POSSIBLE ROLE OF PEPTIDE EPITOPES OF COVID-19 BNT-162B2 MRNA VACCINE IN FOMENTING AUTOIMMUNITY: AN IN SILICO ANALYSIS

BackgroundFollowing the launch of the global COVID-19 vaccination campaign, there have been increased reports of autoimmune diseases developing de novo following vaccination. These cases include rheumatoid arthritis, autoimmune hepatitis, immune thrombotic thrombocytopenia, and connective tissue diseases. Nevertheless, COVID-19 vaccines are considered safe for patients with autoimmune diseases and are strongly recommended.ObjectivesThe aim of this in silico analysis is to investigate the presence of protein epitopes encoded by the BNT-162b2 mRNA vaccine, one of the most commonly administered COVID-19 vaccines, that could elicit an aberrant adaptive immune response in predisposed individuals.MethodsThe FASTA sequence of the protein encoded by the BNT-162b2 vaccine was retrieved from http://genome.ucsc.edu and used as a key input to the Immune Epitope Database and Analysis Resource (www.iedb.org). Linear peptides with 90% BLAST homology were selected, and T-cell, B-cell, and MHC ligand assays without MHC restriction were searched and evaluated. HLA-disease associations were screened on the HLA-SPREAD platform (https://hla-spread.igib.res.in) by selecting only positive markers.ResultsA total of 183 epitopes were found, corresponding to 178 SARS-CoV-2 and 5 SARS-CoV spike epitopes, respectively. Results were obtained from 22 T-cell assays, 398 B-cell assays, and 2 MHC ligand assays. Complementary receptors included 1080 T-cell receptors and 0 B-cell receptors.Specifically, the IEDB_epitope:1329790 (NATNVVIKVCEFQFCNDPFLGVYY) was shown to bind to HLA-DRB1*15:02 and HLA-DRB1*15:03 alleles, whereas the IEDB_epitope:1392457 (TKCTLKSFTVEKGIYQTSNFRVQPT) was reported to bind to HLA-DRB1*07:01, HLA-DRB1*03:01, HLA-DRB3*01:01, and HLA-DRB4*01:01 alleles. The HLA alleles detected were found to be positively associated with various immunological disorders (Table 1).Table 1.MHC-restricted epitopes of the BNT-162b2 vaccine and potentially associated immunological conditionsEpitopeAssayMHC moleculeAssociated disease (population)NATNVVIKVCEFQFCNDPFLGVYY + OX(C10)cellular MHC/mass spectrometry ligand presentationHLA-DRB1*15:02Takayasu arteritis (Japanese) Arthritis (Taiwanese) Scleroderma (Japanese) Colitis (Japanese)HLA-DRB1*15:03Systemic lupus erythematosus (Mexican American)TKCTLKSFTVEKGIYQTSNFRVQPT + SCM(K2)as aboveHLA-DRB1*07:01Allergy, hypersensitivity (Caucasian)HLA-DRB1*03:01Type 1 diabetes (African) Sarcoidosis, good prognosis (Finnish)HLA-DRB3*01:01Graves' disease (Caucasian) Thymoma (Caucasian) Sarcoidosis (Scandinavian) Autoimmune hepatitis (Caucasian)HLA-DRB4*01:01Vitiligo (Saudi Arabian)ConclusionSimilar to the SARS-CoV-2 spike protein, the protein product of the BNT-162b2 mRNA vaccine contains immunogenic epitopes that may trigger autoimmune phenomena in predisposed individuals. Genotyping for HLA alleles may help identify at-risk individuals. However, further research is needed to elucidate the underlying mechanisms and potential clinical implications.References[1]Vita R, Mahajan S, Overton JA et al. The Immune Epitope Database (IEDB): 2018 update. Nucleic Acids Res. 2019 Jan 8;47(D1):D339-D343. doi: 10.1093/nar/gky1006.[2]Dholakia D, Kalra A, Misir BR et al. HLA-SPREAD: a natural language processing based resource for curating HLA association from PubMed s. BMC Genomics 23, 10 (2022). https://doi.org/10.1186/s12864-021-08239-0[3]Parker R, Partridge T, Wormald C et al. Mapping the SARS-CoV-2 spike glycoprotein-derived peptidome presented by HLA class II on dendritic cells. Cell Rep. 2021 May 25;35(8):109179. doi: 10.1016/j.celrep.2021.109179.[4]Knierman MD, Lannan MB, Spindler LJ et al. The Human Leukocyte Antigen Class II Immunopeptidome of the SARS-CoV-2 Spike Glycoprotein. Cell Rep. 2020 Dec 1;33(9):108454. doi: 10.1016/j.celrep.2020.108454.Acknowledgements:NIL.Disclosure of InterestsNone Declared.

Potential inhibition of Melaleuca leucadendron L. compounds against the NSP5 SARS CoV-2 protein

COVID-19 is an infectious disease caused by Severe Acute Respiratory Syndrome (SARS-CoV-2), causing a global health emergency as a pandemic disease. The lack of certain drug molecules or treatment strategies to fight this disease makes it worse. Therefore, effective drug molecules are needed to fight COVID-19. Non Structural Protein (NSP5) or called Main Protease (Mpro) of SARS CoV 2, a key component of this viral replication, is considered a key target for anti-COVID-19 drug development. The purpose of this study is to determine whether the compounds in the Melaleuca leucadendron L. plant such as 1,8-cineole, terpene, guaiol, linalol, a-selinenol, beta-eudesmol and P-eudesmol are predicted to have antiviral activity for COVID-19. Interaction of compounds with NSP5 with PDB code 6WNP analyzed using molecular docking with Molegro Virtual Docker. Based on binding affinity, the highest potential as an anti-viral is Terpineol with binding energy (-119.743 kcal/mol). The results of the interaction showed that terpinol has similarities in all three amino acid residues namely Cys 145, Gly 143, and Glu 166 with remdesivir and native ligand. Melaleuca leucadendron L. may represent a potential herbal treatment to act as: COVID-19 NSP5, however these findings must be validated in vitro and in vivo.

Ginger ring compounds as an inhibitor of spike binding protein of alpha, beta, gamma and delta variants of SARS-CoV-2: An in-silico study

The available drugs against coronavirus disease 2019 (COVOD-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), are limited. This study aimed to identify ginger-derived compounds that might neutralize SARS-CoV-2 and prevent its entry into host cells. Ring compounds of ginger were screened against spike (S) protein of alpha, beta, gamma, and delta variants of SARS-CoV-2. The S protein FASTA sequence was retrieved from Global Initiative on Sharing Avian Influenza Data (GISAID) and converted into ".pdb” format using Open Babel tool. A total of 306 compounds were identified from ginger through food and phyto-databases. Out of those, 38 ring compounds were subjected to docking analysis using CB Dock online program which implies AutoDock Vina for docking. The Vina score was recorded, which reflects the affinity between ligands and receptors. Further, the Protein Ligand Interaction Profiler (PLIP) program for detecting the type of interaction between ligand-receptor was used. SwissADME was used to compute druglikeness parameters and pharmacokinetics characteristics. Furthermore, energy minimization was performed by using Swiss PDB Viewer (SPDBV) and energy after minimization was recorded. Molecular dynamic simulation was performed to find the stability of protein-ligand complex and root-mean-square deviation (RMSD) as well as root-mean-square fluctuation (RMSF) were calculated and recorded by using myPresto v5.0. Our study suggested that 17 out of 38 ring compounds of ginger were very likely to bind the S protein of SARS-CoV-2. Seventeen out of 38 ring compounds showed high affinity of binding with S protein of alpha, beta, gamma, and delta variants of SARS-CoV-2. The RMSD showed the stability of the complex was parallel to the S protein monomer. These computer-aided predictions give an insight into the possibility of ginger ring compounds as potential anti-SARS-CoV-2 worthy of in vitro investigations. © 2023, School of Medicine, Universitas Syiah Kuala. All rights reserved.

Inhibition of SARS-CoV2 Replication Regulated by NSP3 through Ayurveda Phytoconstituents of Indian Traditional Medicine

With Covid-19, a significant proportion of the population who are already vaccinated have tested positive. Therefore, there is a need for better medicines that act against the virus rigorously without causing any side effects. We aim to achieve the same through molecular docking and further simulations for bioactive phytochemicals of ayurvedic medicinal plants. The target for this study has been considered the NSP3 protein of the viral RNA that actively takes part in both replication and immune evasion pathways of the virus. Ligand libraries consisting of bioactive phytochemicals of aswasgandha and analogues of curcumin and piperine are curated. The libraries, along with the NSP3 protein moiety are docked onto two active sites. With the best-scored complexes further taken up for molecular dynamics simulation, the study resulted in favourable outcomes for three such ligands (compound ID 5469426, 69501714, ZINC000003874317). © 2023 Bharati Vidyapeeth, New Delhi.

Novel oxazolidinone zinc(II) complexes as antibacterial and anti-SARS-CoV-2 agents: synthesis, characterization, DFT calculations, ADMET, in silico molecular docking and biological activities

A series of Zn(II) complexes with oxazolidinone derivatives has been synthesized and characterized using spectroscopic techniques: IR, H-1 NMR, UV-Vis spectroscopy, and TGA/DTG thermal investigation. Theoretical computations were carried out using B3LYP/6-31G(d) and B3LYP/LanL2DZ to analyze the vibrational properties, NBO charges, global chemical reactivity indices and to illustrate the FOMs. TD-DFT calculations using WB97XD functional were realized with 6-31 G(d) and LAN2DZ basis set on oxazolidinone ligands and their zinc complexes. The pharmacokinetic properties and toxicity of the investigated compounds were predicted using in silico ADMET studies. Moreover, the S. aureus, E. coli, S. pneumoniae, ribosome 50S subunit, SARS-Cov-2 spike protein and ACE2 human receptor were selected for molecular docking study. The docking study shows that HL4 and ZnL4 bind better to the spike protein and hACE2 receptor. The redox properties were also studied for ligands and their corresponding complexes using cyclic voltammetry. Finally, antioxidant activity studies using DPPH radical scavenging showed efficiency for HL2 and [Zn(L-2)(2)] with low values of IC50 compared to ascorbic acid. The antimicrobial activity against B. subtilis (ATCC 9372), E. faecalis (ATCC 29212), S. aureus (ATCC 6538), E. coli (ATCC 4157), bacteria strains, C. albicans (ATCC 24433) and A. niger fungi strains were evaluated.

A European Drug-Discovery Platform: From In Silico to Experimental Validation

The COVID-19 pandemic highlighted an urgent need for streamlined drug development processes. Enhanced virtual screening methods could expedite drug discovery via rapid screening of large virtual compound libraries to identify high-priority drug candidates. The EXSCALATE4CoV (EXaSCale smArt pLatform Against paThogEns for CoronaVirus) consortium (E4C) research team developed EXSCALATE (EXaSCale smArt pLatform Against paThogEns), the most complex screening simulation to date, containing a virtual library of >500 billion compounds and a high-throughput docking software, LiGen (Ligand Generator). Additionally, E4C developed a smaller virtual screen of a "safe-in-man” drug library to identify optimal candidates for drug repurposing. To identify compounds targeting SARS-CoV-2, EXSCALATE performed >1 trillion docking simulations to optimize the probability of identifying successful drug candidates. Ligands identified in simulations underwent subsequent in vitro experimentation to determine drug candidates that have anti-SARS-CoV-2 agency and have probable in-human efficacy. While many compound candidates were validated to have anti-SARS-CoV-2 properties, raloxifene had the best outcome and subsequently demonstrated efficacy in a phase 2 clinical trial in patients with early mild-to-moderate COVID-19, providing proof of concept that the in silico approaches used here are a valuable resource during emergencies. After its emergence in 2019, the SARS-CoV-2 coronavirus spread internationally at a rapid pace, leading to the designation of COVID-19 as a pandemic in March 2020. In addition to a devastating impact on public health, COVID-19 has resulted in extensive negative social and economic effects in every corner of the globe. When the pandemic arrived, the medical and scientific communities identified an urgent need to establish more rapid therapeutic and vaccine development processes for COVID-19. However, it was clear that any new measures needed to be implemented in a way that also supported rapid mobilization to fight potential future pandemics. Therapeutic discovery is a complicated and prolonged process, often taking 10–15 years to complete all stages, and typically involves a linear workflow starting with in silico investigations, followed by increasingly complex and correspondingly expensive in vitro, in vivo, and clinical studies. In the context of the pandemic, the importance of the in silico stage increased because of the capacity of exascale computational methods to identify and prioritize small molecule (and biological) agents with the greatest therapeutic potential. Better in silico-generated starting points for drug-discovery efforts increase the likelihood of success in downstream laboratory-based experimental stages and can contribute to vitally needed reductions in costs and time to market for new therapies. © 2023, The Author(s), under exclusive license to Springer Nature Switzerland AG.

The Role of Structural Biology Task Force: Validation of the Binding Mode of Repurposed Drugs Against SARS-CoV-2 Protein Targets: Focus on SARS-CoV-2 Main Protease (Mpro): A Promising Target for COVID-19 Treatment

The main protease (Mpro) of SARS-CoV-2, a cysteine protease that plays a key role in generating the active proteins essential for coronavirus replication, is a validated drug target for treating COVID-19. The structure of Mpro has been elucidated by macromolecular crystallography, but owing to its conformational flexibility, finding effective inhibitory ligands was challenging. Screening libraries of ligands as part of EXaSCale smArt pLatform Against paThogEns (ExScalate4CoV) yielded several potential drug molecules that inhibit SARS-CoV-2 replication in vitro. We solved the crystal structures of Mpro in complex with repurposed drugs like myricetin, a natural flavonoid, and MG-132, a synthetic peptide aldehyde. We found that both inhibitors covalently bind the catalytic cysteine. Notably, myricetin has an unexpected binding mode, showing an inverted orientation with respect to that of the flavonoid baicalein. Moreover, the crystallographic model validates the docking pose suggested by molecular dynamics experiments. The mechanism of MG-132 activity against SARS-CoV-2 Mpro was elucidated by comparison of apo and inhibitor-bound crystals, showing that regardless of the redox state of the environment and the crystalline symmetry, this inhibitor binds covalently to Cys145 with a well-preserved binding pose that extends along the whole substrate binding site. MG-132 also fits well into the catalytic pocket of human cathepsin L, as shown by computational docking, suggesting that it might represent a good start to developing dual-targeting drugs against COVID-19. © 2023, The Author(s), under exclusive license to Springer Nature Switzerland AG.

Inhibition of the SARS-CoV-2 Main Protease by Isoquercitrin γ-Cyclodextrin Inclusion Complex Formulations: A Biochemical and In Silico Study

The main protease (Mpro) of SARS-CoV-2 is a well-established drug target for rational drug design of COVID-19 inhibitors. To address the serious challenge of COVID-19, we have performed biochemical inhibition screens with recombinantly expressed SARS-CoV-2 main protease (Mpro). A fluorescent assay was used to identify the flavonoid isoquercitrin as an Mpro inhibitor. Both isoquercitrin encapsulated in γ-cyclodextrin (inclusion complex formulations) and alone inhibited SARS-CoV-2 Mpro. For isoquercitrin, a Ki value of 32 μM (IC50 = 63 μM) was obtained. Isoquercitrin γ-cyclodextrin inclusion complex formulations additionally inhibited Zika virus NS2B-NS3pro leading to an IC50 value of 98 μM. Formulations containing the other flavonoid compounds diosmetin-7-O-glucoside, hesperetin-7-O-glucoside, and naringenin-7-O-glucoside did not inhibit SARS-CoV-2 Mpro. Steady-state kinetics indicate that the inhibition mechanism of Mpro by isoquercitrin is potentially competitive. Molecular modeling studies carried out with MM/PBSA confirm the likely modes of isoquercitrin binding to both proteases. These modeling results can be used in the development of structural analogs of isoquercitrin with better inhibitory profiles and potential candidates for anti-coronavirus drugs. Since the targeted proteases are essential for viral activity, the delivery isoquercitrin-cyclodextrin inclusion complex formulations could be of great interest for the development of future antiviral drugs to target intracellular virus proteins or other components.

Drug–Target Interaction Deep Learning-Based Model Identifies the Flavonoid Troxerutin as a Candidate TRPV1 Antagonist

Based on the advances made by artificial intelligence (AI) technologies in drug discovery, including target identification, hit molecule identification, and lead optimization, this study investigated natural compounds that could act as transient receptor potential vanilloid 1 (TRPV1) channel protein antagonists. Using a molecular transformer drug–target interaction (MT-DTI) model, troxerutin was predicted to be a TRPV1 antagonist at IC50 582.73 nM. In a TRPV1-overexpressing HEK293T cell line, we found that troxerutin antagonized the calcium influx induced by the TRPV1 agonist capsaicin in vitro. A structural modeling and docking experiment of troxerutin and human TRPV1 confirmed that troxerutin could be a TRPV1 antagonist. A small-scale clinical trial consisting of 29 participants was performed to examine the efficacy of troxerutin in humans. Compared to a vehicle lotion, both 1% and 10% w/v troxerutin lotions reduced skin irritation, as measured by skin redness induced by capsaicin, suggesting that troxerutin could ameliorate skin sensitivity in clinical practice. We concluded that troxerutin is a potential TRPV1 antagonist based on the deep learning MT-DTI model prediction. The present study provides a useful reference for target-based drug discovery using AI technology and may provide useful information for the integrated research field of AI technology and biology.

Antiviral activitiy of curcumin, demethoxycurcumin, bisdemethoxycurcumin and cyclocurcumin compounds of Curcuma longa against NSP3 on SARS-CoV-2

SARS-CoV-2 genome encodes two large polyproteins (pp), pp1a and pp1ab which are cleaved and transformed into a mature form by a protease, non-structural protein 3 (NSP3). NSP3 is encoded by open reading frame (ORF) 1a/b. Curcuma longa (C. longa) or turmeric has been documented to have antiviral effects. The aim of this study was to assess the viral activities of C. longa against SARS-CoV-2 focusing on its potency to inhibit viral replication by targeting NSP3. PubChem databases were used to obtain the metabolic profile of C. longa. The compound's interaction with nucleocapsid was analyzed using molecular docking with Molegro Virtual Docker. Bioinformatics analysis based on rerank score presents all compounds of C. longa have higher binding affinity than the native ligand with cyclocurcumin as the lowest score (-128.38 kcal/mol). This anti-viral activity was hypothesized from the similarity of hydrogen bonds with amino acid residues Ser 128 and Asn 40 as key residues present in Ribavirin. This study reveals that C. longa is the potential to be developed as an antiviral agent through replication inhibition in SARS-CoV-2 targeting its replication mediated by NSP3.

Structural and Computational Studies of Cobalt(II) and Copper(II) Complexes with Aromatic Heterocyclic Ligand

Two coordination complexes, a cobalt(II) complex tris(1,10-phenanthroline)-cobalt perchlorate hydrate, [Co(phen)3]·(ClO4)2·H2O(1), and a copper(II) complex tris(1,10-phenanthroline)-copper perchlorate 4-bromo-2-{[(naphthalene-1-yl)imino]methyl}phenol hydrate, [Cu(phen)3]·(ClO4)2·HL·[O] (2), [where, phen = 1,10-phenathroline as aromatic heterocyclic ligand, HL = 4-bromo-2-((Z)-(naphthalene-4-ylimino) methyl) phenol] have been synthesized and structurally characterized. Single crystal X-ray analysis of both complexes has revealed the presence of a distorted octahedral geometry around cobalt(II) and copper(II) ions. density functional theory (DFT)-based quantum chemical calculations were performed on the cationic complex [Co(phen)3]2+ and copper(II) complex [Cu(phen)3]2+ to get the structure property relationship. Hirshfeld surface and 2-D fingerprint plots have been explored in the crystal structure of both the metal complexes. To find potential SARS-CoV-2 drug candidates, both the complexes were subjected to molecular docking calculations with SARS-CoV-2 virus (PDB ID: 7BQY and 7C2Q). We have found stable docked structures where docked metal chelates could readily bound to the SARS-CoV-2 Mpro. The molecular docking calculations of the complex (1) into the 7C2Q-main protease of SARS-CoV-2 virus revealed the binding energy of −9.4 kcal/mol with a good inhibition constant of 1.834 µM, while complex (2) exhibited the binding energy of −9.0 kcal/mol, and the inhibition constant of 1.365 µM at the inhibition binding site of receptor protein. Overall, our in silico studies explored the potential role of cobalt(II) complex (1), and copper(II) complex (2) complex as the viable and alternative therapeutic solution for SARS-CoV-2.

Synthesis, structural characterization, thermal analysis, DFT, biocidal evaluation and molecular docking studies of amide-based Co(II) complexes.

Abstract: Many distinct amino acid and aromatic amine-derived transition metal complexes are used as physiologically active compounds. A few Cobalt (II) complexes have been synthesized by reacting cobalt (II) chloride with 1, 8-diaminonapthalene-based tetraamide macrocyclic ligands in an ethanolic media. These synthesized ligands (TAML1-3) and associated Co(II) complexes were fully characterized with various spectroscopic techniques, such as IR, NMR, CHN analysis, EPR, molar conductance, and magnetic susceptibility measurements, TGA, UV-visible spectra, powder X-ray diffraction and DFT analysis. The IR spectra reveal interactions between the core metal atom and ligands through N of 1, 8-diaminonapthalene. The distorted octahedral geometry of synthesized Co(II) macrocyclic complexes were confirmed by ESR, UV-Vis and DFT studies. The synthesized ligands (TAML1-TAML3) and their Co(II) complexes were tested for antimicrobial activity against A. niger, C. albicans, and F. oxysporum in addition to bacteria like S. aureus, B. subtilis, and Gram-negative bacteria like E. coli. The ligand TAML1 and complex [Co(TAML1)Cl2] showed an excellent antibacterial activity. The minimum inhibitory concentration of TAML1 and [Co(TAML1)Cl2] against S. aureus were found to be 7 mm and 10 mm zone of inhibition at 500 ppm, respectively, compared to drug ampicillin (3 mm). Additionally, each molecule exhibited notable antioxidant activity. The biological significance of the synthesized compounds was then evaluated by molecular docking experiments with the active site of the receptor protein such as Sars-Cov-2, C. Albicans, X. campestris and E. coli. The molecular docking assisted data strongly correlated to the experimental approach of antimicrobial activity. Supplementary Information: The online version contains supplementary material available at 10.1007/s11696-023-02843-y.

Virtual Screening for Sars-Cov-2 Entry Inhibitors by Dual Targeting of Tmprss2 and Ctsl

The COVID-19 pandemic remains to be a global public health crisis due to the emergence of new variants of concern and the scarcity of drug treatments. The cell entry of SARS-CoV-2 requires activation of its spike protein by host proteases TMPRSS2 and CTSL, which triggers membrane fusion and facilitates the endocytic uptake mechanism, respectively. This study employed a structure-based virtual screening technique to identify drugs and natural products that simultaneously target TMPRSS2 and CTSL. Two pharmacophore models were generated from the binding sites of the proteins in complex with their co-crystallized ligands. Both structure-based pharmacophores were used to screen a ligand library composed of 41,775 compounds (10,849 drugs from the ChEMBL database and 30,926 natural products from the NPASS database). A total of 115 compounds (54 drugs and 61 natural products) that fit both TMPRSS2 and CTSL pharmacophore models were identified. The common hits were docked into both proteases to obtain a short list of compounds. Molecular docking filtered 17 compounds (5 drugs and 12 natural products) that have higher binding energy values than the co-crystallized ligands and known inhibitors of both proteins. The top hits were then subjected to ADMET, drug-likeness, and synthetic accessibility filters. Based on docking scores, pharmacokinetics, and drug-likeness, Silibinin was the most promising repurposed drug candidate as a treatment for SARS-CoV-2 infection via dual inhibition of TMPRSS2 and CTSL. Among the natural products, barettin was the best candidate for further development as a novel dual TMPRSS2 and CTSL inhibitor.

Computational Investigations for Identification of Bioactive Molecules from Baccaurea ramiflora and Bergenia ciliata as Inhibitors of SARS-CoV-2 Mpro

In this study, a hybrid compound library of 72 phytocompounds from two antiviral medicinal plants (Baccaurea ramiflora and Bergenia ciliata) was computationally investigated for their inhibitory potential against SARS-CoV-2 Mpro. Molecular docking showed that 6-O-vanilloylicariside B5, 6-O-vanilloylisotachioside, leucoanthocyanidin 4-(2-galloyl), and p-hydroxybenzoyl bergenin has good binding affinity for Mpro. However, p-hydroxybenzoyl bergenin did not bind at the catalytic cavity. The RMSD and RMSF data obtained from 100 ns MD simulations revealed stable protein–ligand complexes for 6-O-vanilloylicariside B5, 6-O-vanilloylisotachioside, leucoanthocyanidin 4-(2-galloyl). Ligand trajectory study found 6-O-vanilloylisotachioside and leucoanthocyanidin 4-(2-galloyl) to be stable. Studies on ligand interaction profile and timeline interaction profile showed that 6-O-vanilloylisotachioside and leucoanthocyanidin 4-(2-galloyl) interacted with HIS41–CYS145 dyad and other crucial amino acids of the catalytic site cavity during the entire 100 ns MD simulations. Molecular mechanics generalized born solvent accessibility binding free energy calculations, density functional theory analysis, quantitative structure–property relationship studies, and ADMET profiling of 6-O-vanilloylisotachioside and leucoanthocyanidin 4-(2-galloyl) supported the results generated by molecular docking and MD simulations studies. Based on the current computational investigations, we conclude that that 6-O-vanilloylisotachioside of B. ramiflora and leucoanthocyanidin 4-(2-galloyl) of B. ciliata are two potential inhibitors of SARS-CoV-2 Mpro that are worthy of further investigations.

PREFMoDeL: A Systematic Review and Proposed Taxonomy of Biomolecular Features for Deep Learning

Of fundamental importance in biochemical and biomedical research is understanding a molecule's biological properties—its structure, its function(s), and its activity(ies). To this end, computational methods in Artificial Intelligence, in particular Deep Learning (DL), have been applied to further biomolecular understanding—from analysis and prediction of protein–protein and protein–ligand interactions to drug discovery and design. While choosing the most appropriate DL architecture is vitally important to accurately model the task at hand, equally important is choosing the features used as input to represent molecular properties in these DL models. Through hypothesis testing, bioinformaticians have created thousands of engineered features for biomolecules such as proteins and their ligands. Herein we present an organizational taxonomy for biomolecular features extracted from 808 articles from across the scientific literature. This objective view of biomolecular features can reduce various forms of experimental and/or investigator bias and additionally facilitate feature selection in biomolecular analysis and design tasks. The resulting dataset contains 1360 nondeduplicated features, and a sample of these features were classified by their properties, clustered, and used to suggest new features. The complete feature dataset (the Public Repository of Engineered Features for Molecular Deep Learning, PREFMoDeL) is released for collaborative sourcing on the web.

Synthesis, characterization, cytotoxicity evaluation, and molecular docking with DNA, bovine serum albumin, and SARS-Cov-2 of copper complexes bearing tris-(2-pyridyl)-pyrazolyl borate ligand

Four copper (II) complexes bearing tris-(2-pyridyl)-pyrazolyl borate (Tppy) ligand with corresponding chloride (Cu-1), aqua (Cu-2), azide (Cu-3), and thiocyanide (Cu-4) substitutions were synthesized and characterized by spectroscopic and analytical methods. Spectroscopic and molecular docking studies were employed to investigate the interactions of these complexes with calf thymus (CT) DNA and bovine serum albumin (BSA). The results inferred intercalation binding mode of the complexes with DNA. All the complexes exhibited good binding with BSA as well. In addition, the binding efficacy of the Cu (II) complexes with SARS-Cov-2 was tested in silico. Further, in vitro anticancer activity of the complexes was investigated against the HeLa-cervical, HepG2-liver and A549-lung cancer, and one normal (L929-fibroblast) cell line. IC50 values unveiled that the complexes were more active than cisplatin against all three cancer cells. It was understood that complex Cu-3 containing azide substitution displayed the highest activity on the HeLa cell line (IC50 = 6.3 μM). More importantly, TppyCu (II) complexes were not active against the normal cell line. Lastly, the acridine orange/ethidium bromide (AO/EB) and 4′,6-diamidino-2-phenylindole staining assays indicated that Cu-3 induced cell death in HeLa cells at the late apoptotic stage. This complex also efficiently generated ROS in HeLa cells promoting apoptosis as understood from the DCFH-DA assay. © 2023 John Wiley & Sons, Ltd.

Investigating structural features of dimeric SARS-CoV-2 Mpro catalytic site with bound covalent ligands at physiological temperature

The SARS-CoV-2 main protease (Mpro) plays an important role in the viral transcription and replication of the SARS-CoV-2 virus that is causing the Covid-19 pandemic worldwide. Therefore, it represents a very attractive target for drug development for treatment of this disease. It is a cysteine protease because it has in the active site the catalytic dyad composed of cysteine (C145) and histidine (H41). The catalytic site represents the binding site for inhibitors, many of them bind to Mpro with a covalent bond. In this research, structural and physiochemical characteristics of the Mpro binding site are investigated when the ligand 11a is covalently and non-covalently bound. All-atom molecular dynamics (MD) simulations were run for 500 ns at physiological temperature (310 K). It is found that conformations of both the Mpro protein and the ligand are stable during the simulation with covalently bound complex showing stronger stability. When the ligand is covalently bound (its final state), residues that stably interact with the ligand are H41, C145, H163, H164 and E166. The optimal conformation of these residues is stabilized also via the Hbond interactions with the catalytic water present in the Mpro binding site. In the case of the non-covalently bound ligand (state before the covalent bond is formed), the binding site residues retain their conformations similar to the covalent binding site, and they still form Hbonds with the catalytic water, except H41. This residue, instead, adopts a different conformation and looses the Hbond with the catalytic water, leaving more freedom to move to the ligand. We hypothesize that H41 could play a role in guiding the ligand to the optimal position for final covalent bonding. Further analyses are in process to check this hypothesis. These results represent an important basis for studying drug candidates against SARS-CoV-2 by means of computer aided drug design.

Tuberculosis and HIV responses threatened by nCOVID-19: A situation prompting an in silico investigation of reported MbtA inhibitors for combined inhibition of SARS-CoV-2 and HIV-TB co-infection

The menace of infectious diseases has constantly been a reason of concern for humankind since time immemorial. As evident by the name, infectious diseases can infect a huge population within a short period, leading to an eruption of pandemics and epidemics. The present human era is fortunate enough to have a wide array of readily available drugs that help cure and prevent various diseases. Moreover, the scientific community has always responded to the needs of society through its drug discovery and development programs. The co-existence of multiple diseases calls forth the scientific community to design and develop drugs that could have a broad spectrum of activity. In this perspective, our goal was to investigate the potential of reported MbtA inhibitors (antitubercular molecules) in inhibiting HIV-1 RT and nCovid-19-RdRp and eventually leading to the identification of a multi-targeted ligand (triple co-infection inhibitor). In this study, the primary success was attained by capitalizing on the structure-based virtual screening drug discovery approach. Results were quite promising. Molecular docking results showed that GV17 interacted strongly with the active site residues of both the target proteins (HIV-1 RT and nCOVID-19-RdRp). Moreover, the docking score of GV17 was more than that of the internal ligands of both the target proteins, which indicates a firm binding. Molecular dynamics further validated these results as identical amino acid residues were observed in the protein's docked pose with the ligand. The detailed atomic interactions of ligand GV17 with the protein residues have been discussed. Overall, the protein–ligand complexes remained stable throughout the simulation, and the system's backbone fluctuations were modest. MM-GBSA analysis revealed free binding energy of − 72.30 ± 7.85 kcal/mol and − 65.40 ± 7.25 kcal/mol for 1RT2 and 7BV2, respectively. The more negative binding energy indicates a stronger affinity of GV17 with both the receptors. GV17 also gave satisfactory predictive in silico ADMET results. Overall, this computational study identified GV17 as a potential HIT molecule and findings can open up a new avenue to explore and develop inhibitors against nCOVID-19-HIV-TB triple-infections.

Complex of Ceftriaxone with Mg(II): Synthesis, Structure, Spectral and Antibacterial Properties

Аннотация. Получен и охарактеризован магниевый комплекс цефтриаксона методами атомно-эмиссионного и элементного анализов, ТГА, ИК- и КР-спектроскопии, РФА и расчетов теории функционала плотности. Цефтриаксон координируется к иону магния через кислород триазинового цикла в шестом положении, азот аминогруппы тиазольного цикла и атомы кислорода карбоксильной и лактамной групп. Динатриевая соль цефтриаксона и комплекс магния были исследованы на антибактериальную активность в отношении Staphylococcus aureus, Escherichia coli и Pseudomonas aeruginosa.Alternate abstract:Magnesium complex of ceftriaxone was obtained and characterized by atomic-emission and elemental analysis, TGA, FTIR and Raman spectroscopy, X-ray diffraction and density functional theory calculations. Ceftriaxone was coordinated to the magnesium ion by the oxygen of the triazine cycle in the 6th position, the nitrogen of the amine group of the thiazole ring, and oxygen atoms of the lactam carbonyl and carboxylate groups. The disodium salt of ceftriaxone and magnesium complex were screened for antibacterial activity against Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa.

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.