Binding site prediction between lysozyme and glucose-regulated protein 78, a hope to fight amyloidosis.

Amyloidosis is an extraordinarily vigorous and heterogeneous group of disorders that causes numerous organ failures due to the precipitation of misfolded proteins. Many of these damaged proteins are discarded before causing any fatal diseases due to the contribution of the protein quality control (PQC) system and its chaperons, including glucose-regulated protein (GRP78). One of the most important enzymatic proteins inside the body is lysozyme, which is reported to have many mutated variants that may cause amyloid fibrils. This study used structural bioinformatics and molecular dynamics simulations to test and suggest binding sites for the human lysozyme protein with GRP78. Multiple sequence alignment (MSA) shows that part of the lysozyme envelope protein (C65-C81 cyclic region) has high similarities (30.77% identity) with the cyclic Pep42. Additionally, the binding between the lysozyme cyclic region (C65-C81) and GRP78 substrate binding domain (SBD) is found favorable. The number and types of interactions vary between each of the mutant isoforms of lysozyme. The more significant the conformational changes in the mutation, the greater its probability of aggregation and the formation of amyloid fibrils. Each mutation leads to different interactions and binding patterns with GRP78. The present computational study suggests a lysozyme-GRP78 binding site, thus paving the way for drug designers to construct suitable carriers that can collect misfolded lysozyme proteins and eliminate them from the body, preventing their aggregation and amyloidogenesis.Communicated by Ramaswamy H. Sarma.

Prediction of the binding location between the nuclear inhibitor of DNA binding and differentiation 2 (ID2) and HSPA5.

Glucose-regulated protein 78 (GRP78), also termed HSPA5, was widely studied in cancer. It was recently approved that GRP78 has nuclear localization potential that sheds light on its role in cancer development. The inhibitor of DNA binding and differentiation 2 (ID2) is the nuclear component that associates with GRP78. The interaction between these two proteins is not understood clearly. In the current study, the binding pattern of GRP78/ID2 is predicted using computational methods. Protein-protein docking is used along with molecular dynamics simulation. The substrate binding domain ß of GRP78 can stably interact with the loop region (C42-S60) of ID2 as predicted in this study. This paves the way for a possible destabilizer for this association and cancer eradication.

In vivo dose measurements for tangential field-in-field ultra-hypofractionated breast radiotherapy.

INTRODUCTION: Ultra-hypofractionated radiotherapy (UHF-RT) mandates more accuracy in each part of the treatment cycle to maximize cure rates and minimize toxicities. In vivo dosimetry is a direct method for verifying overall treatment accuracy. This study evaluated uncertainties in the delivered dose of Hypofractionated (HF) and UHF Whole Breast Irradiation (WBI) and to analyze the accuracy of the workflow to pave the way for a wide-scale use of UHF-RT. METHODS: Thirty-three breast cancer cases, including 16 HF-WBI and 17 UHF-WBI were treated with 3D conformal Radiotherapy (3D-CRT), where 79 fields were analyzed for dose verification. The measurement point was set at the beam entrance (1.5 cm depth). The expected dose at Dmax was calculated via TPS. Before in vivo measurements, diode detectors were tested and calibrated. We developed initial validation measurements for UHF-RT on an anthropomorphic breast phantom for the first time. RESULTS: For RANDO phantom, the percentage difference between measured and calculated doses showed an average of -0.52 ± 5.4%, in addition to an excellent dose reproducibility within 0.6%. The overall in vivo measurements for studied cases showed that 83.5% of the measured doses were within ±5% and only 1.8% of the measured doses were greater than ±10% of the calculated doses. The percentage accuracy was slightly larger for UHF cohort (84.2%) compared to HF cohort (83.2%). The maximum percentage difference between them was less than 1%. CONCLUSION: Breast in vivo dosimetry is an adequate tool for treatment verification that improves the accuracy of the treatment cycle. UHF-RT may contribute in reducing the long waiting lists, increasing patient convenience, and saving the available resources for breast cancer patients.

Chia seeds and coenzyme Q10 alleviate iron overload induced hepatorenal toxicity in mice via iron chelation and oxidative stress modulation.

Iron overload (IOL) can cause hepatorenal damage due to iron-mediated oxidative and mitochondrial damage. Remarkably, combining a natural iron chelator with an antioxidant can exert greater efficacy than monotherapy. Thus, the present study aimed to evaluate the efficacy of Chia and CoQ10 to chelate excess iron and prevent hepatorenal oxidative damage in IOL mice. Male Swiss albino mice (n = 49) were randomly assigned to seven groups: control, dietary Chia, CoQ10, IOL, IOL + Chia, IOL + CoQ10, and IOL + Chia + CoQ10. Computational chemistry indicates that the phytic acid found in the Chia seeds is stable, reactive, and able to bind to up to three iron ions (both Fe2+ and Fe3+). IOL induced a significant (P < 0.05) increase in serum iron, ferritin, transferrin, TIBC, TSI, RBCs, Hb, MCV, MCH, WBCs, AST, ALT, creatinine, and MDA. IOL causes a significant (P < 0.05) decrease in UIBC, platelets, and antioxidant molecules (GSH, SOD, CAT, and GR). Also, IOL elicits mitochondrial membrane change depolarization, and DNA fragmentation and suppresses mitochondrial DNA copies. Furthermore, substantial changes in hepatic and renal tissue, including hepatocellular necrosis and apoptosis, glomerular degeneration, glomerular basement membrane thickening, and tubular degeneration, were observed in the IOL group. Dietary Chia and CoQ10 induced significant (P < 0.05) amelioration in all the mentioned parameters. They can mostly repair the abnormal architecture of hepatic and renal tissues induced by IOL, as signified by normal sinusoids, normal central veins, and neither glomerular damage nor degenerated tubules. In conclusion, the combined treatment with Chia + CoQ10 exerts more pronounced efficacy than monotherapy in hepatorenal protection via chelating excess iron and improved cellular antioxidant status and hepatorenal mitochondrial function in IOL mice.

Targeting of HPV E6 at the binding sites to the host-cell E6AP, p53, and the endoplasmic reticulum-resident chaperone, GRP78.

Background: Human papillomavirus (HPV) represents an etiological factor for many cancer types, especially cervical cancer. Its oncoprotein E6 sheds drug designers who aim to stop its cellular protein associations, such as p53 and E6AP. Recently, it was discovered that the host-cell chaperone glucose-regulated protein 78 (GRP78) plays a crucial function in HPV infectivity by association with the viral E6 and E7 proteins. Therefore, we aimed to test small molecules inhibitor that could contradict the association between E6 and cellular factors E6AP, GRP78, and p53. Methods: In this study, molecular docking protocol was elaborated to test 115 small molecule compounds against the three binding sites of HPV E6 to the host-cell proteins; E6AP, p53, and GRP78. After that, molecular dynamics simulation and free energy calculations were performed on the best three complexes. Results: The results reveal the potency of 18 compounds against the HPV E6 at different binding sites, which give lower free energies than paclitaxel (positive control). The best two compounds, hypericin, and anabsinthin, could bind effectively and stably during the 100 ns MD simulation period to HPV E6. The calculated average free energies for hypericin and anabsinthin are -18.76 and -14.40 kcal/mol, respectively. They formed stable complexes with the three binding sites by forming hydrophobic contacts. The key residues that stabilize the two ligands in HPV E6 binding sites are V31, Y32, V62, and Y70 (E6AP), P13, C16, T22, I23 and A46 (p53), and M1, V31, L50, L67, and Q107 (GRP78). Conclusions: The best two compounds, hypericin, and anabsinthin, are potential candidates against HPV E6 at the host-cell factors binding sites, hence could block the oncoprotein activity of E6 in infected cells. Further experimental validation is yet to be performed and suggested as future work.Communicated by Ramaswamy H. Sarma.

Serine/threonine kinase of Mpox virus: computational modeling and structural analysis.

Kinases catalyze phosphoryl transfer from a nucleoside triphosphate (usually ATP) to an amino acid on a protein for activation purposes. Although kinases are well-appreciated drug targets in different viruses and cancers, these enzymes in poxviruses received limited attention from the research community. In poxvirus, the production of infectious particles in the infected cells depends on a serine/threonine protein kinase (STK) that activates proteins implicated in the assembly of new virions. This work aimed to elucidate the structure and dynamics of the major kinase STK from Mpox virus (Orthopoxvirus). A state-of-the-art computational approach was employed to decipher the structure and dynamics of the STK using AlphaFold2 and molecular dynamics (MD) simulations. Although the predicted structure showed an atypical kinase, the overall structural fold is conserved. Binding free energy calculations via Molecular Mechanics/Generalized Born and Surface Area (MM/GBSA) determined the hotspot residues contributing to binding of ATP. The structural analysis in this work provides insights into the structure and behavior of STK in Mpox virus and possibly its closest members of Poxviridae. These findings also set the basis for setting up a thorough experimental investigation to understand the enzymatic mechanism, peptide substrate binding, and the development of small-molecule inhibitors against this kinase.Communicated by Ramaswamy H. Sarma.

A structural-based virtual screening and in vitro validation reveals novel effective inhibitors for SARS-CoV-2 helicase and endoribonuclease.

Researchers worldwide are looking for molecules that might disrupt the COVID-19 life cycle. Endoribonuclease, which is responsible for processing viral RNA to avoid detection by the host defense system, and helicase, which is responsible for unwinding the RNA helices for replication, are two key non-structural proteins. This study performs a hierarchical structure-based virtual screening approach for NSP15 and helicase to reach compounds with high binding probabilities. In this investigation, we incorporated a variety of filtering strategies for predicting compound interactions. First, we evaluated 756,275 chemicals from four databases using a deep learning method (NCI, Drug Bank, Maybridge, and COCONUT). Following that, two docking techniques (extra precision and induced fit) were utilized to evaluate the compounds' binding affinity, followed by molecular dynamic simulation supported by the MM-GBSA free binding energy calculation. Remarkably, two compounds (90616 and CNP0111740) exhibited high binding affinity values of -66.03 and -12.34 kcal/mol for helicase and NSP15, respectively. The VERO-E6 cell line was employed to test their in vitro therapeutic impact. The CC50 for CNP0111740 and 90616 were determined to be 102.767 µg/ml and 379.526 µg/ml, while the IC50 values were 140.176 µg/ml and 5.147 µg/ml, respectively. As a result, the selectivity index for CNP0111740 and 90616 is 0.73 and 73.73, respectively. Finally, these compounds were found to be novel, effective inhibitors for the virus; however, further in vivo validation is needed.Communicated by Ramaswamy H. Sarma.

Simulation of gold nanoparticle movement through normal and cancer cell membranes.

Gold nanoparticles (Au-NPs) have been used for a long time to target cancer cells. Different modalities have been suggested to utilize Au-NPs in cancer patients. We construct both normal and cancer cell membranes to simulate the Au-NP entry to understand better how it can penetrate the cancer cell membrane. We use molecular dynamics simulation (MDS) on both normal and cancer cell membrane models for 150 ns. At the same time, we prepared the Au-NP of spherical shape (16 nm radius) capped with citrate using MDS for 100 ns. Finally, we added the Au-NP close to the membranes and moved it using 1000 kJ mol-1 nm-1 force constant during the 7.7 ns MDS run. We analyzed the membranes in the presence and absence of the Au-NP and compared normal and cancer membranes. The results show that normal cell membranes have higher stability than cancer membranes. Additionally, Au-NP forms pore in the membranes that facilitate water and ions entry during the movement inside the lipid bilayer region. These pores are responsible for the enhanced response of Au-NP-loaded chemotherapeutic agents in cancer treatment.

New progresses on cell surface protein HSPA5/BiP/GRP78 in cancers and COVID-19.

Heat-shock-protein family A (Hsp70) member 5 (HSPA5), aliases GRP78 or BiP, is a protein encoded with 654 amino acids by the HSPA5 gene located on human chromosome 9q33.3. When the endoplasmic reticulum (ER) was stressed, HSPA5 translocated to the cell surface, the mitochondria, and the nucleus complexed with other proteins to execute its functions. On the cell surface, HSPA5/BiP/GRP78 can play diverse functional roles in cell viability, proliferation, apoptosis, attachments, and innate and adaptive immunity regulations, which lead to various diseases, including cancers and coronavirus disease 2019 (COVID-19). COVID-19 is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, which caused the pandemic since the first outbreak in late December 2019. HSPA5, highly expressed in the malignant tumors, likely plays a critical role in SARS-CoV-2 invasion/attack in cancer patients via tumor tissues. In the current study, we review the newest research progresses on cell surface protein HSPA5 expressions, functions, and mechanisms for cancers and SARS-CoV-2 invasion. The therapeutic and prognostic significances and prospects in cancers and COVID-19 disease by targeting HSPA5 are also discussed. Targeting HSPA5 expression by natural products may imply the significance in clinical for both anti-COVID-19 and anti-cancers in the future.

An insight into synthesis and antitumor activity of citrate and gallate stabilizing gold nanospheres.

Both gallic and citrate are well-established antioxidants that show promise as new selective anti-cancer drugs. Gold nanoparticles (AuNPs) as well can be developed as flexible and nontoxic nano-carriers for anti-cancer drugs. This article evaluating the efficiency and biocompatibility of gallic acid and citrate capping gold nanoparticles to be used as anti-cancer drug. The biosafety and therapeutic efficiency of prepared nano-formulations were tested on Hela and normal BHK cell line. Gold nanospheres coated with citrate and gallate were synthesized via wet chemical reduction method. The prepared nano-formulations, citrate and gallate coated gold nanospheres (Cit-AuNPs and Ga-AuNPs), were characterized with respect to their morphology, FTIR spectra, and physical properties. In addition, to assess their cytotoxicity, cell cycle arrest and flow cytometry to measure biological response were performed. Cit-Au NPs and Ga-Au NPs were shown to significantly reduce the viability of Hela cancer cells. Both G0/G cell cycle arrest and comet assay results showed that genotoxic effect was induced in Hela cells by Cit-Au NPs and Ga-Au NPs. The results of this study showed that Cit-Au NPs and Ga-AuNPs inhibit the growth of metastatic cervical cancer cells, which could have therapeutic implications.

Targeting SARS-CoV-2 endoribonuclease: a structure-based virtual screening supported by in vitro analysis.

Researchers are focused on discovering compounds that can interfere with the COVID-19 life cycle. One of the important non-structural proteins is endoribonuclease since it is responsible for processing viral RNA to evade detection of the host defense system. This work investigates a hierarchical structure-based virtual screening approach targeting NSP15. Different filtering approaches to predict the interactions of the compounds have been included in this study. Using a deep learning technique, we screened 823,821 compounds from five different databases (ZINC15, NCI, Drug Bank, Maybridge, and NCI Diversity set III). Subsequently, two docking protocols (extra precision and induced fit) were used to assess the binding affinity of the compounds, followed by molecular dynamic simulation supported by the MM-GBSA free binding energy. Interestingly, one compound (ZINC000104379474) from the ZINC15 database has been found to have a good binding affinity of - 7.68 kcal/Mol. The VERO-E6 cell line was used to investigate its therapeutic effect in vitro. Half-maximal cytotoxic concentration and Inhibitory concentration 50 were determined to be 0.9 mg/ml and 0.01 mg/ml, respectively; therefore, the selectivity index is 90. In conclusion, ZINC000104379474 was shown to be a good hit for targeting the virus that needs further investigations in vivo to be a drug candidate.

Target-filter combination effects on breast tissue characterization using mammographic X-rays: A Monte Carlo simulation study.

BACKGROUND: Characterization of normal and malignant breast tissues using X-ray scattering techniques has shown promising results and applications. OBJECTIVE: To examine possibility of characterizing normal and malignant breast tissues using the scattered photon distribution of polyenergetic beams of 30 kV X-rays. METHODS: A Monte Carlo simulation is upgraded so that it is capable of simulating input mammographic X-ray spectra from different target-filter combinations, tracing photon transport, and producing the distribution of scattered photons. The target-filter combinations include Mo-Mo, Mo-Al, Mo-Rh, Rh-Rh, Rh-Al, W-Rh, and W-Al. Analysis of obtained scattered photon distribution is carried out by comparing the ratio of count under the peak in the momentum transfer region from 0 to 1.55 nm-1, to that in the region from 1.6 to 9.1 nm-1 (covering the regions of scattering from fat and soft tissue, respectively) for breast samples with different percentages of normal tissue (0-100%). RESULTS: Mo-Mo target-filter combination shows a high linear dependence of the count under peak ratio on the percentage of normal tissue in breast samples (R2 = 0.9513). Despite slightly less linear than Mo-Mo, target-filter combinations other than Rh-Rh, W-Rh, and W-Al produce high linear responses (R2 > 0.9)CONCLUSION:Mo-Mo target-filter combination would probably be the most relevant in characterizing normal and malignant breast tissues from their scattered photon distribution.

Multidimensional in silico strategy for identification of natural polyphenols-based SARS-CoV-2 main protease (Mpro) inhibitors to unveil a hope against COVID-19.

SARS-CoV-2, a rapidly spreading new strain of human coronavirus, has affected almost all the countries around the world. The lack of specific drugs against SARS-CoV-2 is a significant hurdle towards the successful treatment of COVID-19. Thus, there is an urgent need to boost up research for the development of effective therapeutics against COVID-19. In the current study, we investigated the efficacy of 81 medicinal plant-based bioactive compounds against SARS-CoV-2 Mpro by using various in silico techniques. The interaction affinities of polyphenolic compounds towards SARS-CoV-2 Mpro was assessed via intramolecular (by Quantum Mechanic), intermolecular (by Molecular Docking), and spatial (by Molecular Dynamic) simulations. Our obtained result demonstrate that Hesperidin, rutin, diosmin, and apiin are most effective compounds agents against SARS-CoV-2 Mpro as compared to Nelfinavir (positive control). This study will hopefully pave a way for advanced experimental research to evaluate the in vitro and in vivo efficacy of these compounds for the treatment of COVID-19.

Interference of Chaga mushroom terpenoids with the attachment of SARS-CoV-2; in silico perspective.

Finding a potent inhibitor to the pandemic SARS-CoV-2 is indispensable nowadays. Currently, in-silico methods work as expeditious investigators to screen drugs for possible repurposing or design new ones. Targeting one of the possible SARS-CoV-2 attachment and entry receptors, Glucose-regulated protein 78 (GRP78), is an approach of major interest. Recently, GRP78 was reported as a recognized representative in recognition of the latest variants of SARS-CoV-2. In this work, molecular docking and molecular dynamics simulations were performed on the host cell receptor GRP78. With its many terpenoid compounds, Chaga mushroom was tested as a potential therapeutic against the SARS-CoV-2 receptor, GRP78. Results revealed low binding energies (high affinities) toward the GRP78 substrate-binding domain ß (SBDß) of Chaga mushroom terpenoids. Even the highly specific cyclic peptide Pep42, which selectively targeted GRP78 over cancer cells in vivo, showed lower binding affinity against GRP78 SBDß compared to the binding affinities of terpenoids. These are auspicious results that need to be tested experimentally. Intriguingly, terpenoids work as a double sword as they can be used to interfere with VUI 202,012/01, 501.V2, and B.1.1.248 variants of SARS-CoV-2 spike recognition.

[Saw tooth cardiomyopathy: How to better diagnose?] / Saw tooth cardiomyopathy : comment mieux faire le diagnostic ?

With the increasing use of cardiac MRI, several cases were described as "sawtooth cardiomyopathy" or "tiger heart". The pathological aspects of these rare forms of myocardial dysplasia, frequently assimilated to non-compaction of the left ventricle, and its prognostic implications remain unclear. We present a case of "sawtooth cardiomyopathy" in a patient with a transient ischemic attack. This article aims to determine, with the other clinical cases in the literature, the MRI and echocardiography criteria for the diagnosis of this cardiomyopathy. Sawtooth cardiomyopathy is probably under diagnosed and deserves to be better known.

The anti-HCV, Sofosbuvir, versus the anti-EBOV Remdesivir against SARS-CoV-2 RNA dependent RNA polymerase in silico.

Coronavirus diseases 2019 (COVID-19) are seriously affecting human health all over the world. Nucleotide inhibitors have promising results in terms of its efficacy against different viral polymerases. In this study, detailed molecular docking and dynamics simulations are used to evaluate the binding affinity of a clinically approved drug, sofosbuvir, with the solved structure of the viral protein RNA-dependent RNA polymerase (RdRp) and compare it to the clinically approved drug, Remdesivir. These drugs are docked onto the three-dimensional structure of the nsp12 protein of SARS-CoV-2, which controls the polymerization process. Hence, it is considered one of the primary therapeutic targets for coronaviruses. Sofosbuvir is a drug that is currently used for HCV treatment; therefore, HCV RdRp is used as a positive control protein target. The protein dynamics are simulated for 100 ns, while the binding is tested during different dynamics states of the SARS-CoV-2 RdRp. Additionally, the drug-protein complexes are further simulated for 20 ns to explore the binding mechanism. The interaction of SARS-CoV-2 RdRp as a target with the active form of sofosbuvir as a ligand demonstrates binding effectiveness. One of the FDA-approved antiviral drugs, such as sofosbuvir, can help us in this mission, aiming to limit the danger of COVID-19. Sofosbuvir was found to bind nsp12 with comparable binding energies to that of Remdesivir, which has been reported for its potential against COVID-19 RdRp and is currently approved by the FDA.

GRP78: A possible relationship of COVID-19 and the mucormycosis; in silico perspective.

Mucormycosis is a severe fungal infection reported in many cancer survivors, diabetic and immune-suppressed patients during organ transplants. A vast spark in the reported COVID-19 cases is noticed in India during the second wave in May 2021, when Mucormycosis is declared an epidemic. Despite being a rare disease, the mortality rate associated with Mucormycosis is more than 40%. Spore coat proteins (CotH) are essential proteins in many pathogenic bacteria and fungi. CotH3 was reported as the vital protein required for fungal virulence in Mucormycosis. We previously reported the involvement of the host cell-surface receptor GRP78 in SARS-CoV-2 spike recognition. Additionally, GRP78 is known to be the virulence factor during Mucormycosis. Using state-of-the-art structural bioinformatics and molecular modeling tools, we predicted the GRP78 binding site to the Rhizopus delemar CotH3 protein. Our findings pave the way toward rationally designing small molecule inhibitors targeting the GRP78 and its counter proteins in both pathogenic viral (SARS-CoV-2 spike) and fungal (R. delemar CotH3) diseases.

Novel adenosine derivatives against SARS-CoV-2 RNA-dependent RNA polymerase: an in silico perspective.

BACKGROUND: SARS-CoV-2 is a newly emerged human coronavirus that severely affected human health and the economy. The viral RNA-dependent RNA polymerase (RdRp) is a crucial protein target to stop virus replication. The adenosine derivative, remdesivir, was authorized for emergency use 10 months ago by the United States FDA against COVID-19 despite its doubtful efficacy against SARS-CoV-2. METHODS: A dozen modifications based on remdesivir are tested against SARS-CoV-2 RdRp using combined molecular docking and dynamics simulation in this work. RESULTS: The results reveal a better binding affinity of 11 modifications compared to remdesivir. Compounds 8, 9, 10, and 11 show the best binding affinities against SARS-CoV-2 RdRp conformations gathered during 100 ns of the Molecular Dynamics Simulation (MDS) run (- 8.13 ± 0.45 kcal/mol, - 8.09 ± 0.67 kcal/mol, - 8.09 ± 0.64 kcal/mol, and - 8.07 ± 0.73 kcal/mol, respectively). CONCLUSIONS: The present study suggests these four compounds as potential SARS-CoV-2 RdRp inhibitors, which need to be validated experimentally.

COVID-19 and Cell Stress.

The present century will undoubtedly be marked with the COVID-19 global health crisis. It is not time yet to talk about the total number of deaths and hospitalizations, as they are enormously growing daily. Understanding the nature of COVID-19-induced pneumonia is vital in order to deal with the associated health complications. Cell stress is an established mechanism known to be associated with infection and cancer. Different proteins crucial for cellular response to stress are reported to be a possible target to stop the infection and to reduce the chemo-resistance in cancer. Heat shock protein (HSP) families of chaperones play an essential role in cells both in normal state and under stress. The upregulation of HSP5A, also termed GRP78 or Bip, is reported in different viral infections. This chapter introduces the current knowledge about severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has caused the COVID-19 pandemic, and cell stress aimed at defining possible strategies to combat the COVID-19 pandemic.

Natural products may interfere with SARS-CoV-2 attachment to the host cell.

SARS-CoV-2 has been emerged in December 2019 in China, causing deadly (5% mortality) pandemic pneumonia, termed COVID-19. More than one host-cell receptor is reported to be recognized by the viral spike protein, among them is the cell-surface Heat Shock Protein A5 (HSPA5), also termed GRP78 or BiP. Upon viral infection, HSPA5 is upregulated, then translocating to the cell membrane where it is subjected to be recognized by the SARS-CoV-2 spike. In this study, some natural product compounds are tested against the HSPA5 substrate-binding domain ß (SBDß), which reported to be the recognition site for the SARS-CoV-2 spike. Molecular docking and molecular dynamics simulations are used to test some natural compounds binding to HSPA5 SBDß. The results show high to a moderate binding affinity for the phytoestrogens (Diadiazin, Genistein, Formontein, and Biochanin A), chlorogenic acid, linolenic acid, palmitic acid, caffeic acid, caffeic acid phenethyl ester, hydroxytyrosol, cis-p-Coumaric acid, cinnamaldehyde, thymoquinone, and some physiological hormones such as estrogens, progesterone, testosterone, and cholesterol to the HSPA5 SBDß. Based on its binding affinities, the phytoestrogens and estrogens are the best in binding HSPA5, hence may interfere with SARS-CoV-2 attachment to the stressed cells. These compounds can be successful as anti-COVID-19 agents for people with a high risk of cell stress like elders, cancer patients, and front-line medical staff.Communicated by Ramaswamy H. Sarma.