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The rare zoonotic Borna disease virus (BDV) causes fatal neurological disease in various animals, with a high mortality rate exceeding 90% in central Europe. However, unlike most viruses, it establishes persistent infections within the host cell nucleus, hindering treatment. As successful BDV treatments remain elusive, the researchers turned to a computational approach, utilizing molecular docking, ADME/T, post-docking MMGBSA, MD simulation, DCCM, and PCA to identify promising phytochemical drug candidates targeting the BDV Nucleoprotein (PDB ID: 1N93). From IMPPAT 1940 unique phytochemical compounds of a total of 8617 compounds from 36 Indian medicinal plants were retrieved. Three compounds were chosen as leads with higher binding affinity of -6.244, -6.116, and -6.07 kcal/mol with CID 163114683 (IMPHY000668) Nimbochalcin, CID 20871246 (IMPHY007896) 3,4-Dihydroxy-5-oxocyclohex-3-ene-1-carboxylic acid, and CID 243 (IMPHY002962) Benzoic acid. The three top compounds coordinated with the protein's common amino acid residues at GLN 161, ARG 165, ILE 145, ILE 162, ILE 149, and VAL 229 during molecular docking, which implies that both lead compounds and the control ligand interact within the protein's shared active site. Afterwards, negative binding free energies of Nimbochalcin, 3,4-Dihydroxy-5-oxocyclohex-3-ene-1-carboxylic acid, and Benzoic acid were -51.21, -13.94, and -22.95 kcal/mol, accordingly. Favorable Pk and toxicological characteristics are shared by all of the chosen drugs, indicating their efficacy and safety. Using MD simulation, these three compounds were further assessed, and their stability in binding to the target protein was confirmed and subsequently, DCCM and PCA analyses were carried out from MD trajectory. MD simulations found that the protein binding site is highly stable when complexed with CID 20871246 and has a higher negative binding free energy value, indicating a strong interaction between the compound and the protein. Principal component analysis (PCA) identified three main components (PC1, PC2, and PC3) that accounted for 53.43%, 12.31%, and 5.97% of the variance, respectively. These findings provide intriguing evidence that the CID 20871246-1N93 complex is more stable than the other complexes. The BDV nucleoprotein was the target of this study's investigation where CID 20871246 (3,4-dihydroxy-5-oxocyclohex-3-ene-1-carboxylic acid) exhibited tremendous antiviral activity which is found in the flower of the plant Mangifera indica revealing as a possible therapeutic candidate., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Siddiquee et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Cryptococcus neoformans causes cryptococcal meningitis, which is lethal to immune-compromised people, especially AIDS patients. This study employed diverse in silico techniques to find the best phytochemical to block farnesyltransferase (FTase). Based on molecular docking, the top two compounds selected from a screening of 5807 phytochemical compounds from 29 medicinal plants were CID_8299 (hydroxyacetone) and CID_71346280 (1,7-bis (4-hydroxyphenyl)-1,4,6-heptatrien-3-one), with docking scores of -5.786 and -0.078 kcal/mol, respectively, indicating stronger binding affinities than the control CID_3365 (fluconazole), which scored -4.2 kcal/mol. The control and lead compounds bind at the common active site of protein by interacting with common amino acid residues (HIS97, GLN408, PHE93, and TRP94). Post-docking MM-GBSA verified docking score where CID_8299 and CID_71346280 had negative binding free energies of -19.81 and -0.27 kcal/mol, respectively. These two lead compounds were reassessed through molecular dynamics simulation (100 ns), and several post-dynamics analyses were conducted. CID_71346280, 8299, and 3365 (control) showed average RSMD values of 3.17, 1.904, and 2.08; average root mean square fluctuation values of 1.167, 0.886, and 1.028 Å; average radius of gyration values of 5.13, 1.58, and 3.54 Å; average solvent accessible surface area values of 121.16, 3.51, and 183.81 Å 2 ; average H-bond values of 466.05, 470.84, and 456.84 Å, respectively. The results revealed that CID_8299 had the highest stability and consistent interaction with the target protein throughout the simulation period. According to the toxicity analysis, CID_8299, which is found in the Glycyrrhiza glabra plant, can also cross the BBB, which makes it unbeatable in treating neuro-disease caused by C. neoformans and may potentially block FTase protein's activity inhibiting post-translational lipidation of essential signal transduction protein., (© 2024 Wiley‐VHCA AG, Zurich, Switzerland.)

The highly pathogenic Marburg virus (MARV) is a member of the Filoviridae family, a non-segmented negative-strand RNA virus. This article represents the computer-aided drug design (CADD) approach for identifying drug-like compounds that prevent the MARV virus disease by inhibiting nucleoprotein, which is responsible for their replication. This study used a wide range of in silico drug design techniques to identify potential drugs. Out of 368 natural compounds, 202 compounds passed ADMET, and molecular docking identified the top two molecules (CID: 1804018 and 5280520) with a high binding affinity of -6.77 and -6.672 kcal/mol, respectively. Both compounds showed interactions with the common amino acid residues SER_216, ARG_215, TYR_135, CYS_195, and ILE_108, which indicates that lead compounds and control ligands interact in the common active site/catalytic site of the protein. The negative binding free energies of CID: 1804018 and 5280520 were -66.01 and -31.29 kcal/mol, respectively. Two lead compounds were re-evaluated using MD modeling techniques, which confirmed CID: 1804018 as the most stable when complexed with the target protein. PC3 of the (Z)-2-(2,5-dimethoxybenzylidene)-6-(2-(4-methoxyphenyl)-2-oxoethoxy) benzofuran-3(2H)-one (CID: 1804018) was 8.74 %, whereas PC3 of the 2'-Hydroxydaidzein (CID: 5280520) was 11.25 %. In this study, (Z)-2-(2,5-dimethoxybenzylidene)-6-(2-(4-methoxyphenyl)-2-oxoethoxy) benzofuran-3(2H)-one (CID: 1804018) unveiled the significant stability of the proteins' binding site in ADMET, Molecular docking, MM-GBSA and MD simulation analysis studies, which also showed a high negative binding free energy value, confirming as the best drug candidate which is found in Angelica archangelica which may potentially inhibit the replication of MARV nucleoprotein., Competing Interests: Declaration of competing interest The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Argemone mexicana L. is a medicinal plant, but its impact on Alzheimer's disease (AD) is right now undetermined. We intended to investigate the in-vitro anti-AD potential of leaves and flowers of A. mexicana methanol, ethanol, and ethyl extracts and to identify multi-modal anti-AD phytochemicals by computational approaches. Molecular docking of 196 phytochemicals identified three hit phytochemicals (protoberberine, protopine, and codeine) with higher binding affinity and multi-targeting ability toward AChE, BChE, BACE-1, and GSK-3β. Further MM-GBSA assays confirmed the integrity of these phytochemicals as the hit phytochemicals. However, these phytochemicals demonstrated favorable pharmacokinetics (PK) and drugable properties having no toxicity. Molecular dynamics simulations confirmed the binding strength of the hit phytoconstituents in the active pockets of AChE, BChE, BACE-1, and GSK-3β with multi-targeting inhibitory activities. All the extracts exhibited dose-dependent antioxidant and anti-cholinesterase activities supporting the in silico results in the context of oxidative stress and cholinergic pathways. Our results offer scientific validation of the anti-AD properties of Argemone mexicana L. and identified protoberberine, protopine, and codeine that could be used for the development of multi-modal inhibitors of AChE, BChE, BACE-1, and GSK-3β to combat AD. Additional in vivo validation is recommended to ensure a thorough assessment in the present research., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have influenced the work presented in this paper., (© 2024 Published by Elsevier Ltd.)

Background: Rearranged during transfection (RET), an oncogenic protein, is associated with various cancers, including non-small-cell lung cancer (NSCLC), papillary thyroid cancer (PTC), pancreatic cancer, medullary thyroid cancer (MTC), breast cancer, and colorectal cancer. Dysregulation of RET contributes to cancer development, highlighting the importance of identifying lead compounds targeting this protein due to its pivotal role in cancer progression. Therefore, this study aims to discover effective lead compounds targeting RET across different cancer types and evaluate their potential to inhibit cancer progression., Methods: This study used a range of computational techniques, including Phase database creation, high-throughput virtual screening (HTVS), molecular docking, molecular mechanics with generalized Born surface area (MM-GBSA) solvation, assessment of pharmacokinetic (PK) properties, and molecular dynamics (MD) simulations, to identify potential lead compounds targeting RET., Results: Initially, a high-throughput virtual screening of the ZINC database identified 2,550 compounds from a pool of 170,269. Subsequent molecular docking studies revealed 10 compounds with promising negative binding scores ranging from -8.458 to -7.791 kcal/mol. MM-GBSA analysis further confirmed the potential of four compounds to exhibit negative binding scores. MD simulations demonstrated the stability of CID 95842900, CID 137030374, CID 124958150, and CID 110126793 with the target receptors., Conclusion: These findings suggest that these selected four compounds have the potential to inhibit phosphorylated RET (pRET) tyrosine kinase activity and may represent promising candidates for the treatment of various cancers., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Talukder, Aktaruzzaman, Siddiquee, Islam, Wani, Alkahtani, Zargar, Raihan, Rahman, Pokhrel and Ahammad.)

In humans, FOXP gene family is involved in embryonic development and cancer progression. The FOXP4 (Forkhead box protein P4) gene belongs to this FOXP gene family. FOXP4 gene plays a crucial role in oncogenesis. Single nucleotide polymorphisms are biological markers and common determinants of human diseases. Mutations can largely affect the function of the corresponding protein. Therefore, the molecular mechanism of nsSNPs in the FOXP4 gene needs to be elucidated. Initially, the SNPs of the FOXP4 gene were extracted from the dbSNP database and a total of 23124 SNPs was found, where 555 nonsynonymous, 20525 intronic, 1114 noncoding transcript, 334 synonymous were obtained and the rest were unspecified. Then, a series of bioinformatics tools (SIFT, PolyPhen2, SNAP2, PhD SNP, PANTHER, I-Mutant2.0, MUpro, GOR IV, ConSurf, NetSurfP 2.0, HOPE, DynaMut2, GeneMANIA, STRING and Schrodinger) were used to explore the effect of nsSNPs on FOXP4 protein function and structural stability. First, 555 nsSNPs were analyzed using SIFT, of which 57 were found as deleterious. Following, PolyPhen2, SNAP2, PhD SNP and PANTHER analyses, 10 nsSNPs (rs372762294, rs141899153, rs142575732, rs376938850, rs367607523, rs112517943, rs140387832, rs373949416, rs373949416 and rs376160648) were common and observed as deleterious, damaging and diseases associated. Following that, using I-Mutant2.0 and MUpro servers, 7 nsSNPs were found to be the most unstable. GOR IV predicted that these seven nsSNPs affect protein structure by altering the protein contents of alpha helixes, extended strands, and random coils. Following DynaMut2, 5 nsSNPs showed a decrease in the ΔΔG value compared with the wild-type and were found to be responsible for destabilizing the corresponding protein. GeneMANIA and STRING network revealed interaction of FOXP4 with other genes. Finally, molecular dynamics simulation analysis revealed consistent fluctuation in RMSD and RMSF values, Rg and hydrogen bonds in the mutant proteins compared with WT, which might alter the functional and structural stability of the corresponding protein. As a result, the aforementioned integrated comprehensive bioinformatic analyses provide insight into how various nsSNPs of the FOXP4 gene change the structural and functional properties of the corresponding protein, potentially proceeding with the pathophysiology of human diseases., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

Single nucleotide polymorphisms (SNPs) are one of the most common determinants and potential biomarkers of human disease pathogenesis. SNPs could alter amino acid residues, leading to the loss of structural and functional integrity of the encoded protein. In humans, members of the minichromosome maintenance (MCM) family play a vital role in cell proliferation and have a significant impact on tumorigenesis. Among the MCM members, the molecular mechanism of how missense SNPs of minichromosome maintenance complex component 6 (MCM6) contribute to DNA replication and tumor pathogenesis is underexplored and needs to be elucidated. Hence, a series of sequence and structure-based computational tools were utilized to determine how mutations affect the corresponding MCM6 protein. From the dbSNP database, among 15,009 SNPs in the MCM6 gene, 642 missense SNPs (4.28%), 291 synonymous SNPs (1.94%), and 12,500 intron SNPs (83.28%) were observed. Out of the 642 missense SNPs, 33 were found to be deleterious during the SIFT analysis. Among these, 11 missense SNPs (I123S, R207C, R222C, L449F, V456M, D463G, H556Y, R602H, R633W, R658C, and P815T) were found as deleterious, probably damaging, affective and disease-associated. Then, I123S, R207C, R222C, V456M, D463G, R602H, R633W, and R658C missense SNPs were found to be highly harmful. Six missense SNPs (I123S, R207C, V456M, D463G, R602H, and R633W) had the potential to destabilize the corresponding protein as predicted by DynaMut2. Interestingly, five high-risk mutations (I123S, V456M, D463G, R602H, and R633W) were distributed in two domains (PF00493 and PF14551). During molecular dynamics simulations analysis, consistent fluctuation in RMSD and RMSF values, high Rg and hydrogen bonds in mutant proteins compared to wild-type revealed that these mutations might alter the protein structure and stability of the corresponding protein. Hence, the results from the analyses guide the exploration of the mechanism by which these missense SNPs of the MCM6 gene alter the structural integrity and functional properties of the protein, which could guide the identification of ways to minimize the harmful effects of these mutations in humans., (© 2024. The Author(s).)

The aim of this research is to examine possible neurological activity of methanol, ethyl acetate, and aqueous extracts of Hygrophila spinosa and identify possible lead compounds through in silico analysis. In vivo , neuropharmacological activity was evaluated by using four distinct neuropharmacological assessment assays. Previously reported GC-MS data and earlier literature were utilized to identify the phytochemicals present in Hygrophila spinosa . Computational studies notably molecular docking and molecular dynamic simulations were conducted with responsible receptors to assess the stability of the best interacting compound. Pharmacokinetics properties like absorption, distribution, metabolism, excretion, and toxicity were considered to evaluate the drug likeliness properties of the identified compounds. All the in vivo results support the notion that different extracts (methanol, ethyl acetate, and aqueous) of Hygrophila spinosa have significant (* p  = 0.05) sedative-hypnotic, anxiolytic, and anti-depressant activity. Among all the extracts, specifically methanol extracts of Hygrophila spinosa (MHS 400 mg/kg.b.w.) showed better sedative, anxiolytic and antidepressant activity than aqueous and ethyl acetate extracts. In silico molecular docking analysis revealed that among 53 compounds 7 compounds showed good binding affinities and one compound, namely apomorphine (CID: 6005), surprisingly showed promising binding affinity to all the receptors . An analysis of molecular dynamics simulations confirmed that apomorphine (CID: 6005) had a high level of stability at the protein binding site. Evidence suggests that Hygrophila spinosa has significant sedative, anxiolytic, and antidepressant activity. In silico analysis revealed that a particular compound (apomorphine) is responsible for this action. Further research is required in order to establish apomorphine as a drug for anxiety, depression, and sleep disorders.Communicated by Ramaswamy H. Sarma.

Christella dentata (Forssk.) Brownsey & Jermy has been commonly used in traditional medicinal practices but its effects on multi-drug-resistant (MDR) bacteria have remained unexplored. We aimed to assess the in vitro antibacterial potential of the ethanol extract of Christella dentata (EECD) against MDR Pseudomonas aeruginosa and to identify potential multi-targeting antibacterial phytocompounds through computer-aided drug design focusing on the LasR and LpxC proteins. PPS, FT-IR and GC-MS were used for profiling of the phytocompounds in EECD. The antimicrobial activity of EECD was assessed using in vitro agar well diffusion, disc diffusion, MIC and MBC. Computer-aided drug design was used to identify multi-targeting leads from GC-MS-annotated phytocompounds. EECD exhibited dose-dependent antibacterial activity and revealed the presence of 51 phytocompounds in GC-MS analysis. Among these, three phytocompounds; (2 E ,4 E )- N -isobutylhexadeca-2,4-dienamide (CID 6442402), bicyclo[4.3.0]nonane, 2,2,6,7-tetramethyl-7-hydroxy- (CID 536446) and 1,4-diethylbenzene (CID 7734) were identified as promising antibacterial phytocompounds as they strongly bonded with LasR and LpxC. Of them, CID 536446 and CID 7734 exhibited multiple targeting abilities with LasR and LpxC. On further screening, both CID 536446 and CID 7734 exhibited favorable drug-able, pharmacokinetics and toxicity properties. Finally, molecular dynamics (MD) simulation proved the binding stability of bicyclo[4.3.0]nonane, 2,2,6,7-tetramethyl-7-hydroxy- and 1,4-diethylbenzene to active pockets of LasR and LpxC. The results of this study offer scientific validation for the traditional use of Christella dentata in bacterial infection-related diseases. It also suggests that bicyclo[4.3.0]nonane, 2,2,6,7-tetramethyl-7-hydroxy- and 1,4-diethylbenzene from Christella dentata might be responsible for the antibacterial activity and could act as phytopharmacological leads for the development of LasR and LpxC inhibitors against MDR P. aeruginosa ., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have influenced the work presented in this paper., (This journal is © The Royal Society of Chemistry.)

Glypican-3 (GPC3), a membrane-bound heparan sulfate proteoglycan, has long been found to be dysregulated in human lung adenocarcinomas (LUADs). Nevertheless, the function, mutational profile, epigenetic regulation, co-expression profile, and clinicopathological significance of the GPC3 gene in LUAD progression are not well understood. In this study, we analyzed cancer microarray datasets from publicly available databases using bioinformatics tools to elucidate the above parameters. We observed significant downregulation of GPC3 in LUAD tissues compared to their normal counterparts, and this downregulation was associated with shorter overall survival (OS) and relapse-free survival (RFS). Nevertheless, no significant differences in the methylation pattern of GPC3 were observed between LUAD and normal tissues, although lower promoter methylation was observed in male patients. GPC3 expression was also found to correlate significantly with infiltration of B cells, CD8+, CD4+, macrophages, neutrophils, and dendritic cells in LUAD. In addition, a total of 11 missense mutations were identified in LUAD patients, and ~1.4% to 2.2% of LUAD patients had copy number amplifications in GPC3. Seventeen genes, mainly involved in dopamine receptor-mediated signaling pathways, were frequently co-expressed with GPC3. We also found 11 TFs and 7 miRNAs interacting with GPC3 and contributing to disease progression. Finally, we identified 3 potential inhibitors of GPC3 in human LUAD, namely heparitin, gemcitabine and arbutin. In conclusion, GPC3 may play an important role in the development of LUAD and could serve as a promising biomarker in LUAD., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Merkel cell carcinoma (MCC) is a rare neuroendocrine skin malignancy caused by human Merkel cell polyomavirus (MCV), leading to the most aggressive skin cancer in humans. MCV has been identified in approximately 43%-100% of MCC cases, contributing to the highly aggressive nature of primary cutaneous carcinoma and leading to a notable mortality rate. Currently, no existing vaccines or drug candidates have shown efficacy in addressing the ailment caused by this specific pathogen. Therefore, this study aimed to design a novel multiepitope vaccine candidate against the virus using integrated immunoinformatics and vaccinomics approaches. Initially, the highest antigenic, immunogenic, and non-allergenic epitopes of cytotoxic T lymphocytes, helper T lymphocytes, and linear B lymphocytes corresponding to the virus whole protein sequences were identified and retrieved for vaccine construction. Subsequently, the selected epitopes were linked with appropriate linkers and added an adjuvant in front of the construct to enhance the immunogenicity of the vaccine candidates. Additionally, molecular docking and dynamics simulations identified strong and stable binding interactions between vaccine candidates and human Toll-like receptor 4. Furthermore, computer-aided immune simulation found the real-life-like immune response of vaccine candidates upon administration to the human body. Finally, codon optimization was conducted on the vaccine candidates to facilitate the in silico cloning of the vaccine into the pET28+(a) cloning vector. In conclusion, the vaccine candidate developed in this study is anticipated to augment the immune response in humans and effectively combat the virus. Nevertheless, it is imperative to conduct in vitro and in vivo assays to evaluate the efficacy of these vaccine candidates thoroughly. These evaluations will provide critical insights into the vaccine's effectiveness and potential for further development., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Imon, Samad, Alam, Alsaiari, Talukder, Almehmadi, Ahammad and Mohammad.)

Mitochondrial dysfunction remains a pivotal mechanism in manifold neurodegenerative diseases. Mitochondrial homeostasis within the cell is an essential aspect of cell biology. Mitochondria, the power-generating organelle of the cell, have a dominant role in several processes associated with genomic integrity and cellular equilibrium. They are involved in maintaining optimal cell functioning and ensuring guidance against possible DNA damage, which could lead to mutations and the onset of diseases. Conversely, system perturbations, which could be due to environmental factors or senescence, induce changes in the physiological balance and result in mitochondrial function impairment. As a result, we present a general overview of the pathological pathways involved in Alzheimer's and Parkinson's diseases caused by changes in mitochondrial homeostasis. The focal point of this review is on mitochondrial dysfunction being a significant condition in the onset of neuronal disintegration. We explain the pathways associated with the dysfunction of the mitochondria, which are common among the most recurring neurodegenerative diseases, including Alzheimer's and Parkinson's disease. Are mitochondrial dysfunctions an early event in the progression of neuropathological processes? We discovered that mtDNA mutation is a major contributor to the metabolic pathology of most neurological disorders, causing changes in genes important for physiological homeostasis. As a result, genetic changes in presenilin, Amyloid-, ABAD, DJ-1, PINK-1, PARKIN, alpha-synuclein, and other important controlling genes occur. Therefore, we suggest possible therapeutic solutions., Competing Interests: The authors declare no competing interests., (© 2023 The Authors. Published by Elsevier Ltd.)

Background: Crimean-Congo hemorrhagic fever (CCHF) is a widespread disease transmitted to humans and livestock animals through the bite of infected ticks or close contact with infected persons' blood, organs, or other bodily fluids. The virus is responsible for severe viral hemorrhagic fever outbreaks, with a case fatality rate of up to 40%. Despite having the highest fatality rate of the virus, a suitable treatment option or vaccination has not been developed yet. Therefore, this study aimed to formulate a multiepitope vaccine against CCHF through computational vaccine design approaches., Methods: The glycoprotein, nucleoprotein, and RNA-dependent RNA polymerase of CCHF were utilized to determine immunodominant T- and B-cell epitopes. Subsequently, an integrative computational vaccinology approach was used to formulate a multi-epitopes vaccine candidate against the virus., Results: After rigorous assessment, a multiepitope vaccine was constructed, which was antigenic, immunogenic, and non-allergenic with desired physicochemical properties. Molecular dynamics (MD) simulations of the vaccine-receptor complex show strong stability of the vaccine candidates to the targeted immune receptor. Additionally, the immune simulation of the vaccine candidates found that the vaccine could trigger real-life-like immune responses upon administration to humans., Conclusions: Finally, we concluded that the formulated multiepitope vaccine candidates would provide excellent prophylactic properties against CCHF., (© 2023. The Author(s).)

Angiotensin-converting enzyme 2 (ACE2), also known as peptidyl-dipeptidase A, belongs to the dipeptidyl carboxydipeptidases family has emerged as a potential antiviral drug target against SARS-CoV-2. Most of the ACE2 inhibitors discovered till now are chemical synthesis; suffer from many limitations related to stability and adverse side effects. However, natural, and selective ACE2 inhibitors that possess strong stability and low side effects can be replaced instead of those chemicals' inhibitors. To envisage structurally diverse natural entities as an ACE2 inhibitor with better efficacy, a 3D structure-based-pharmacophore model (SBPM) has been developed and validated by 20 known selective inhibitors with their correspondence 1166 decoy compounds. The validated SBPM has excellent goodness of hit score and good predictive ability, which has been appointed as a query model for further screening of 11,295 natural compounds. The resultant 23 hits compounds with pharmacophore fit score 75.31 to 78.81 were optimized using in-silico ADMET and molecular docking analysis. Four potential natural inhibitory molecules namely D-DOPA (Amb17613565), L-Saccharopine (Amb6600091), D-Phenylalanine (Amb3940754), and L-Mimosine (Amb21855906) have been selected based on their binding affinity (-7.5, -7.1, -7.1, and -7.0 kcal/mol), respectively. Moreover, 250 ns molecular dynamics (MD) simulations confirmed the structural stability of the ligands within the protein. Additionally, MM/GBSA approach also used to support the stability of molecules to the binding site of the protein that also confirm the stability of the selected four natural compounds. The virtual screening strategy used in this study demonstrated four natural compounds that can be utilized for designing a future class of potential natural ACE2 inhibitor that will block the spike (S) protein dependent entry of SARS-CoV-2 into the host cell., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Middle East respiratory syndrome coronavirus (MERS-CoV) is a highly infectious zoonotic virus first reported into the human population in September 2012 on the Arabian Peninsula. The virus causes severe and often lethal respiratory illness in humans with an unusually high fatality rate. The N-terminal domain (NTD) of receptor-binding S1 subunit of coronavirus spike (S) proteins can recognize a variety of host protein and mediates entry into human host cells. Blocking the entry by targeting the S1-NTD of the virus can facilitate the development of effective antiviral drug candidates against the pathogen. Therefore, the study has been designed to identify effective antiviral drug candidates against the MERS-CoV by targeting S1-NTD. Initially, a structure-based pharmacophore model (SBPM) to the active site (AS) cavity of the S1-NTD has been generated, followed by pharmacophore-based virtual screening of 11,295 natural compounds. Hits generated through the pharmacophore-based virtual screening have re-ranked by molecular docking and further evaluated through the ADMET properties. The compounds with the best ADME and toxicity properties have been retrieved, and a quantum mechanical (QM) based density-functional theory (DFT) has been performed to optimize the geometry of the selected compounds. Three optimized natural compounds, namely Taiwanhomoflavone B (Amb23604132), 2,3-Dihydrohinokiflavone (Amb23604659), and Sophoricoside (Amb1153724), have exhibited substantial docking energy >-9.00 kcal/mol, where analysis of frontier molecular orbital (FMO) theory found the low chemical reactivity correspondence to the bioactivity of the compounds. Molecular dynamics (MD) simulation confirmed the stability of the selected natural compound to the binding site of the protein. Additionally, molecular mechanics generalized born surface area (MM/GBSA) predicted the good value of binding free energies (ΔG bind) of the compounds to the desired protein. Convincingly, all the results support the potentiality of the selected compounds as natural antiviral candidates against the MERS-CoV S1-NTD.