Product Library Research Articles

Structure-based screening of natural product libraries in search of potential antiviral drug-leads as first-line treatment to COVID-19 infection

The study focuses on identifying and screening natural products (NPs) based on their structural similarities with chemical drugs followed by their possible use in first-line treatment to COVID-19 infection. In the present study, the in-house natural product libraries, consisting of 26,311 structures, were screened against potential targets of SARS-CoV-2 based on their structural similarities with the prescribed chemical drugs. The comparison was based on molecular properties, 2 and 3-dimensional structural similarities, activity cliffs, and core fragments of NPs with chemical drugs. The screened NPs were evaluated for their therapeutic effects based on their predicted in-silico pharmacokinetic and pharmacodynamics properties, binding interactions with the appropriate targets, and structural stability of the bound complex using molecular dynamics simulations. The study yielded NPs with significant structural similarities to synthetic drugs currently used to treat COVID-19 infections. The study proposes the probable biological action of the selected NPs as Anti-retroviral protease inhibitors, RNA-dependent RNA polymerase inhibitors, and viral entry inhibitors.

Investigation of Antiparasitic Activity of Two Marine Natural Products, Estradiol Benzoate, and Octyl Gallate, on Toxoplasma gondii In Vitro.

Toxoplasmosis, caused by Toxoplasma gondii, is a common disease worldwide and could be severe and even fatal in immunocompromised individuals and fetuses. Limitation in current available treatment options drives the need to develop novel therapeutics. This study assessed the anti-T. gondii potential of 103 marine natural products. A luminescence-based β-galactosidase activity assay was used to screen the marine natural products library. Afterward, those compounds that displayed over 70% parasite inhibition ratio were further chosen to assess their cytotoxicity. Compounds exhibiting low cytotoxicity (≥80% cell viability) were applied to evaluate the inhibition efficacy on discrete steps of the T. gondii lytic cycle, including invasion, intracellular growth, and egress abilities as well as the cell cycle. We found that both estradiol benzoate and octyl gallate caused >70% inhibition of tachyzoite growth with IC50 values of 4.41 ± 0.94 and 5.66 ± 0.35 μM, respectively, and displayed low cytotoxicity with TD50 values of 34.11 ± 2.86 and 26.4 ± 0.98 μM, respectively. Despite their defects in inhibition of invasion and egress of tachyzoite, the two compounds markedly inhibited the tachyzoite intracellular replication. Flow cytometric analyses further suggested that the anti-T. gondii activity of estradiol benzoate, rather than octyl gallate, may be linked to halting cell cycle progression of tachyzoite from G1 to S phase. Taken together, these findings suggest that both estradiol benzoate and octyl gallate are potential inhibitors for anti-T. gondii infection and support the further exploration of marine natural products as a thinkable source of alternative and active agents against T. gondii.

In Silico and In Vitro Identification of Pan-Coronaviral Main Protease Inhibitors from a Large Natural Product Library.

The main protease (Mpro or 3CLpro) in coronaviruses represents a promising specific drug target as it is essential for the cleavage of the virus polypeptide and has a unique cleavage site that does not exist in human host proteases. In this study, we explored potential natural pan-coronavirus drugs using in vitro and in silico approaches and three coronavirus main proteases as treatment targets. The PyRx program was used to screen 39,442 natural-product-like compounds from the ZINC database and 121 preselected phytochemicals from medicinal plants with known antiviral activity. After assessment with Lipinski’s rule of five, molecular docking was performed for the top 33 compounds of both libraries. Enzymatic assays were applied for the top candidates from both in silico approaches to test their ability to inhibit SARS-CoV-2 Mpro. The four compounds (hypericin, rosmarinic acid, isorhamnetin, and luteolin) that most efficiently inhibited SARS-CoV-2 Mpro in vitro were further tested for their efficacy in inhibiting Mpro of SARS-CoV-1 and MERS-CoV. Microscale thermophoresis was performed to determine dissociation constant (Kd) values to validate the binding of these active compounds to recombinant Mpro proteins of SARS-CoV-2, SARS-CoV-1, and MERS-CoV. The cytotoxicity of hypericin, rosmarinic acid, isorhamnetin, and luteolin was assessed in human diploid MRC-5 lung fibroblasts using the resazurin cell viability assay to determine their therapeutic indices. Sequence alignment of Mpro of SARS-CoV-2 demonstrated 96.08%, 50.83%, 49.17%, 48.51%, 44.04%, and 41.06% similarity to Mpro of other human-pathogenic coronaviruses (SARS-CoV-1, MERS-CoV, HCoV-NL63, HCoV-OC43, HCoV-HKU1, and HCoV-229E, respectively). Molecular docking showed that 12 out of 121 compounds were bound to SARS-CoV-2 Mpro at the same binding site as the control inhibitor, GC376. Enzyme inhibition assays revealed that hypericin, rosmarinic acid, isorhamnetin, and luteolin inhibited Mpro of SARS-CoV-2, while hypericin and isorhamnetin inhibited Mpro of SARS-CoV-1; hypericin showed inhibitory effects toward Mpro of MERS-CoV. Microscale thermophoresis confirmed the binding of these compounds to Mpro with high affinity. Resazurin assays showed that rosmarinic acid and luteolin were not cytotoxic toward MRC-5 cells, whereas hypericin and isorhamnetin were slightly cytotoxic. We demonstrated that hypericin represents a potential novel pan-anti-coronaviral agent by binding to and inhibiting Mpro of several human-pathogenic coronaviruses. Moreover, isorhamnetin showed inhibitory effects toward SARS-CoV-2 and SARS-CoV-1 Mpro, indicating that this compound may have some pan-coronaviral potential. Luteolin had inhibitory effects against SARS-CoV-2 Mpro.

An in silico hierarchal approach for drug candidate mining and validation of natural product inhibitors against pyrimidine biosynthesis enzyme in the antibiotic-resistant Shigella flexneri.

Shigella flexneri is the main causative agent of the communicable diarrheal disease, shigellosis. It is estimated that about 80-165 million cases and>1 million deaths occur every year due to this disease. S. flexneri causes dysentery mostly in young children, elderly and immunocompromised patients, all over the globe. Recently, due to the emergence of S. flexneri antibiotic resistance strains, it is a dire need to predict novel therapeutic drug targets in the bacterium and screen natural products against it, which could eliminate the curse of antibiotic resistance. Therefore, in current study, available antibiotic-resistant genomes (n=179) of S. flexneri were downloaded from PATRIC database and a pan-genome and resistome analysis was conducted. Around 5059 genes made up the accessory, 2469 genes made up the core, and 1558 genes made up the unique genome fraction, with 44, 34, and 13 antibiotic-resistant genes in each fraction, respectively. Core genome fraction (27% of the pan-genome), which was common to all strains, was used for subtractive genomics and resulted in 384 non-homologous, and 85 druggable targets. Dihydroorotase was chosen for further analysis and docked with natural product libraries (Ayurvedic and Streptomycin compounds), while the control was orotic acid or vitamin B13 (which is a natural binder of this protein). Dynamics simulation of 50ns was carried out to validate findings for top-scored inhibitors. The current study proposed dihydroorotase as a significant drug target in S. flexneri and 4-tritriacontanone & patupilone compounds as potent drugs against shigellosis. Further experiments are required to ascertain validity of our findings.

Identification of Gossypol Acetate as an Autophagy Modulator with Potent Anti-tumor Effect against Cancer Cells.

Autophagy, an evolutionarily conserved process, is intricately involved in many aspects of human health and a variety of human diseases, including cancer. Discovery of small-molecule autophagy modulators with potent anticancer effect would be of great significance. To this end, a natural product library consisting of 170 natural compounds were screened as autophagy modulators with potent cytotoxicity in our present study. Among these compounds, gossypol acetate (GAA), the mostly used medicinal form of gossypol, was identified. GAA effectively increased the number of autophagic puncta in GFP-LC3B-labeled 293T cells and significantly decreased cell viability in different cancer cells. In A549 cells, GAA at concentrations below 10 μM triggered caspase-independent cell death via targeting autophagy, as evidenced by elevated LC3 conversion and decreased p62/SQSTM1 levels. Knocking down of LC3 significantly attenuated GAA-induced cell death. Mechanistically, GAA at low concentrations induced autophagy through targeting AMPK-mTORC1-ULK1 signaling. Interestingly, high concentrations of GAA induced LC3 conversion, p62 accumulation, and yellow autophagosome formation, indicating that GAA at high concentrations blocked autophagic flux. Mechanistically, GAA decreased intracellular ATP level and suppressed lysosome activity. Exogenous ATP partially reversed the inhibitory effect of GAA on autophagy, suggesting that decreased ATP level and lysosome activity might be involved in the blocking of autophagy flux by GAA. Collectively, our present study reveals the mechanisms by which GAA modulates autophagy and illustrates whether autophagy regulation by GAA is functionally involved in GAA-induced cancer cell death.

Binding Studies of the Prodrug HAO472 to SARS-Cov-2 Nsp9 and Variants.

SARS-CoV-2 (COVID-19) has infected over 219 million people and caused the death of over 4.55 million worldwide. In a previous screen of a natural product library against purified SARS-CoV-2 Nsp9 using a native mass spectrometry-based approach, we identified an ent-kaurane natural product, oridonin (1), with micromolar affinities. In this work, we have found that the prodrug HAO472 (2) directly binds to Nsp9, establishing replacement of the labile ester with a bioisostere as a candidate drug strategy. We further tested 1 and its clinical analogue 2 against two Nsp9 variants from human coronavirus 229E (HCoV-229E) and ferret systemic coronavirus F56 (FSCoV-F56). Both compounds showed significant binding selectivity to COVID-19 and HCoV-229E Nsp9 over FSCoV-F56 Nsp9, confirming the covalent bond with Cys73.

Efficient ofloxacin degradation via photo-Fenton process over eco-friendly MIL-88A(Fe): Performance, degradation pathways, intermediate library establishment and toxicity evaluation

The high-throughput production of the eco-friendly MIL-88A(Fe) was achieved under mild reaction conditions with normal pressure and temperature. The as-prepared MIL-88A(Fe) exhibited efficient photo-Fenton catalytic ofloxacin (OFL) degradation upon visible light irradiation with good stability and reusability. The OFL (20.0 mg/L) was completely degraded within 50 min under visible light with the aid of MIL-88A(Fe) (0.25 g/L) and H2O2 (1.0 mL/L) in aqueous solution (pH = 7.0). The hydroxyl radicals (·OH) are the main active species during the photo-Fenton oxidation process. Meanwhile, the degradation intermediates and the corresponding degradation pathways were identified and proposed with the aid of both ultra-high performance liquid chromatography tandem quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS) and density functional theory (DFT) calculations. Finally, the degradation product library was firstly established to identify intermediate transformation products (TPs) with their variation of concentration, and their corresponding toxicologic activities were assessed via Toxtree and T.E.S.T software as well. Finally, the MIL-88A is efficient and stable with four cycles’ catalysis operations, demonstrating good potential for water treatment.

Synthesis and antiviral activity of formycin derivatives with anti-influenza virus activity

In a screening using our unique natural product library, the C-nucleoside antibiotic formycin A, which exerts strong anti-influenza virus activity, was rediscovered. Aiming to develop a new type of anti-influenza virus drug, we synthesized new derivatives of formycin and evaluated its anti-influenza virus activity. Structural modifications were focused on the base moiety and sugar portion, respectively, and >40 novel formycin derivatives were synthesized. Modification of the C-7 position of the pyrazolopyrimidine ring strongly contributed to improve the activity. In particular, excellent anti-influenza virus activity was observed in the NHMe (10), SMe (12), and SeMe (15) derivatives, in which heteroatoms were introduced. In addition, in the modification of the sugar moiety, the presence of a hydroxyl group and its stereochemistry greatly affected both the expression and intensity of the activity. Furthermore, the evaluation results of the 7-SEt derivative (29) and the 2′-modified derivative (59) suggested that structural modifications may reduce cytotoxicity.

The Triprenylated Anthranoid Ferruginin A, a Promising Scaffold for the Development of Novel Antibiotics against Gram-Positive Bacteria.

In today’s post-antibiotic era, the search for new antimicrobial compounds is of major importance and nature represents one of the primary sources of bioactive molecules. In this work, through a cheminformatics approach, we clustered an in-house library of natural products and their derivatives based on a combination of fingerprints and substructure search. We identified the prenylated emodine-type anthranoid ferruginin A as a novel antimicrobial compound. We tested its ability to inhibit and kill a panel of Gram-positive and Gram-negative bacteria, and compared its activity with that of two analogues, vismione B and ferruanthrone. Furthermore, the capability of these three anthranoids to disrupt staphylococcal biofilm was investigated, as well as their effect on the viability of human keratinocytes. Ferruginin A showed a potent activity against both the planktonic and biofilm forms of Gram-positive bacteria (i.e., Staphylococcus aureus and S. epidermidis) and had the best therapeutic index compared to vismione B and ferruanthrone. In conclusion, ferruginin A represents a promising scaffold for the further development of valuable antimicrobial agents.

Modern Approaches in the Discovery and Development of Plant-Based Natural Products and Their Analogues as Potential Therapeutic Agents.

Natural products represents an important source of new lead compounds in drug discovery research. Several drugs currently used as therapeutic agents have been developed from natural sources; plant sources are specifically important. In the past few decades, pharmaceutical companies demonstrated insignificant attention towards natural product drug discovery, mainly due to its intrinsic complexity. Recently, technological advancements greatly helped to address the challenges and resulted in the revived scientific interest in drug discovery from natural sources. This review provides a comprehensive overview of various approaches used in the selection, authentication, extraction/isolation, biological screening, and analogue development through the application of modern drug-development principles of plant-based natural products. Main focus is given to the bioactivity-guided fractionation approach along with associated challenges and major advancements. A brief outline of historical development in natural product drug discovery and a snapshot of the prominent natural drugs developed in the last few decades are also presented. The researcher’s opinions indicated that an integrated interdisciplinary approach utilizing technological advances is necessary for the successful development of natural products. These involve the application of efficient selection method, well-designed extraction/isolation procedure, advanced structure elucidation techniques, and bioassays with a high-throughput capacity to establish druggability and patentability of phyto-compounds. A number of modern approaches including molecular modeling, virtual screening, natural product library, and database mining are being used for improving natural product drug discovery research. Renewed scientific interest and recent research trends in natural product drug discovery clearly indicated that natural products will play important role in the future development of new therapeutic drugs and it is also anticipated that efficient application of new approaches will further improve the drug discovery campaign.

N-acetylglucosamine-phosphatidylinositol de-N-acetylase as a novel target for probing potential inhibitor against Leishmania donovani

Leishmania donavani is the causative agent of leishmaniasis, responsible for social and economic disruption, especially in developing countries. Lack of effective drugs with few side effects have necessitated the discovery of newer therapeutic solutions for leishmaniasis. Glycophosphatidylinositol (GPI) synthesis plays a vital role in protozoan cell membranes structural formation and antigenic modification. Hence, any disruption in its biosynthesis can prove fatal to the parasitic protozoans. N-acetylglucosamine-phosphatidylinositol de-N-acetylase (NAGP-deacetylase) is an enzyme from the GPI biosynthetic pathway that catalyzes the deacetylation of N-acetylglucosaminylphosphatidylinositol to glucosaminylphosphatidylinositol, a step essential for the proper functioning of the enzyme. In the quest for novel scaffolds as anti-leishmaniasis agents, we have executed in silico virtual screening, density function theory, molecular dynamics and MM-GBSA based energy calculations with a natural product library and a diverse library set from Chembridge database. Two compounds, 14671 and 4610, were identified at the enzyme's active site and interacted with catalytic residues, Asp43, Asp44, His41, His147, His 150, Arg80 and Arg231. Both molecules exhibited stable conformation in their protein-ligand complexes with binding free energies for compound-14671 and compound-4610 of −54 ± 4 and −50 ± 4 kcal/mol, respectively. These scaffolds can be incorporated in future synthetic determinations, focusing on developing druggable inhibitor support, increasing potency, and introducing species selectivity. Communicated by Ramaswamy H. Sarma

DNA-Compatible Nitro Reduction and Synthesis of Benzimidazoles.

A key factor for productive DNA-encoded libraries is the chemical diversity of the small molecule moiety attached to an encoding DNA oligomer. The library structure diversity is often limited to DNA-compatible chemical reactions in aqueous media. Herein, we describe a facile process for reducing aryl nitro groups to aryl amines by using sodium dithionite (Na2S2O4). The new protocol offers simple operation and circumvents the pyrophoric potential of the conventional method (Raney nickel). The utility of this method is demonstrated by the versatile synthesis of benzimidazoles on DNA.

Computer-aided identification of potential inhibitors against Necator americanus glutathione S-transferase 3

Hookworm infection is caused by the blood-feeding hookworm gastrointestinal nematodes. Its harmful effects include anemia and retarded growth and are common in the tropics. A current control method involves the mass drug administration of synthetic drugs, mainly albendazole and mebendazole. There are however concerns of low efficacy and drug resistance due to their repeated and excessive use. Although, Necator americanus glutathione S-transferase 3 (Na-GST-3) is a notable target, using natural product libraries for computational elucidation of promising leads is underexploited. This study sought to use pharmacoinformatics techniques to identify compounds of natural origins with the potential to be further optimized as promising inhibitors. A compendium of 3182 African natural products together with five known helminth GST inhibitors including Cibacron blue was screened against the active sites of the Na-GST-3 structure (PDB ID: 3W8S). The hit compounds were profiled to ascertain the mechanisms of binding, anthelmintic bioactivity, physicochemical and pharmacokinetic properties. The AutoDock Vina docking protocol was validated by obtaining 0.731 as the area under the curve calculated via the receiver operating characteristics curve. Four compounds comprising ZINC85999636, ZINC35418176, ZINC14825190, and Dammarane Triterpene13 were identified as potential lead compounds with binding energies less than −9.0 kcal/mol. Furthermore, the selected compounds formed key intermolecular interactions with critical residues Tyr95, Gly13 and Ala14. Notably, ZINC85999636, ZINC14825190, and dammarane triterpene13 were predicted as anthelmintics, whilst all the four molecules shared structural similarities with known inhibitors. Molecular modelling showed that the compounds had reasonably good binding free energies. More so, they had high binding affinities when screened against other variants of the Na-GST, namely Na-GST-1 and Na-GST-2. Ligand quality assessment using ligand efficiency dependent lipophilicity, ligand efficiency, ligand efficiency scale and fit quality scale showed the molecules are worthy candidates for further optimization. The inhibitory potentials of the molecules warrant in vitro studies to evaluate their effect on the heme regulation mechanisms.

Phenotypic screening of compound libraries as a platform for the identification of antibiotic adjuvants: Identification of colistin adjuvants from a natural product library.

The identification of antibiotic adjuvants, small molecules that potentiate the activity of conventional antibiotics, provides an orthogonal approach to the development of new antibiotics in the fight against drug resistant bacterial infections. Methods to identify novel adjuvants could potentially aid efforts to overcome the increasing prevalence of resistance and stave off the onset of a "post-antibiotic era." Phenotypic whole cell screens allow for the identification of hits with the necessary properties to access their biomolecular target, and may also facilitate the discovery of novel adjuvant targets. A phenotypic screening platform is outlined, in which a natural product library was explored for activity with antibiotics from several mechanistically distinct classes against clinically important bacterial species. General approaches to delineating the mechanism of action of hit compounds identified from phenotypic screens are described, followed by specific approaches to uncovering the mechanism of action of the colistin adjuvants identified from the natural product screen.

Computational identification of natural product inhibitors against EGFR double mutant (T790M/L858R) by integrating ADMET, machine learning, molecular docking and a dynamics approach.

Double mutated epidermal growth factor receptor is a clinically important target for addressing drug resistance in lung cancer treatment. Therefore, discovering new inhibitors against the T790M/L858R (TMLR) resistant mutation is ongoing globally. In the present study, nearly 150 000 molecules from various natural product libraries were screened by employing different ligand and structure-based techniques. Initially, the library was filtered to identify drug-like molecules, which were subjected to a machine learning based classification model to identify molecules with a higher probability of having anti-cancer activity. Simultaneously, rules for constrained docking were derived from three-dimensional protein–ligand complexes and thereafter, constrained docking was undertaken, followed by HYDE binding affinity assessment. As a result, three molecules that resemble interactions similar to the co-crystallized complex were selected and subjected to 100 ns molecular dynamics simulation for stability analysis. The interaction analysis for the 100 ns simulation period showed that the leads exhibit the conserved hydrogen bond interaction with Gln791 and Met793 as in the co-crystal ligand. Also, the study indicated that Y-shaped molecules are preferred in the binding pocket as it enables them to occupy both pockets. The MMGBSA binding energy calculations revealed that the molecules have comparable binding energy to the native ligand. The present study has enabled the identification of a few ADMET adherent leads from natural products that exhibit the potential to inhibit the double mutated drug-resistant EGFR.

DNA Encoding of Natural Products.

DNA-encoded library (DEL) links the powers of genetics and chemicals via high-efficient enzymatic ligation of DNA barcodes and the "split and pool" combinatorial synthesis. Natural products (NPs) are evolutionary optimized compounds that have played a key role in the history of human drug discovery. Herein, we describe a method for functionality-independent annotation of complex natural products with amplifiable DNA barcodes to generate a DNA-encoded natural product library (nDEL). This method provides a simple and practical solution to leverage natural products by DNA barcoding.

In silico study to identify new monoamine oxidase type a (MAO-A) selective inhibitors from natural source by virtual screening and molecular dynamics simulation

Neurological (such as stroke, Alzheimer's, Parkinson's, epilepsy) and neuropsychiatric (such as autism, migraine, depression, anxiety, stress) disorders continue to be on rising every year with an increase of 20.5% and 13%, respectively. These diseases are critical, life-threatening and in most cases may lead to other precarious human disorders and causing a psychological as well as economic burden on patients and society all over the world that consequently led to a high mortality rate. Notably, Monoamine oxidase (MAO) enzymes are classified as potential drug target for the treatment of such neurological disorders because of their significant role in neurotransmitter degradation that results in the production of certain neurotoxic compounds (such as H2O2, NH3). So far, many MAO inhibitors have been introduced however, the need for a novel potent therapeutic alternative still exists due to significant hypertensive crises, hepatotoxicity and extremely poor selectivity related to nonselective irreversible MAOIs. Therefore, the goal of the current study was to find novel natural compounds that may be used as medicine to treat neurological disorders without causing any harmful side effect. For this purpose, a computational-based virtual screening of 29,000 natural product library (of Natural Product Atlas) from the microbial source is performed through molecular docking and dynamics simulation approach. As a result, about 20 novel potent compounds were successfully shortlisted by implementing molecular docking studies, certain pharmacological, physiological and ADMET properties criteria. Among them, six compounds i.e., NPA000487, 001,637, 007,129, 012,149, 15,149 and NPA0018844 were predicted with a potential to cross BBB and target MAO-A. Furthermore, MD simulations were performed to evaluate the stability and dynamics behavior of these compounds with MAO-A complex for about 50 ns. Eventually, NPA007129, NPA0012149, and NPA0015149 were identified as highly steady complex after 15 ns. Our findings implied that NPA007129, NPA0012149, and NPA0015149 are potential MAO-A inhibitors. Nevertheless, further experimental validation is needed as part of the follow-up investigation.

Structure-Based Pharmacophore Modeling, Virtual Screening, Molecular Docking, ADMET, and Molecular Dynamics (MD) Simulation of Potential Inhibitors of PD-L1 from the Library of Marine Natural Products.

Background: In the past decade, several antibodies directed against the PD-1/PD-L1 interaction have been approved. However, therapeutic antibodies also exhibit some shortcomings. Using small molecules to regulate the PD-1/PD-L1 pathway may be another way to mobilize the immune system to fight cancer. Method: 52,765 marine natural products were screened against PD-L1(PDBID: 6R3K). To identify natural compounds, a structure-based pharmacophore model was generated, following by virtual screening and molecular docking. Then, the absorption, distribution, metabolism, and excretion (ADME) test was carried out to select the most suitable compounds. Finally, molecular dynamics simulation was also performed to validate the binding property of the top compound. Results: Initially, 12 small marine molecules were screened based on the pharmacophore model. Then, two compounds were selected for further evaluation based on the molecular docking scores. After ADME and toxicity studies, molecule 51320 was selected for further verification. By molecular dynamics analysis, molecule 51320 maintains a stable conformation with the target protein, so it has the chance to become an inhibitor of PD-L1. Conclusions: Through structure-based pharmacophore modeling, virtual screening, molecular docking, ADMET approaches, and molecular dynamics (MD) simulation, the marine natural compound 51320 can be used as a small molecule inhibitor of PD-L1.

Predictive modeling and therapeutic repurposing of natural compounds against the receptor-binding domain of SARS-CoV-2

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a member of the Coronaviridae family, causing major destructions to human life directly and indirectly to the economic crisis around the world. Although there is significant reporting on the whole genome sequences and updated data for the different receptors are widely analyzed and screened to find a proper medication. Only a few bioassay experiments were completed against SARS-CoV-2 spike protein. We collected the compounds dataset from the PubChem Bioassay database having 1786 compounds and split it into the ratio of 80–20% for model training and testing purposes, respectively. Initially, we have created 11 models and validated them using a fivefold validation strategy. The hybrid consensus model shows a predictive accuracy of 95.5% for training and 94% for the test dataset. The model was applied to screen a virtual chemical library of Natural products of 2598 compounds. Our consensus model has successfully identified 75 compounds with an accuracy range of 70–100% as active compounds against SARS-CoV-2 RBD protein. The output of ML data (75 compounds) was taken for the molecular docking and dynamics simulation studies. In the complete analysis, the Epirubicin and Daunorubicin have shown the docking score of −9.937 and −9.812, respectively, and performed well in the molecular dynamics simulation studies. Also, Pirarubicin, an analogue of anthracycline, has widely been used due to its lower cardiotoxicity. It shows the docking score of −9.658, which also performed well during the complete analysis. Hence, after the following comprehensive pipeline-based study, these drugs can be further tested in vivo for further human utilization. Communicated by Ramaswamy H. Sarma

A natural product, (S)-10-Hydroxycamptothecin inhibits pseudorabies virus proliferation through DNA damage dependent antiviral innate immunity

Pseudorabies virus (PRV), a member of the subfamily alphaherpesvirinae, is one of the most important pathogenes that cause acute death in infected pigs and leads to substantial economic losses in the global swine industry. Recently, China's emerging PRV mutant strains resulted in the traditionally commercial vaccines not providing complete protection. Some studies reported that PRV could infect humans and cause endophthalmitis and encephalitis under certain circumstances. It is necessary to develop alternative manners to control the virus infection. Here, by screening a library of natural products, (S)-10-Hydroxycamptothecin (10-HCPT) was revealed to inhibit PRV replication with a selective index of 270.04. And 10-HCPT inhibited PRV replication by blocking the viral genome replication but not inhibiting the viral attachment, internalization, and release. RNA interference assay showed that 10-HCPT inhibited PRV replication by targeting DNA topoisomerase 1 (TOP1). Meanwhile, 10-HCPT treatment induced DNA damage response and stimulated antiviral innate immunity. Animal challenge experiments showed that 10-HCPT effectively alleviated clinical signs and hispathology, and increased INF-β responses in lung and brain tissues of mice induced by PRV infection. The results demonstrate that 10-HCPT is a promising therapeutic agent to control PRV infection.