Investigation of the potential inhibitor effects of lycorine on SARS-CoV-2 main protease (Mpro) using molecular dynamics simulations and MMPBSA

The main protease (Mpro or 3CLpro) plays important roles in viral replication and is one of attractive targets for drug development for SARS-CoV-2. In this study, we investigated the potential inhibitory effect of lycorine molecule as a ligand on SARS-CoV-2 using computational approaches. For this purpose, we conducted molecular docking and molecular dynamics simulations MM-PB(GB)SA analyses. The findings showed that the lycorine ligand was successfully docked with catalytic dyad (Cys145 and His41) of SARS-CoV-2 Mpro with binding affinity changing between -6.71 and -7.03 kcal mol-1. MMPB(GB)SA calculations resulted according to GB (Generalized Born) approach in a Gibbs free energy changing between -24.925-+01152 kcal/mol between lycorine and SARS-CoV-2 which is promising. PB (Poisson Boltzmann) approach gave less favorable energy (-2.610..0.2611 kcal mol-1). Thus, Entropy calculations from the normal mode analysis (S) were performed and it supported GB approach and conducted -23.100..6.4635 kcal mol-1. These results showed lycorine has a druggable potential but the drug effect of lycorine on COVID-19 is limited and experimental studies should be done with pharmacokinetic modifications that increase the drug effect of lycorine.

In silico-based studies on phytochemicals from native Indian plants as potential inhibitors of SARS-CoV-2

This study aims to analyze the AntiCovid effect of Phytocompounds extracted from Native Indian Plant species by computational methods such as Molecular Docking. Through this study keeping the Indian Heritage alive we characterized the ability of these phytochemicals as inhibiting agents of the Main Protease enzyme of this Virus. The lack of any effective treatment and the reoccurrence of cases despite Vaccination necessitates the quick provision of anti-SARS-CoV-2 drugs. Natural substances are getting a lot of attention for SARS-CoV-2 therapy as they have proven antimicrobial activities and are a key source for numerous antiviral drugs. Despite the fact that this virus has several identified target receptors, Main Protease (Mpro) is crucial for viral replication. In this study, 26 phytochemicals from 10 native Indian plant species were studied. Our docking studies demonstrated that compounds Quercetin, Withaferin A, Sominone, and Nimbin were likely to be more favorable than the natural inhibitor N3, with binding energies of-8.42, -9.21, -9.95, and -8.88 kcal/mol, respectively. These four candidate natural compounds were further examined for their bioavailability scores through ADMET analysis to prove the safety of these compounds as well as their drug likeliness. Through the results it was indicated that these natural phytochemicals have a significant potential of inhibiting the SARS-CoV-2 Mpro enzyme and might be utilized to treat SARS-CoV-2 and manage public health, subject to in vitro validation in the future.

A molecular dynamic investigation of human rhinovirus 3c protease drug target: insights towards the design of potential inhibitors

The 3C protease is distinguished from most proteases due to the presence of cysteine nucleophile that plays an essential role in viral replication. This peculiar structure encompassed with its role in viral replication has promoted 3C protease as an interesting target for therapeutic agents in the treatment of diseases caused by human rhinovirus (HRV). However, the molecular mechanisms surrounding the chirality of inhibitors of HRV 3C protease remain unresolved. Herein using in silico techniques such molecular dynamic simulation and binding free estimations via molecular mechanics poisson-boltzmann surface area (MM/PBSA), we present a comprehensive molecular dynamics study of the comparison of two potent inhibitors, SG85 and rupintrivir, complexed with HRV3C protease. The binding free energy studies revealed a higher binding affinity for SG85 of 58.853 kcal/mol than that for rupintrivir of 54.0873 kcal/mol and this was found to be in correlation with the experimental data. The energy decomposition analysis showed that residues Leu 127, Thr 142, Ser 144, Gly 145, Tyr 146, Cys 147, His 161, Val 162, Gly 163, Gly 164, Asn 165, and Phe 170 largely contributed to the binding of SG85, whereas His 40, Leu 127, and Gly 163 impacted the binding of rupintrivir. The results further showed that His 40, Glu 71, Leu 127, Cys 147, Gly 163, and Gyl 164 were crucial residues that played a key role in ligand-enzyme binding, and amongst these crucial residues, His 40, Glu 71, and Cys 147 appeared to be conserved in the active site of HRV-3C protease when bound by both inhibitors. These findings provided a comprehensive understanding of the dynamics and structural features and would serve as guidance in the design and development of potent novel inhibitors of HRV.

In silico exploration of Lycoris alkaloids as potential inhibitors of SARS-CoV-2 main protease (Mpro)

Coronavirus disease 2019 (COVID-19) is a pandemic whose adverse effects have been felt all over the world. As of August 2022, reports indicated that over 500 million people in the world had been infected and the number of rising deaths from the disease were slightly above 6.4 million. New variants of the causative agent, SARS-CoV-2 are emanating now and then and some are more efficacious and harder to manage. SARS-CoV-2 main protease (Mpro) has essential functions in viral gene expression and replication through proteolytic cleavage of polyproteins. Search for SARS-CoV-2 Mpro inhibitors is a vital step in the treatment and management of COVID-19. In this study, we investigated whether alkaloids with antiviral and myriad other bioactivities from the genus Lycoris can act as SARS-CoV-2 Mpro inhibitors. We conducted a computer-aided drug design study through screening optimal ligands for SARS-CoV-2 Mpro from a list of over 150 Lycoris alkaloids created from online databases such as ChEMBL, PubChem, ChemSpider, and published journal papers. The In silico study involved molecular docking of Lycoris alkaloids to SARS-CoV-2 Mpro active site, absorption, distribution, metabolism, elimination and toxicity (ADMET) screening and finally molecular dynamic (MD) simulations of the most promising ligand-SARS-CoV-2 Mpro complexes. The study identified 3,11-dimethoxy-lycoramine, narwedine, O-demethyllycoramine and epilycoramine as drug-like and lead-like Lycoris alkaloids with favorable ADMET properties and are very likely to have an inhibition activity on SARS-CoV-2 Mpro and may become potential drug candidates.

International Conference on Pharmaceutical Material, Engineering and Applied Science (ICOPMES) 2020

This proceedings contains 13 papers focusing on the effect of green tea extract in modulating the antibacterial activity of standard antibiotics against clinical isolates of Acinetobacter baumannii, in silico screening of Ziziphus spina-christi and Strychnos ligustrine compounds as a proteinase inhibitor of SARS-COV-2, antioxidant and antifungal propterties of palu shallot (Allium ascalonicum var. aggregatum), probiotic properties and safety of lactic acid bactera isolated from South Sulawesi ethnic cheese, pharmacognostics of 2 Orthoshipon aristatus varieties and effect of honey consumption after physical exercises on electrolytes and blood sugar levels, among others.

In silico screening of Ziziphus spina-christi (L.) Desf. and Strychnos ligustrine compounds as a protease inhibitor of SARS-CoV-2

Diseases caused by the coronavirus have become an important concern in early 2020. The coronavirus is a new type of virus that is included in the SARS-CoV-2 group. One of the possible mechanisms of SARS-CoV-2 inhibition involves protease receptors inhibition. This research was aimed to in silico screening of Ziziphus spina-christi (L.) Desf., and Strychnos ligustrine active ingredients as the main protease inhibitors of SARS-CoV-2 by assessing the ligand-binding affinity in the binding pocket of SARS-CoV-2 main protease protein. The molecular docking method is generally used to predict the inhibitory site and bonds formation. In the current study, some generally used antiviral compounds from the PDB (Protein Data Bank) were also used to compare the affinity strength of the test compound against the protease receptor (code of 5R7Y). The inhibitory activity against the main protease receptor proven by the ChemPLP score is more negative than the receptor's native ligand and the comparison compounds. Jubanine B, a compound of Z. spina-christi has the most robust inhibition activity on the SARS-CoV-2 protease receptor. Results of this study can be concluded that this can be used to develop as a candidate for traditional medicine against SARS-CoV-2 but still it required some more in vitro and in vivo studies.

Proteins of SARS CoV-2, which causes COVID-19, and the Interacting proteins. (Proteins of SARS CoV-2, which causes COVID-19, and the Interacting proteins.)

This journal issue on the topic of COVID proteins features four articles: (1) A review on the biochemical activities of the nonstructural proteins (NSPs) and the spike protein and a description of a recent ribosomal profiling study that revealed 23 new SARS CoV-2 proteins (2) An in silico study of the mutational stability of SARS CoV-2 proteins (3) A docking study of milk peptides binding to various SARS CoV-2 proteins (4) A docking study of possible anti-SARS CoV-2 main protease inhibitors.

A consensus statement on the use of angiotensin receptor blockers and angiotensin converting enzyme inhibitors in relation to COVID-19 (corona virus disease 2019)

There has been a lot of speculation that patients with coronavirus disease 2019 (COVID-19) who are receiving angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) may be at increased risk for adverse outcomes. We reviewed the available evidence, and have not found this to be the case. We recommend that patients on such medications should continue on them unless there is a clinical indication to stop their use.

A Dual‐Color Fluorescent Probe Allows Simultaneous Imaging of Main and Papain‐like Proteases of SARS‐CoV‐2‐Infected Cells for Accurate Detection and Rapid Inhibitor Screening

The main protease (Mpro) and papain‐like protease (PLpro) play critical roles in SARS‐CoV‐2 replication and are promising targets for antiviral inhibitors. The simultaneous visualization of Mpro and PLpro is extremely valuable for SARS‐CoV‐2 detection and rapid inhibitor screening. However, such a crucial investigation has remained challenging because of the lack of suitable probes. We have now developed a dual‐color probe (3MBP5) for the simultaneous detection of Mpro and PLpro by fluorescence (or Förster) resonance energy transfer (FRET). This probe produces fluorescence from both the Cy3 and Cy5 fluorophores that are cleaved by Mpro and PLpro. 3MBP5‐activatable specificity was demonstrated with recombinant proteins, inhibitors, plasmid‐transfected HEK 293T cells, and SARS‐CoV‐2‐infected TMPRSS2‐Vero cells. Results from the dual‐color probe first verified the simultaneous detection and intracellular distribution of SARS‐CoV‐2 Mpro and PLpro. This is a powerful tool for the simultaneous detection of different proteases with value for the rapid screening of inhibitors.

Human Cell Receptors and Downstream Cascades: A Review of Molecular Aspects and Potential Therapeutic Targets in COVID-19

Context: There have been two coronavirus-related pandemics during the past 18 years, including severe acute respiratory syndrome (SARS)-CoV and Middle East respiratory syndrome (MERS)-CoV in 2002 and 2012, respectively. In 2019, Seven years after the emergence of MERS, a new coronavirus (i.e., SARS-CoV-2) was detected in several patients. SARS-CoV-2 spread widely, and its high prevalence enabled the virus to start a new pandemic in 2020. It is believed that the higher infectivity of the virus in comparison to that of SARS-CoV is related to its molecular interaction affinity of transmembrane spike glycoprotein and human angiotensin-converting enzyme 2 (ACE-2) cell receptors. Moreover, the primary reason for the high case fatality rate (CFR) is the cytokine storm and acute respiratory distress syndrome (ARDS) because of the immune system response to the invaders. Hence, a solid understanding of the components involved in the mechanism of viral entry and immune system response is crucial for finding approaches to disrupt the virus-cell interplay and neutralizing its impacts on the host immune system. In this review, we investigated the molecular aspect and potential therapeutic targets associated with cell receptors and downstream signaling cascades. Evidence Acquisition: A systematic search was implemented on several online databases, including Google Scholar, PubMed, and Scopus during 2019-2021 using the following keywords: "SARS-CoV-2", "COVID-19", "ACE-2", "Therapeutic Targets", "Acute Respiratory Distress Syndrome", and "Cytokine Storm". Results: Various internal or external agents are responsible for the virus infectivity and stimulating acute immune system response. Since currently there is no cure for the treatment of COVID-19, several repurposed drugs can be employed to disrupt the process of viral entry and mitigate the symptoms raised by the cytokine storm. Inhibition of several agents, including signal transduction mediators and TMPRSS2 may be momentous. Conclusions: Despite the increase in the CFR, no drugs were developed with significant efficacy. Understanding the virus entry mechanism and the immune system’s role could help us surmount the problems in developing a promising drug or employing the repurposed ones. © 2021, Author(s).

Capillary electrophoresis as a fragment screening tool to cross-validate hits from chromogenic assay: Application to FXIIa.

In this study, a partial-filling affinity capillary electrophoresis (pf-ACE) method was developed for the cross-validation of fragment hits revealed by chromogenic factor XIIa (FXIIa) assay. Chromogenic assay produces false positives, mainly due to spectrophotometric interferences and sample purity issues. pf-ACE was selected as counter-screening technology because of its separative character and the fact that the target does not have to be attached or tagged. The effects of protein plug length, applied voltage and composition of the running buffer were examined and optimized. Detection limit in terms of dissociation constant was estimated at 400 µM. The affinity evaluation was performed close to physiological conditions (pH 7.4, ionic strength 0.13 mol L-1) in a poly (ethylene oxide)-coated capillary of 75 µm internal diameter x 33 cm length with an applied voltage of 3 kV. This method uncovered chromogenic assay's false positives due to zinc contamination. Moreover, pf-ACE supported the evaluation of compounds absorbing at 405 nm.