Sustained Delivery of Rifampicin Nanoformulation Administration Intravitreally Into Rabbit Eyes for Ocular Tuberculosis.

INTRODUCTION: Diagnosis and treatment of ocular tuberculosis is very challenging. It poses a significant and potential management dilemma after diagnosis as a primary, active, or secondary infection. The higher amounts of orally administered antitubercular drugs are needed to achieve the therapeutic concentration in the eye, which may lead to a higher risk of side effects. However, the intravitreal administration of drugs is not practiced because of the frequent administration of the injections. METHODS: This study was carried out to develop, optimize, and characterize rifampicin-loaded poly (lactic-co-glycolic acid) (PLGA) nanoparticles to make them sustained release followed by the direct administration of plain rifampicin and rifampicin nano-formulations in the vitreous of rabbit eyes. Both groups were comparatively assessed for the sustained delivery of the two preparations in the vitreous and their systemic toxicity. RESULTS: The characteristics of rifampicin-loaded nanoparticles were 786 nm in size with narrow size distribution along with a zeta potential of -12 mV. The drug encapsulation efficiency and loading capacity were 67.68% w/w and 42.28% w/w, respectively. The four New Zealand white rabbits were divided into two groups and given plain rifampicin (50µl volume) and PLGA nanoformulations of rifampicin (50µl volume) in each eye. In vivo, rifampicin-loaded PLGA nanoparticles produced sustained release of rifampicin for a week, even obtaining the 0.51 µg/ml levels on the seventh day in vitreous against negligible levels after one day for free rifampicin. The Cmax levels for free Rifampicin and Rifampicin nanoparticles were 0.44 µg/ml and 1.86 µg/ml, respectively. CONCLUSION: In this experimental proof-of-concept study, we have found that rifampicin-loaded PLGA nanoparticles released rifampicin in a sustained manner for up to seven days compared to free drugs only for one day into the vitreous. The intravitreal-administered drug did not reach systemic circulation.

Dostarlimab: Review on success story and clinical trials.

The PD-1/PD-L1 pathway plays a significant role in inhibiting, escaping from immune response, and promoting self-tolerance of the tumour. Dostarlimab is a selective humanized monoclonal antibody designed to target PD-1 and block its activity with PD-L1, which further prevents the escape of tumour cells from immune surveillance. It got accelerated approval from the FDA for treating adults with mismatch repair deficient, recurrent, or advanced endometrial cancer, and studies confirmed its beneficial effects. A recently published clinical trial reported 100 % remission of advanced rectal cancer without significant side effects in the participants. This clinical trial is still going on and enrolling patients with different types of cancer, including ovarian cancer, melanoma, head and neck cancer, and breast cancer therapy. The clinical trial result gave hope and proof to the medical fraternity and patients for better treatment. The focus of this review is to summarise pre-clinical and clinical studies of Dostarlimab.

Identification and in-vitro analysis of potential proteasome inhibitors targeting PSMß5 for multiple myeloma.

The proteasome subunit ß5 (PSMß5) is a chief target of proteasome inhibitors (PIs) for treatment of multiple myeloma (MM). The relevance of PSMß5 mutations and their functional impact on the development of resistance to PIs have been demonstrated recently. Therefore, this present study deals with an in-depth E-pharmacophore based screening and repurposing of FDA-approved drugs that could target PSMß5 for MM. Our molecular docking-based investigation revealed risedronate and zoledronate as potential alternative therapeutic molecules for targeting the PSMß5 gene. Risedronate and zoledronate displayed high binding affinity (-9.51 and -8.56 kcal/mol respectively) to PSMß5. Moreover, 100 ns molecular dynamics simulation analysis of docking complexes revealed risedronate and zoledronate with a superior binding free energies and stable interactions with PSMß5. The RMSD plot shows that the risedronate-PSMß5 (mean: 0.24 nm) and zoledronate-PSMß5 (mean: 0.25 nm) complexes are identical and stays stable until 100 ns. We further validated the activity of zoledronate in MM cell lines RPMI8226 and U266 where zoledronate showed significant anti-proliferative and apoptotic activity. Importantly, zoledronate showed an enhanced anti-proliferative activity when combined with bortezomib in MM cell lines. Thus, this study demonstrates that combining bortezomib with zoledronate could have a significant impact on reducing MM cell growth and can be an alternative strategy for treating MM.

DFT and MD investigations of the biomolecules of phenothiazine derivatives: interactions with gold and water molecules and investigations in search of effective drug for SARS-CoV-2.

Theoretical analyses of two phenothiazine derivatives, 10-[3-(dimethylamino)-2-methylpropyl]phenothiazine-2-carbonitrile (CYM) and 2-[4-[3-(2-chlorophenothiazin-10-yl)propyl]piperazin-1-yl]ethanol (PAZ) are reported using density functional theory (DFT) and molecular dynamics (MD) simulations. Spectroscopic studies, different electronic and chemical parameters are predicted. Red and yellow in electrostatic potential plot is in rings and oxygen atom in PAZ and C≡N and rings in CYM are sensitive to nucleophilic attacks. The blue in hydrogen atoms refer to electrophilic attack in both PAZ and CYM. Stability of the protein-ligand complex formed with these derivatives and angiotensin-converting enzyme 2 (ACE2) was investigated using MD simulation. Radius of gyration of C-alpha atom of 6VW1 displayed the conformational convergence toward a compact structure leading to stable 6VW1-ligand complex which are also in agreement with root mean square fluctuation (RMSF) values. Localized area predicts reactive sites for Au and H2O molecules interaction with these compounds for further practical applications. Charge density is localized on both molecules and also tries to move toward Au-Au dimer and water molecule and such they are expected to contribute to the sensing performance.Communicated by Ramaswamy H. Sarma.

A comprehensive exploration of pharmacological properties, bioactivities and inhibitory potentiality of luteolin from Tridax procumbens as anticancer drug by in-silico approach.

Tridax procumbens is a flowering plant of the Asteraceae family with a wide range of medicinal uses like anti-inflammatory, anti-diabetic, anti-microbial, immunomodulatory, etc. This study aimed to investigate the anti-cancerous activity of human lung cancer for targeting luteolin, a phytochemical of Tridax procumbens. The computational study has been done for studying the structural properties of luteolin. The drug-likeness of the molecule has been predicted by virtual screening of ADMET properties. The molecular docking technique of the in-silico method is performed to check the complex formation between protein and ligand. The reactivity and stability of the molecule are investigated with the help of molecular dynamics (MD) simulations. In the present work, we have tried to establish a strong candidature of any of the phytochemical of Tridax Procumbens as an inhibitor against human lung cancer. Supplementary information: The online version contains supplementary material available at 10.1007/s11224-022-01882-7.

Identification of bioactive molecules from Triphala (Ayurvedic herbal formulation) as potential inhibitors of SARS-CoV-2 main protease (Mpro) through computational investigations.

Severe acute respiratory syndrome coronavirus disease (SARS-CoV-2) induced coronavirus disease 2019 (COVID-19) pandemic is the present worldwide health emergency. The global scientific community faces a significant challenge in developing targeted therapies to combat the SARS-CoV-2 infection. Computational approaches have been critical for identifying potential SARS-CoV-2 inhibitors in the face of limited resources and in this time of crisis. Main protease (Mpro) is an intriguing drug target because it processes the polyproteins required for SARS-CoV-2 replication. The application of Ayurvedic knowledge from traditional Indian systems of medicine may be a promising strategy to develop potential inhibitor for different target proteins of SARS-CoV-2. With this endeavor, we docked bioactive molecules from Triphala, an Ayurvedic formulation, against Mpro followed by molecular dynamics (MD) simulation (100 ns) to investigate their inhibitory potential against SARS-CoV-2. The top four best docked molecules (terflavin A, chebulagic acid, chebulinic acid, and corilagin) were selected for MD simulation study and the results obtained were compared to native ligand X77. From docking and MD simulation studies, the selected molecules showed promising binding affinity with the formation of stable complexes at the active binding pocket of Mpro and exhibited negative binding energy during MM-PBSA calculations, indication their strong binding affinity with the target protein. The identified bioactive molecules were further analyzed for drug-likeness by Lipinski's filter, ADMET and toxicity studies. Computational (in silico) investigations identified terflavin A, chebulagic acid, chebulinic acid, and corilagin from Triphala formulation as promising inhibitors of SARS-CoV-2 Mpro, suggesting experimental (in vitro/in vivo) studies to further explore their inhibitory mechanisms.

Adsorption properties of dacarbazine with graphene/fullerene/metal nanocages - Reactivity, spectroscopic and SERS analysis.

Drug delivery devices are an effective way to minimize anticancer drug toxicity and nanostructures are used in the targeted drug delivery. In the present work, adsorption and interaction behavior of 4-(dimethylaminodiazenyl)-1H-imidazole-5-carboxamide (DAIC) with nano complexes (graphene, fullerene and fullerene like metal cages) are reported theoretically. From the reactivity studies, the electrophilicity index of DAIC-nanoclusters are increasing and this gives the bioactivity of the nanocluster systems. Adsorption energy is highest in the case of AlP and lowest in the case of BP clusters. Mulliken charge distribution of all systems is an evidence for chemical enhancement. DAIC adsorption over nanocages causes changes in electronic properties resulting in chemical enhancement and variation in Raman spectra which suggests that nanocages could be a good candidate for DAIC detection.

Investigation of reactive properties, adsorption on fullerene, DFT, molecular dynamics simulation of an anthracene derivative targeting dihydrofolate reductase and human dUTPase.

Anthracenes are aromatic compounds with flexible structure and reactivity which are of great interest to theoretical and experimental chemists. Theoretical investigations of 1,4-dihydroxy-5,8-bis[2-(2-hydroxyethylamino)ethylamino]anthracene-9,10-dione (Mitoxantrone) (DDEA) based on density functional theory, molecular dynamics and adsorption on fullerene are reported in the present research. The suitable situation for adsorption with fullerene (C60) is the cyclohex-2-ene-1,4-dione ring of DDEA. Selected quantum-molecular descriptors have been calculated to predict the most reactive sites of the DDEA molecule. Interactions of DDEA with water have been studied using MD simulations. MD simulations were also used to study solubility parameter, a significant quantity for the development of pharmaceutical formulations. The affinity of DDEA on human dihydrofolate reductase and deoxyuridine triphosphatase enzymes was investigated by MD simulation of the protein-ligand complex obtained by molecular docking study.Communicated by Ramaswamy H. Sarma.

Insights into COVID-19 Vaccine Development Based on Immunogenic Structural Proteins of SARS-CoV-2, Host Immune Responses, and Herd Immunity.

The first quarter of the 21st century has remarkably been characterized by a multitude of challenges confronting human society as a whole in terms of several outbreaks of infectious viral diseases, such as the 2003 severe acute respiratory syndrome (SARS), China; the 2009 influenza H1N1, Mexico; the 2012 Middle East respiratory syndrome (MERS), Saudi Arabia; and the ongoing coronavirus disease 19 (COVID-19), China. COVID-19, caused by SARS-CoV-2, reportedly broke out in December 2019, Wuhan, the capital of China's Hubei province, and continues unabated, leading to considerable devastation and death worldwide. The most common target organ of SARS-CoV-2 is the lungs, especially the bronchial and alveolar epithelial cells, culminating in acute respiratory distress syndrome (ARDS) in severe patients. Nevertheless, other tissues and organs are also known to be critically affected following infection, thereby complicating the overall aetiology and prognosis. Excluding H1N1, the SARS-CoV (also referred as SARS-CoV-1), MERS, and SARS-CoV-2 are collectively referred to as coronaviruses, and taxonomically placed under the realm Riboviria, order Nidovirales, suborder Cornidovirineae, family Coronaviridae, subfamily Orthocoronavirinae, genus Betacoronavirus, and subgenus Sarbecovirus. As of 23 September 2021, the ongoing SARS-CoV-2 pandemic has globally resulted in around 229 million and 4.7 million reported infections and deaths, respectively, apart from causing huge psychosomatic debilitation, academic loss, and deep economic recession. Such an unprecedented pandemic has compelled researchers, especially epidemiologists and immunologists, to search for SARS-CoV-2-associated potential immunogenic molecules to develop a vaccine as an immediate prophylactic measure. Amongst multiple structural and non-structural proteins, the homotrimeric spike (S) glycoprotein has been empirically found as the most suitable candidate for vaccine development owing to its immense immunogenic potential, which makes it capable of eliciting both humoral and cell-mediated immune responses. As a consequence, it has become possible to design appropriate, safe, and effective vaccines, apart from related therapeutic agents, to reduce both morbidity and mortality. As of 23 September 2021, four vaccines, namely, Comirnaty, COVID-19 vaccine Janssen, Spikevax, and Vaxzevria, have received the European Medicines Agency's (EMA) approval, and around thirty are under the phase three clinical trial with emergency authorization by the vaccine-developing country-specific National Regulatory Authority (NRA). In addition, 100-150 vaccines are under various phases of pre-clinical and clinical trials. The mainstay of global vaccination is to introduce herd immunity, which would protect the majority of the population, including immunocompromised individuals, from infection and disease. Here, we primarily discuss category-wise vaccine development, their respective advantages and disadvantages, associated efficiency and potential safety aspects, antigenicity of SARS-CoV-2 structural proteins and immune responses to them along with the emergence of SARS-CoV-2 VOC, and the urgent need of achieving herd immunity to contain the pandemic.

Host Cell and SARS-CoV-2-Associated Molecular Structures and Factors as Potential Therapeutic Targets.

Coronavirus disease 19 (COVID-19) is caused by an enveloped, positive-sense, single-stranded RNA virus, referred to as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which belongs to the realm Riboviria, order Nidovirales, family Coronaviridae, genus Betacoronavirus and the species Severe acute respiratory syndrome-related coronavirus. This viral disease is characterized by a myriad of varying symptoms, such as pyrexia, cough, hemoptysis, dyspnoea, diarrhea, muscle soreness, dysosmia, lymphopenia and dysgeusia amongst others. The virus mainly infects humans, various other mammals, avian species and some other companion livestock. SARS-CoV-2 cellular entry is primarily accomplished by molecular interaction between the virus's spike (S) protein and the host cell surface receptor, angiotensin-converting enzyme 2 (ACE2), although other host cell-associated receptors/factors, such as neuropilin 1 (NRP-1) and neuropilin 2 (NRP-2), C-type lectin receptors (CLRs), as well as proteases such as TMPRSS2 (transmembrane serine protease 2) and furin, might also play a crucial role in infection, tropism, pathogenesis and clinical outcome. Furthermore, several structural and non-structural proteins of the virus themselves are very critical in determining the clinical outcome following infection. Considering such critical role(s) of the abovementioned host cell receptors, associated proteases/factors and virus structural/non-structural proteins (NSPs), it may be quite prudent to therapeutically target them through a multipronged clinical regimen to combat the disease.

Interactions of the Receptor Binding Domain of SARS-CoV-2 Variants with hACE2: Insights from Molecular Docking Analysis and Molecular Dynamic Simulation.

Since the beginning of the coronavirus 19 (COVID-19) pandemic in late 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been evolving through the acquisition of genomic mutations, leading to the emergence of multiple variants of concern (VOCs) and variants of interest (VOIs). Currently, four VOCs (Alpha, Beta, Delta, and Gamma) and seven VOIs (Epsilon, Zeta, Eta, Theta, Iota, Kappa, and Lambda) of SARS-CoV-2 have been identified in worldwide circulation. Here, we investigated the interactions of the receptor-binding domain (RBD) of five SARS-CoV-2 variants with the human angiotensin-converting enzyme 2 (hACE2) receptor in host cells, to determine the extent of molecular divergence and the impact of mutation, using protein-protein docking and dynamics simulation approaches. Along with the wild-type (WT) SARS-CoV-2, this study included the Brazilian (BR/lineage P.1/Gamma), Indian (IN/lineage B.1.617/Delta), South African (SA/lineage B.1.351/Beta), United Kingdom (UK/lineage B.1.1.7/Alpha), and United States (US/lineage B.1.429/Epsilon) variants. The protein-protein docking and dynamics simulation studies revealed that these point mutations considerably affected the structural behavior of the spike (S) protein compared to the WT, which also affected the binding of RBD with hACE2 at the respective sites. Additional experimental studies are required to determine whether these effects have an influence on drug-S protein binding and its potential therapeutic effect.

Drug Information Services in Low-Resource Setting: A Responsibility of Pharmacists or Pharmacologists or Both the Professions Conjointly.

OBJECTIVE: The objective of this study was to assess the pharmacy professionals' understanding and viewpoints on drug information center (DIC) services and differences, if any, with pharmacologist's survey conducted earlier. MATERIALS AND METHODS: An electronic cross-sectional knowledge, practice, and attitude survey was carried out. A questionnaire in the form of the hyperlink was sent to pharmacy professionals through e-mail, Facebook messenger, and WhatsApp. Factors linked to pharmacy professionals' vision in expanding countrywide DIC services were studied with logistic regression in R. RESULTS: A total of 125 pharmacy professionals responded. The participant believing in the published literature as a standard reference for establishing and running the DIC services; participants identifying more challenges in the day-to-day DIC functioning; and participants believing in the ability of DIC in reducing morbidity, mortality, and cost of care had 4.76 (95% confidence interval [CI] = 0.97-6.44), 4.24 (95% CI = 0.97-6.44), and 2.43 (95% CI = 0.97-6.44) times association with good knowledge score. Good attitude scores were discovered of participants working in fully and partially functional DIC (odds ratio [OR] = 9.66, CI = 0.97-6.44 and OR = 9.49, CI = 0.97-6.44) to participants not involved in DIC duties. The participant who understood DIC services' real purpose had 2.83 (95% CI = 0.97-6.44) times association with good practice scores. Overall, pharmacy professionals carried better attitude scores, but lesser knowledge, and practice scores than pharmacology professionals. CONCLUSION: Lower knowledge and practice score of pharmacy professionals asks for training in critical appraisal of published literature and due modifications in graduate and postgraduate curricula. A collaborative approach between pharmacists and pharmacologists is needed to improve the quality of drug information services and evidence-based medicine practice in low-resource countries like India.

Molecular docking, DFT analysis, and dynamics simulation of natural bioactive compounds targeting ACE2 and TMPRSS2 dual binding sites of spike protein of SARS CoV-2.

The scientific community is continuously working to discover drug candidates against potential targets of SARS-CoV-2, but effective treatment has not been discovered yet. The virus enters the host cell through molecular interaction with its enzymatic receptors i.e., ACE2 and TMPRSS2, which, if, synergistically blocked can lead to the development of novel drug candidates. In this study, 1503 natural bioactive compounds were screened by HTVS, followed by SP and XP docking using Schrodinger Maestro software. Bio-0357 (protozide) and Bio-597 (chrysin) were selected for dynamics simulation based on synergistic binding affinity on S1 (docking score -9.642 and -8.78 kcal/mol) and S2 domains (-5.83 and -5.3 kcal/mol), and the RMSD, RMSF and Rg analyses showed stable interaction. The DFT analysis showed that the adsorption of protozide/chrysin, the band gap of protozide/chrysin-F/G reduced significantly. From SERS, results, it can be concluded that QDs nanocluster will act as a sensor for the detection of drugs. The docking study showed Bio-0357 and Bio-0597 bind to both S1 and S2 domains through stable molecular interactions, which can lead to the discovery of new drug candidates to prevent the entry of SARS-CoV-2. This in-silico study may be helpful to researchers for further in vitro experimental validation and development of new therapy for COVID-19.

Modeling the structural and reactivity properties of hydrazono methyl-4H-chromen-4-one derivatives-wavefunction-dependent properties, molecular docking, and dynamics simulation studies.

This study explains the vibration and interaction of three pharmaceutically active hydrazine derivatives, (E)-3-((2-(2,5-difluorophenyl)hydrazono)methyl)-4H-chromen-4-one (DFH), (E)-3-((2-(4-(trifluoromethyl)phenyl)hydrazono)methyl)-4H-chromen-4-one (TMH), and (E)-3-((2-(3,5-bis(trifluoromethyl)phenyl)hydrazono)methyl)-4H-chromen-4-one (BPH) using theoretical approach. The trend in chemical reactivity and stability of the studied compounds was observed to show increasing stability and decreasing reactivity and this was obtained from orbital energies. The effect of bromine and chlorine atoms, instead of fluorine atoms, is also noted. Surface analysis on the covalent bond was attained by ELF and LOL analysis. Biological activities were predicted using molecular docking studies. Docking results were analyzed with standard drugs, 5-fluorouracil/piperine. Antitumor activity of hydrazine derivatives was found to be higher than reference ones. Molecular dynamics (MD) simulation was performed for 100 ns to validate the stability behavior of hydrazine derivatives with the dual specificity threonine tyrosine kinase (TTK) protein. RMSD, RMSF, Rg, SASA, and intermolecular analysis of DFH, TMH, and BPH with threonine tyrosine kinase forms stable ligand-protein interactions. The molecular and predictive biological properties of three pharmaceutically active hydrazine derivatives which can be helpful to researchers in future experimental validation through in vitro and in vivo studies.

Role of Structural and Non-Structural Proteins and Therapeutic Targets of SARS-CoV-2 for COVID-19.

Coronavirus belongs to the family of Coronaviridae, comprising single-stranded, positive-sense RNA genome (+ ssRNA) of around 26 to 32 kilobases, and has been known to cause infection to a myriad of mammalian hosts, such as humans, cats, bats, civets, dogs, and camels with varied consequences in terms of death and debilitation. Strikingly, novel coronavirus (2019-nCoV), later renamed as severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), and found to be the causative agent of coronavirus disease-19 (COVID-19), shows 88% of sequence identity with bat-SL-CoVZC45 and bat-SL-CoVZXC21, 79% with SARS-CoV and 50% with MERS-CoV, respectively. Despite key amino acid residual variability, there is an incredible structural similarity between the receptor binding domain (RBD) of spike protein (S) of SARS-CoV-2 and SARS-CoV. During infection, spike protein of SARS-CoV-2 compared to SARS-CoV displays 10-20 times greater affinity for its cognate host cell receptor, angiotensin-converting enzyme 2 (ACE2), leading proteolytic cleavage of S protein by transmembrane protease serine 2 (TMPRSS2). Following cellular entry, the ORF-1a and ORF-1ab, located downstream to 5' end of + ssRNA genome, undergo translation, thereby forming two large polyproteins, pp1a and pp1ab. These polyproteins, following protease-induced cleavage and molecular assembly, form functional viral RNA polymerase, also referred to as replicase. Thereafter, uninterrupted orchestrated replication-transcription molecular events lead to the synthesis of multiple nested sets of subgenomic mRNAs (sgRNAs), which are finally translated to several structural and accessory proteins participating in structure formation and various molecular functions of virus, respectively. These multiple structural proteins assemble and encapsulate genomic RNA (gRNA), resulting in numerous viral progenies, which eventually exit the host cell, and spread infection to rest of the body. In this review, we primarily focus on genomic organization, structural and non-structural protein components, and potential prospective molecular targets for development of therapeutic drugs, convalescent plasm therapy, and a myriad of potential vaccines to tackle SARS-CoV-2 infection.

In silico screening of hundred phytocompounds of ten medicinal plants as potential inhibitors of nucleocapsid phosphoprotein of COVID-19: an approach to prevent virus assembly.

Currently, there is no specific treatment to cure COVID-19. Many medicinal plants have antiviral, antioxidant, antibacterial, antifungal, anticancer, wound healing etc. Therefore, the aim of the current study was to screen for potent inhibitors of N-terminal domain (NTD) of nucleocapsid phosphoprotein of SARS-CoV-2. The structure of NTD of RNA binding domain of nucleocapsid phosphoprotein of SARS coronavirus 2 was retrieved from the Protein Data Bank (PDB 6VYO) and the structures of 100 different phytocompounds were retrieved from Pubchem. The receptor protein and ligands were prepared using Schrodinger's Protein Preparation Wizard. Molecular docking was done by using the Schrodinger's maestro 12.0 software. Drug likeness and toxicity of active phytocompounds was predicted by using Swiss adme, admetSAR and protox II online servers. Molecular dynamic simulation of the best three protein- ligand complexes (alizarin, aloe-emodin and anthrarufin) was performed to study the interaction stability. We have identified three potential active sites (named as A, B, C) on receptor protein for efficient binding of the phytocompounds. We found that, among 100 phytocompounds, emodin, aloe-emodin, anthrarufin, alizarine, and dantron of Rheum emodi showed good binding affinity at all the three active sites of RNA binding domain of nucleocapsid phosphoprotein of COVID-19.The binding energies of emodin, aloe-emodin, anthrarufin, alizarine, and dantron were -8.299, -8.508, -8.456, -8.441, and -8.322 Kcal mol-1 respectively (site A), -7.714, -6.433, -6.354, -6.598, and -6.99 Kcal mol-1 respectively (site B), and -8.299, 8.508, 8.538, 8.841, and 8.322 Kcal mol-1 respectively (site C). All the active phytocompounds follows the drug likeness properties, non-carcinogenic, and non-toxic. Theses phytocompounds (alone or in combination) could be developed into effective therapy against COVID-19. From MD simulation data, we found that all three complexes of 6VYO with alizarin, aloe-emodin and anthrarufin were stable up to 50 ns. These phytocompounds can be tested further for in vitro or in vivo and used as a potential drug to cure SARS-CoV-2 infection.Communicated by Ramaswamy H. Sarma.

Virtual screening, ADMET prediction and dynamics simulation of potential compounds targeting the main protease of SARS-CoV-2.

The coronavirus disease-2019 caused by a novel SARS CoV-2 virus has emerged as a global threat. Still, no drugs are available for its treatment. The main protease is the most conserved structure responsible for the posttranslational processing of non-structural polyproteins of this virus. Therefore, it can be the potential target for drug discovery against SARS CoV-2. Twenty-one thousand two hundred and seven chemical compounds used for sequential virtual screening studies including coronavirus screening compounds (Life Chemical database) and antiviral compounds (Asinex database). The Schrodinger suite 2019 employed for high throughput screening, molecular docking and MM-GBSA through the Glide module. Subsequently, 23 compounds were selected in the phase first selection criteria for re-docking with AutoDock and iDock followed by ADMET prediction. The drug-likeness predicted through Lipinski's rule of five, Veber's rule and Muegge's rule. Finally, three ligands were selected for molecular dynamics simulation studies over 150 ns against the main protease of the SARS CoV-2. They showed promising docking scores on Glide, iDock and AutoDock Vina algorithms (ligand F2679-0163: -10.75, -10.29 and -9.2; ligand F6355-0442: -9.38, -8.61 and -7.6; ligand 8250: -9.795, -7.94 and -7.5), respectively. The RMSD parameter remained stable at 2.5 Å for all the three ligands for 150 ns. The high RMSF fluctuations, RoG of around 22 Å and the binding free energy were favorable in each case. The hydrogen bond interactions of 8250, F6355-0442 and F2679-0163 were six, five and three, respectively. These compounds can be further explored for in vitro experimental validation against SARS-CoV-2. Communicated by Ramaswamy H. Sarma.

Virtual screening and dynamics of potential inhibitors targeting RNA binding domain of nucleocapsid phosphoprotein from SARS-CoV-2.

The emergence of the coronavirus disease-2019 pandemic has led to an outbreak in the world. The SARS-CoV-2 is seventh and latest in coronavirus family with unique exonucleases for repairing any mismatches in newly transcribed genetic material. Therefore, drugs with novel additional mechanisms are required to simultaneously target and eliminate the virus. Thus, a newly deciphered N protein is taken as a target that belongs to SARS-CoV-2. They play a vital role in RNA transcription, viral replication and new virion formation. This study used virtual screening, molecular modeling and docking of the 8987 ligands from Asinex and PubChem databases against this novel target protein. Three hotspot sites having DScore ≥1 (Site 1, Site 2 and Site 3) for ligand binding were selected. Subsequently, high throughput screening, standard precision and extra precision docking process and molecular dynamics concluded three best drugs from two libraries. Two antiviral moieties from Asinex databases (5817 and 6799) have docking scores of -10.29 and -10.156; along with their respective free binding energies (ΔG bind) of -51.96 and -64.36 on Site 3. The third drug, Zidovudine, is from PubChem database with docking scores of -9.75 with its binding free energies (ΔG bind) of -59.43 on Site 3. The RMSD and RMSF were calculated for all the three drugs through molecular dynamics simulation studies for 50 ns. Zidovudine shows a very stable interaction with fluctuation starting at 2.4 Å on 2 ns and remained stable at 3 Å from 13 to 50 ns. Thus, paving the way for further biological validation as a potential treatment.Communicated by Ramaswamy H. Sarma.