APP (encoding the amyloid precursor protein) and PSEN1 and PSEN2 (encoding presenilin-1 and presenilin-2). APP is proteolytically processed successively by β-secretase and γ-secretase to produce the amyloid β-peptide (Aβ). Presenilin is the catalytic component of γ-secretase, a membrane-embedded aspartyl protease complex that cleaves APP within its single transmembrane domain to produce Aβ of varying lengths. Thus, all FAD mutations are found in the substrate and the enzyme that produce Aβ. The 42-residue variant Aβ42 has been the primary focus of Alzheimer drug discovery for over two decades, as this particular peptide is highly prone to aggregation, is the major protein deposited in the characteristic cerebral plaques of Alzheimer's disease, and is proportionately elevated in FAD. Despite extensive efforts, all agents targeting Aβ and Aβ42 have failed in the clinic, including γ-secretase inhibitors, leading to questioning of the amyloid hypothesis of Alzheimer pathogenesis. However, processing of the APP transmembrane domain by γ-secretase is complex, involving initial endoproteolysis followed by successive carboxypeptidase trimming steps to secreted Aβ peptides such as Aβ42. Recent findings reveal that FAD mutations in PSEN1 and in APP result in deficient trimming of initially formed long Aβ peptides. A logical drug discovery strategy for FAD could therefore involve the search for compounds that rescue this deficient carboxypeptidase activity. The rare early-onset FAD arguably presents a simpler path to developing effective therapeutics compared to the much more complex heterogeneous sporadic Alzheimer's disease.

Development of Allosteric Modulators of Voltage-Gated Na+ Channels: A Novel Approach for an Old Target.

Given their primacy in governing the action potential (AP) of excitable cells, voltage-gated Na+ (Nav) channels are important pharmacological targets of therapeutics for a diverse array of clinical indications. Despite historically being a traditional drug target, therapeutics targeting Nav channels lack isoform selectivity, giving rise to off-target side effects. To develop isoform-selective modulators of Nav channels with improved target-specificity, the identification and pharmacological targeting of allosteric sites that display structural divergence among Nav channel isoforms represents an attractive approach. Despite the high homology among Nav channel α subunit isoforms (Nav1.1-Nav1.9), there is considerable amino acid sequence divergence among their constituent C-terminal domains (CTD), which enables structurally and functionally specific protein: protein interactions (PPI) with auxiliary proteins. Although pharmacological targeting of such PPI interfaces between the CTDs of Nav channels and auxiliary proteins represents an innovate approach for developing isoform-selective modulators of Nav channels, appreciable modulation of PPIs using small molecules has conventionally been difficult to achieve. After briefly discussing the challenges of modulating PPIs using small molecules, this current frontier review that follows subsequently expounds on approaches for circumventing such difficulties in the context of developing small molecule modulators of PPIs between transmembrane ion channels and their auxiliary proteins. In addition to broadly discussing such approaches, the implementation of such approaches is specifically discussed in the context of developing small molecule modulators between the CTD of Nav channels and auxiliary proteins. Developing allosteric modulators of ion channels by targeting their PPI interfaces with auxiliary proteins represents an innovative and promising strategy in ion channel drug discovery that could expand the "druggable genome" and usher in first-in-class PPI-targeting therapeutics for a multitude of channelopathies.

MGATRx: Discovering Drug Repositioning Candidates Using Multi-View Graph Attention.

In-silico drug repositioning or predicting new indications for approved or late-stage clinical trial drugs is a resourceful and time-efficient strategy in drug discovery. However, inferring novel candidate drugs for a disease is challenging, given the heterogeneity and sparseness of the underlying biological entities and their relationships (e.g., disease/drug annotations). By integrating drug-centric and disease-centric annotations as multi-views, we propose a multi-view graph attention network for indication discovery (MGATRx). Unlike most current similarity-based methods, we employ graph attention network on the heterogeneous drug and disease data to learn the representation of nodes and identify associations. MGATRx outperformed four other state-of-art methods used for computational drug repositioning. Further, several of our predicted novel indications are either currently investigated or are supported by literature evidence, demonstrating the overall translational utility of MGATRx.

A CDR-based approach to generate covalent inhibitory antibody for human rhinovirus protease

Covalent target modulation with small molecules has been emerging as a promising strategy for drug discovery. However, covalent inhibitory antibody remains unexplored due to the lack of efficient strategies to engineer antibody with desired bioactivity. Herein, we developed an intracellular selection method to generate covalent inhibitory antibody against human rhinovirus 14 (HRV14) 3C protease through unnatural amino acid mutagenesis along the heavy chain complementarity-determining region 3 (CDR-H3). A library of antibody mutants was thus constructed and screened in vivo through co-expression with the target protease. Using this screening strategy, six covalent antibodies with proximity-enabled bioactivity were identified, which were shown to covalently target HRV14-3C protease with high inhibitory potency and exquisite selectivity. Compared to structure-based rational design, this library-based screening method provides a simple and efficient way for the discovery and engineering of covalent antibody for enzyme inhibition.

The in vitro and in vivo study of oleanolic acid indole derivatives as novel anti-inflammatory agents: Synthesis, biological evaluation, and mechanistic analysis

Oleanolic acid (OA) is a well-known natural product possessing many important pharmacological activities; however, its weak bioactivities significantly restrict the potential application in drug development. The structural modification of oleanolic acid is an effective mean to enhance its bioactivity with lower toxicity but it is challenging. In the present study, we systematically synthesized a series of new 11-oxooleanolic acid derivatives and evaluated their anti-inflammatory activities with a LPS induced BV2 cells inflammation model and a 12-O-tetradecanoyl phorbol-13-acetate (TPA) induced ear inflammation mice model. It was found that compounds 8 and 9 show more potent anti-inflammatory effects than OA and exhibit a low cytotoxicity. The possible mechanism of action was also investigated. The in vitro and in vivo results revealed that these two new 11-oxooleanolic acid derivatives may exert anti-inflammatory activities through the inhibition of NO, pro-inflammatory cytokines and chemokines (IL-1β, IL-6, IL-12, TNF-α, MCP-1 and MIP-1α) and upregulation of anti-inflammatory cytokines (IL-10), which may be caused by inhibiting the activation of NF-κB, MAPKs and PI3K/Akt related inflammatory signaling pathways and the activation of Nrf2/HO-1 signaling pathway. The results suggest that these two 11-oxooleanolic acid derivatives may be potential candidates for further anti-inflammatory drug development and our study demonstrated an important and practical strategy for drug discovery through the rational modification of natural products.

Therapeutic approaches for SARS-CoV-2 infection.

Therapeutic approaches to COVID-19 treatment require appropriate inhibitors to target crucial proteins of SARS-CoV-2 replication machinery. It’s been approximately 12 months since the pandemic started, yet no known specific drugs are available. However, research progresses with time in terms of high throughput virtual screening (HTVS) and rational design of repurposed, novel synthetic and natural products discovery by understanding the viral life cycle, immuno-pathological and clinical outcomes in patients based on host’s nutritional, metabolic, and lifestyle status. Further, complementary and alternative medicine (CAM) approaches have also improved resiliency and immune responses. In this article, we summarize all the therapeutic antiviral strategies for COVID-19 drug discovery including computer aided virtual screening, repurposed drugs, immunomodulators, vaccines, plasma therapy, various adjunct therapies, and phage technology to unravel insightful mechanistic pathways of targeting SARS-CoV-2 and host’s intrinsic, innate immunity at multiple checkpoints that aid in the containment of the disease.

A machine learning platform to estimate anti-SARS-CoV-2 activities

Strategies for drug discovery and repositioning are urgently need with respect to COVID-19. Here we present REDIAL-2020, a suite of computational models for estimating small molecule activities in a range of SARS-CoV-2-related assays. Models were trained using publicly available, high-throughput screening data and by employing different descriptor types and various machine learning strategies. Here we describe the development and use of eleven models that span across the areas of viral entry, viral replication, live virus infectivity, in vitro infectivity and human cell toxicity. REDIAL-2020 is available as a web application through the DrugCentral web portal ( http://drugcentral.org/Redial ). The web application also provides similarity search results that display the most similar molecules to the query, as well as associated experimental data. REDIAL-2020 can serve as a rapid online tool for identifying active molecules for COVID-19 treatment. There is an urgent need to identify drugs that may be effective against SARS-CoV-2. A platform with a range of machine learning models is made available to predict anti-COVID-19 activity in candidate drugs and to help prioritize compounds for virtual screening.