Despite the intense research work since the beginning of the pandemic, the pathogenesis of COVID-19 is not yet clearly understood. The previous mechanism of COVID-19, based on ACE2 tropism and explained through a single receptor, is insufficient to explain the pathogenesis due to the absence of angiotensin-converting enzyme 2 (ACE2) receptors in most of the affected organs. In the current study, we used the PatchDock server to run a molecular docking study of both the gonadotropin-releasing hormone receptor (GnRHR) and G-protein-coupled-receptor (GPCR) with the SARS-CoV-2 spike protein. Molecular Dynamics (MD) simulations were run to analyze the stability of the complexes using the GROMACS package. The docking results showed a high affinity between the spike protein with the GnRHR (−1424.9 kcal/mol) and GPCR (−1451.8 kcal/mol). The results of the MD simulations revealed the significant stability of the spike protein with the GnRHR and GPCR up to 100 ns. The SARS-CoV-2 spike protein had strong binding interactions with the GPCRs and GnRHRs, which are highly expressed in the brain, endocrine organs, and olfactory neurons. This study paves the way towards understanding the complex mechanism of neuroendocrine involvement and peripheral organ involvement, may explain the changing symptoms in patients due to new variants, and may lead to the discovery of new drug targets for COVID-19. In vitro studies involving genetic engineering or gene knockdown of the GPCRs and GnRHRs are needed to further investigate the role of these receptors in COVID-19 pathogenesis.

No abstract

No abstract

Dostarlimab is antitumor drug that mainly prescribed for treating endometrial cancer (cancer of the lining of the uterus or womb) that is mismatch repair deficient (dMMR) in patients whose cancer has returned, or it has spread or cannot be removed by surgery. Dostarlimab is a type of humanized monoclonal antibody that binds with high affinity to PD-1, resulting in inhibition of binding to PD-L2 and PD-L1. Surprisingly, it was showed that a dozen of patients with colorectal cancer (A total of 12 patients) have experienced complete response to this type of treatment after 12 months completion of dostarlimab therapy. A recent clinical trial conducted by researchers at Memorial Sloan Kettering Cancer Center (MSK) has found Dostarlimab to cure 100% of the CRC patients who were given this drug. According to literature, the primary mechanism by which Dostarlimab could achieve this breakthrough is due to its ability to block PD-1(B7-H1). Surprisingly, we insilico, discovered that Dostarlimab exhibited a high binding affinity (329 kcal/mol) with good quality model (LGScore (4.540) to IL-6R and this binding affinity is comparable with its binding affinity to B7-2 receptors (-332.35 kcal/mol) (LGScore(2.540). Moreover, we discovered that Dostarlimab could bind to CTLA-4 with binding affinity (-305.91 kcal/mol). As a result, this means that dostarlimab not only bind with high affinity to B7-2 or BH-3(PD-1) but also to IL-6R and CATLA4. According to our novel results dostarlimab could experimentally inhibit IL-6, CTLA-4 and B7 receptors and this may explain the 100% Remission Rate observed in this small clinical trial and considered as one of its novel mechanisms in treating CR cancer particularly, inhibiting of IL-6 and CATLA4. Docking study of each IL-6, CTLA-4 and B7-2 receptors and Dostarlimab were carried out using HDOCK server (http://hdock.phys.hust.edu.cn/). The binding mode of Tislelizumab Fab antibody and B7-2, CTLA-4, IL6 proteins which its retrieved form the PDB https://www.rcsb.org/ with accession number (7CGW, 1NCN, 7ELX, 5FUC) respectively CONCLUSIONS Surprisingly, our docking results discovered that Tislelizumab could potentially inhibit three receptors that could implicated in suppressing antitumor immunity and promoting cancer growth and invasion. Herein Tislelizumab was found to bind to IL-6 and B7 (PD-1) with comparable high binding affinities in addition to CATLA4 which is a major factor that inhibit activation of cancer killing T cells. As a result, it's not surprising that Tislelizumab succeeded to cure 100% of the CRC patients who were given this drug because of its triple inhibitory action. Numerous studies have showed that the predominant role of IL-6 in tumor is the promotion of cancer growth via the interaction of IL-6 and its receptor-activated JAKs with following induction/activation of STAT3 through tyrosine phosphorylation driving PD-L1 Y112 phosphorylation. When CTLA-4 is bound to another protein called B7(B7-2), it helps keep T cells from killing other cells, including cancer cells. The immune functions of the B7 family of proteins. B7-1 and B7-2 molecules expressed on APCs exhibit positive or negative functions via interaction with either cognate stimulatory receptor, CD28, or inhibitory receptor, CTLA-4, respectively. This study paves the way towards understanding the complex mechanism of Dostarlimab in CRC, and may lead to the discovery of new mechanisms of Dostarlimab for different types of cancer

Dostarlimab is antitumor drug that mainly prescribed for treating endometrial cancer (cancer of the lining of the uterus or womb) that is mismatch repair deficient (dMMR) in patients whose cancer has returned, or it has spread or cannot be removed by surgery. Dostarlimab is a type of humanized monoclonal antibody that binds with high affinity to PD-1, resulting in inhibition of binding to PD-L2 and PD-L1. Surprisingly, it was showed that a dozen of patients with colorectal cancer (A total of 12 patients) have experienced complete response to this type of treatment after 12 months completion of dostarlimab therapy. A recent clinical trial conducted by researchers at Memorial Sloan Kettering Cancer Center (MSK) has found Dostarlimab to cure 100% of the CRC patients who were given this drug. According to literature, the primary mechanism by which Dostarlimab could achieve this breakthrough is due to its ability to block PD-1(B7-H1). Surprisingly, we insilico, discovered that Dostarlimab exhibited a high binding affinity (329 kcal/mol) with good quality model (LGScore (4.540) to IL-6R and this binding affinity is comparable with its binding affinity to B7-2 receptors (-332.35 kcal/mol) (LGScore(2.540). Moreover, we discovered that Dostarlimab could bind to CTLA-4 with binding affinity (-305.91 kcal/mol). As a result, this means that dostarlimab not only bind with high affinity to B7-2 or BH-3(PD-1) but also to IL-6R and CATLA4. According to our novel results dostarlimab could experimentally inhibit IL-6, CTLA-4 and B7 receptors and this may explain the 100% Remission Rate observed in this small clinical trial and considered as one of its novel mechanisms in treating CR cancer particularly via inhibiting of IL-6 and CATLA4. Docking study of each IL- 6, CTLA-4 and B7-2 receptors and Dostarlimab were carried out using HDOCK server (http://hdock.phys.hust.edu.cn/). The binding mode of Tislelizumab Fab antibody and B7-2, CTLA-4, IL6 proteins which its retrieved form the PDB https://www.rcsb.org/ with accession number (7CGW, 1NCN, 7ELX, 5FUC) respectively CONCLUSIONS Surprisingly, our docking results discovered that Tislelizumab could potentially inhibit three receptors that could implicated in suppressing antitumor immunity and promoting cancer growth and invasion. Herein Tislelizumab was found to bind to IL-6 and B7 (PD-1) with comparable high binding affinities in addition to CATLA4 which is a major factor that inhibit activation of cancer killing T cells. As a result, it's not surprising that Tislelizumab succeeded to cure 100% of the CRC patients who were given this drug because of its triple inhibitory action. Numerous studies have showed that the predominant role of IL-6 in tumor is the promotion of cancer growth via the interaction of IL-6 and its receptor-activated JAKs with following induction/activation of STAT3 through tyrosine phosphorylation driving PD-L1 Y112 phosphorylation. When CTLA-4 is bound to another protein called B7(B7-2), it helps keep T cells from killing other cells, including cancer cells. The immune functions of the B7 family of proteins. B7-1 and B7- 2 molecules expressed on APCs exhibit positive or negative functions via interaction with either cognate stimulatory receptor, CD28, or inhibitory receptor, CTLA-4, respectively. This study paves the way towards understanding the complex mechanism of Dostarlimab in CRC, and may lead to the discovery of new mechanisms of Dostarlimab for different types of cancer

Great strides have been made to reduce the number of human immunodeficiency virus (HIV) infections and HIV/acquired immunodeficiency syndrome (AIDS)-related deaths, but the war against HIV is far from over. From 1981 to the present, human immunodeficiency virus, the etiological agent of AIDS, has unwaveringly killed an estimated 39 million individuals. Although, the chemokine receptor CCR5 is the predominant co-receptor exploited for transmission and replication of HIV in vivo but our docking analysis, predicted and discovered a novel receptor termed STRA 6 that may play a critical role in the pathogenicity of HIV and its immune suppression. According to our breakthrough HIV may bind to STRA6 which is a receptor of Retinol /Vitamin A leading to retinol in sufficiency, immune dysregulation and hyper inflammation. Therefore, it is not surprising that Vitamin A deficiency is common in people with HIV infection. STRA6 receptor expressed in many organs and immune cells, upregulated by retinoic acid jm6 (STRA 6) was the first protein to be identified in a novel category of proteins, cytokine signaling transporters, due to its ability to function as both a cell surface receptor and a membrane protein that binds to retinol binding protein facilitating cellular uptake of retinol. It is well established that vitamin A supplementation improves growth and reduces morbidity in HIV-infected children. RA which is the active metabolite of Vitamin A is produced by gut-associated dendritic cells, which are among the first cells encountered by HIV. Acute HIV infection results in rapid reduction of RA levels and dysregulation of immune cell populations whose identities and function are largely controlled by RA. Surprisingly, our molecular docking based analysis showed that spike protein receptor Binding Domain (RDB) of HIV strongly and efficiently binds to STRA6 receptor, definitely to the RDB vital residues of RBP-binding motif located in STRA 6 receptor. In this study, the STRA 6 – HIV was examined in order to describe the mechanism of the viral protein's interaction with the various patient symptoms and see the reaction's features for the first time, which may be employed as a therapeutic option. The interaction between the viral protein and the STRA 6 is created here for detection and to identify the mode of action of the mechanism, and the proteins of the HIV and STRA 6 receptor were generated and docked using the HDOCK server. The binding pocket of the STRA 6-HIV protein complexes docking score is -334.71 kcal/mol, according to the surface aspect of the complex. The results of the MD simulations revealed the significant stability of the spike protein with the STRA6 up to 100 ns. Conclusion STRA 6 receptor is a membrane receptor responsible for signaling and transporting of vitamin A (Retinol) from plasma retinol binding protein (RBP) to our cells. In an outstanding manner, HIV Spike protein exhibited high docking score with human STRA 6 with low binding energy. According to our HIV could bind to the cytosolic part of the cellular membrane via binding to STRA6 leading to lead to deformation of the cytosolic membrane and inserting its viral particles into the cell also, our findings demonstrate that vitamin A supplements, retinoic acid and STRA6 induction will be promising and effective treatments for HIV infection and its unknown etiology symptoms. This study paves the way towards understanding the complex mechanism of HIV infection and its immune dysregulation, and may lead to the discovery of new drug targets for HIV. In vitro studies involving genetic engineering or gene knockdown of the STRA6 are needed to further investigate the role of these receptors in HIV pathogenesis.

No abstract

In recent years, novel strategies to control insects have been based on protease inhibitors (PIs). In this regard, molecular docking and molecular dynamics simulations have been extensively used to investigate insect gut proteases and the interactions of PIs for the development of resistance against insects. We, herein, report an in silico study of (disodium 5′-inosinate and petunidin 3-glucoside), (calcium 5′-guanylate and chlorogenic acid), chlorogenic acid alone, (kaempferol-3,7-di-O-glucoside with hyperoside and delphinidin 3-glucoside), and (myricetin 3′-glucoside and hyperoside) as potential inhibitors of acetylcholinesterase receptors, actin, α-tubulin, arginine kinase, and histone receptor III subtypes, respectively. The study demonstrated that the inhibitors are capable of forming stable complexes with the corresponding proteins while also showing great potential for inhibitory activity in the proposed protein-inhibitor combinations.