Preclinical Human and Murine Models of Hepatocellular Carcinoma (HCC).

Hepatocellular carcinoma (HCC) is the most frequent liver cancer, which account for more than 90 % of all liver cancer cases. It is the fifth leading cause of cancer globally and the second leading cause of cancer-related mortality in men. The availability of competent HCC preclinical models is fundamental to the success of mechanistic studies, molecular target identification, and drug testing. However, there are challenges associated with the use of these models. In this review, we provided updates on various cell lines, animals, and human HCC models, their specific preclinic use and associated potential challenges. Overall, the understanding of the merits and demerits of a particular HCC model will improve model selection for various preclinical studies.

Hitting Epstein Barr virus where it hurts: computational methods exploration for siRNA therapy in alleviating Epstein Barr virus-induced multiple sclerosis.

Multiple sclerosis (MS), an intricate neurological disorder, continues to challenge our understanding of the pivotal interplay between the immune system and the central nervous system (CNS). This condition arises from the immune system's misdirected attack on nerve fiber protection, known as myelin sheath, alongside nerve fibers themselves. This enigmatic condition, characterized by demyelination and varied clinical manifestations, prompts exploration into its multifaceted etiology and potential therapeutic avenues. Research has revealed a potential connection between Epstein Barr virus (EBV), specifically Epstein Barr Nuclear Antigen 1 (EBNA-1), and MS. The immune response to EBNA-1 antigen triggers the production of anti-EBNA-1 molecules, including IgG that identify a similar amino acid sequence to EBNA-1 in myelin, inadvertently targeting myelin sheath and contributing to MS progression. Currently, no treatment exists for EBNA-1-induced MS apart from symptom management. Addressing this, a novel potential therapeutic avenue utilizing small interference RNAs (siRNA) has been designed. By targeting the conserved EBNA-1 gene sequences in EBV types 1 and 2, five potential siRNAs were identified in our analysis. Thorough evaluations encompassing off-target binding, thermodynamics and secondary structure elucidation, efficacy prediction, siRNA-mRNA sequence binding affinity exploration, melting temperature, and docking of siRNAs with human argonaute protein 2 (AGO2) were conducted to elucidate the siRNAs efficiency. These designed siRNA molecules harnessed promising silencing activity in the EBNA-1 gene encoding the EBNA-1 antigen protein and thus have the potential to mitigate the severity of this dangerous virus.

Driver Mutations in Pancreatic Cancer and Opportunities for Targeted Therapy.

Pancreatic cancer is the sixth leading cause of cancer-related mortality globally. As the most common form of pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC) represents up to 95% of all pancreatic cancer cases, accounting for more than 300,000 deaths annually. Due to the lack of early diagnoses and the high refractory response to the currently available treatments, PDAC has a very poor prognosis, with a 5-year overall survival rate of less than 10%. Targeted therapy and immunotherapy are highly effective and have been used for the treatment of many types of cancer; however, they offer limited benefits in pancreatic cancer patients due to tumor-intrinsic and extrinsic factors that culminate in drug resistance. The identification of key factors responsible for PDAC growth and resistance to different treatments is highly valuable in developing new effective therapeutic strategies. In this review, we discuss some molecules which promote PDAC initiation and progression, and their potential as targets for PDAC treatment. We also evaluate the challenges associated with patient outcomes in clinical trials and implications for future research.

Targeted Therapy for Highly Desmoplastic and Immunosuppressive Tumor Microenvironment of Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a very poor prognosis. Despite advancements in treatment strategies, PDAC remains recalcitrant to therapies because patients are often diagnosed at an advanced stage. The advanced stage of PDAC is characterized by metastasis, which typically renders it unresectable by surgery or untreatable by chemotherapy. The tumor microenvironment (TME) of PDAC comprises highly proliferative myofibroblast-like cells and hosts the intense deposition of a extracellular matrix component that forms dense fibrous connective tissue, a process called the desmoplastic reaction. In desmoplastic TMEs, the incessant aberration of signaling pathways contributes to immunosuppression by suppressing antitumor immunity. This feature offers a protective barrier that impedes the targeted delivery of drugs. In addition, the efficacy of immunotherapy is compromised because of the immune cold TME of PDAC. Targeted therapy approaches towards stromal and immunosuppressive TMEs are challenging. In this review, we discuss cellular and non-cellular TME components that contain actionable targets for drug development. We also highlight findings from preclinical studies and provide updates about the efficacies of new investigational drugs in clinical trials.

Predicting Plasmodium falciparum kinase inhibitors from antimalarial medicinal herbs using computational modeling approach.

Malaria remains a significant public health challenge, with resistance to available drugs necessitating the development of novel therapies targeting invasion-dependent proteins. Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK-1) is essential for host erythrocyte invasion and parasite asexual development. This study screened a library of 490 compounds using computational methods to identify potential PfCDPK-1 inhibitors. Three compounds; 17-hydroxyazadiradione, Picracin, and Epicatechin-gallate derived from known antimalarial botanicals, showed potent inhibitory effects on PfCDPK-1. These compounds exhibited better binding affinities (-8.8, -9.1, -9.3 kCal/mol respectively), pharmacokinetics, and physicochemical properties than the purported inhibitory standard of PfCDPK-1, Purfalcamine. Molecular dynamics simulations (50 ns) and molecular mechanics analyses confirmed the stability and binding rigidity of these compounds at the active pocket of PfCDPK-1. The results suggest that these compounds are promising pharmacological targets with potential therapeutic effects for malaria treatment/management without undesirable side effects. Therefore, this study provides new insights into the development of effective antimalarial agents targeting invasion-dependent proteins, which could help combat the global malaria burden. Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-023-00175-z.

Catechin from Anonna senegalensis is a Potential Inhibitor of Erectile Dysfunction: Implication for Its Use in Male Sexual Enhancement.

Erectile dysfunction (ED) is a major challenge for men. The drugs for its treatment are associated with side effects. Hence, in phytomedicinal research, where Anonna senegalensis (A. senegalensis) is a candidate with abundant phytochemicals possessing various pharmacological properties, but the sex-enhancing phytochemical is elusive in the literature. This study aimed to understand the molecular interaction of its potent molecule mediating male sexual enhancement. A library of 69 compounds from A. senegalensis was docked against the ED-targeted proteins. Sildenafil citrate was used as the reference standard. Thereafter, the lead compound was screened for drug-likeness by applying the Lipinski rule of 5 (RO5), pharmacokinetic properties, and bioactivity using SwissADME and Molinspiration web servers, respectively. The results show catechin as the lead phytochemical compound with a stronger binding affinity for most of the proteins of ED. Also, catechin demonstrates good compliance with the RO5, great pharmacokinetic profiles, and could be said to be a polypharmacological molecule with good bioactivity scores. The research findings unravel the potential of catechin (a phytochemical belonging to the flavonoids class) from A. senegalensis leaf as a potential male sexual enhancement molecule via its high binding affinity for most erectile dysfunction-targeted proteins. They may require further toxicity and therapeutic evaluations in vivo.

Is the new angel better than the old devil? Challenges and opportunities in CD47- SIRPα-based cancer therapy.

The efficacy of immunotherapies is limited due to the impenetrable nature of the tumor microenvironment (TME). The TME of many tumors is immune-privileged, thus allowing them to evade host immunosurveillance. One mechanism through which this occurs is via the overexpression of CD47, a 'don't eat me' protein that can interact with SIRPα on myeloid cells to suppress their phagocytic action. In recent times, many studies are focusing on CD47-SIRPα-dependent immunotherapies to incite a 'seek and eat' interaction between phagocytes and tumors. Thus, in this review, we highlight the basic molecular properties and mechanisms of CD47-SIRPα cascade. In addition, we discuss the major challenges and potential remedies associated with CD47-SIRPα-based immunotherapies.

GCMS fingerprints and phenolic extracts of Allium sativum inhibit key enzymes associated with type 2 diabetes.

Objectives: Inhibition of carbohydrate digestion enzymes (α-amylase and α-glucosidase) has been reported in studies as a therapeutic approach for the management or treatment of type 2 diabetes mellitus, owing to its potential to decrease postprandial hyperglycemia. The anti-diabetic potential of Allium sativum (also known as garlic) against diabetes mellitus has been established. Therefore, in this study, we assessed the antidiabetic potential of A. sativum using in vitro enzyme assays after which we explored computational modelling approach using the quantified GC-MS identities to unravel the key bioactive compounds responsible for the anti-diabetic potential. Methods: We used in vitro enzyme inhibition assays (α-amylase and α-glucosidase) to evaluate antidiabetic potential and subsequently performed gas chromatography-mass spectroscopy (GC-MS) to identify and quantify the bioactive compounds of the plant extract. The identified bioactive compounds were subjected to in silico docking and pharmacokinetic assessment. Results: A. sativum phenolic extract showed high dose-dependent inhibition of α-amylase and α-glucosidase (p < 0.05). Interestingly, the extract inhibited α-glucosidase with a half maximal inhibitory concentration of 53.75 µg/mL, a value higher than that obtained for the standard acarbose. Docking simulation revealed that morellinol and phentolamine were the best binders of α-glucosidase, with mean affinity values of -7.3 and -7.1 kcal/mol, respectively. These compounds had good affinity toward active site residues of the enzyme, and excellent drug-like and pharmacokinetic properties supporting clinical applications. Conclusions: Our research reveals the potential of A. sativum as a functional food for the management of type 2 diabetes, and suggests that morellinol and phentolamine may be the most active compounds responsible for this anti-diabetic prowess. Therefore these compounds require further clinical asessment to demonstrate their potential for drug development.

Reinstating apoptosis using putative Bcl-xL natural product inhibitors: Molecular docking and ADMETox profiling investigations.

Objectives: While a fine balance in the pro-apoptotic and anti-apoptotic family members of the B-cell lymphoma-2 (Bcl-2) protein family represents a normal signaling profile, a tilt in balance towards anti-apoptotic family members has fortified different forms of cancers with survival advantage and resistance against treatment. Induction of apoptosis is a key therapeutic approach in cancer drug discovery, and the inhibition of the anti-apoptotic B cell lymphoma extra-large (Bcl-xL) is a long-standing clinical target for cancer therapy. In this study, we combined computer-aided approaches to report putative binders for this target. Methods: Before our virtual screening campaign, we conducted a redocking experiment strategy of the x-ray bound inhibitor of the Bcl-xL protein with some of the available docking software at our disposal to determine the software with the best efficiency for this screening. iGEMDOCK emerged to reproduce the x-ray crystallographic information and was used to dock the library of ligand, which was developed from diverse literature reporting compounds with anti-apoptotic profiles through the Bcl-2 family. Results: Of the compounds in the library, alpha-mangostin and oubain scored as hits with binding energy values of -123.025 kcal/mol and -122.271 kcal/mol, respectively, which is more than -120.8 kcal/mol observed by the standard. Conclusions: These compounds revealed a more binding affinity potential than ABT-737, which is a standard inhibitor of the protein. In addition, these scaffolds not only interact with relevant and hotspot residues for the inhibition of Bcl-xL but also possess good pharmacokinetic and excellent toxicity, an endpoint that should be considered for further testing and drug development.

Promising disruptors of p53-MDM2 dimerization from some medicinal plant phytochemicals: a molecular modeling study.

Cancer is a major global health issue that has a high mortality rate. p53, which functions as a tumor suppressor, is critical in preventing tumor development by regulating the cell cycle and inducing apoptosis in damaged cells. However, the tumor suppressor function of p53 is effectively inhibited by its direct interaction with the hydrophobic cleft of MDM2 protein via multiple mechanisms As a result, restoring p53 activity by blocking the p53-MDM2 protein-protein interaction has been proposed as a compelling therapeutic strategy for cancer treatment. The use of molecular docking and phytochemical screening procedures are appraised to inhibit MDM2's hydrophobic cleft and disrupt the p53-MDM2 interaction. For this purpose, a library of 51 bioactive compounds from 10 medicinal plants was compiled and subjected to structure-based virtual screening. Out of these, only 3 compounds (Atalantoflavone, Cudraxanthone 1, and Ursolic acid) emerged as promising inhibitors of MDM2-p53 based on their binding affinities (-9.1 kcal/mol, -8.8 kcal/mol, and -8.8 kcal/mol respectively) when compared to the standard (-8.8 kcal/mol). Moreover, these compounds showed better pharmacokinetic and drug-like profiling than the standard inhibitor (Chromonotriazolopyrimidine 1). Finally, the 100 ns MD simulation analysis confirmed no significant perturbation in the conformational dynamics of the simulated binary complexes when compared to the standard. In particular, Ursolic acid was found to satisfy the molecular enumeration the most compared to the other inhibitors. Our overall molecular modeling finding shows why these compounds may emerge as potent arsenals for cancer therapeutics. Nonetheless, extensive experimental and clinical research is needed to augment their use in clinics.Communicated by Ramaswamy H. Sarma.

Docking covalent targets for drug discovery: stimulating the computer-aided drug design community of possible pitfalls and erroneous practices.

The continuous approval of covalent drugs in recent years for the treatment of diseases has led to an increased search for covalent agents by medicinal chemists and computational scientists worldwide. In the computational parlance, molecular docking which is a popular tool to investigate the interaction of a ligand and a protein target, does not account for the formation of covalent bond, and the increasing application of these conventional programs to covalent targets in early drug discovery practice is a matter of utmost concern. Thus, in this comprehensive review, we sought to educate the docking community about the realization of covalent docking and the existence of suitable programs to make their future virtual-screening events on covalent targets worthwhile and scientifically rational. More interestingly, we went beyond the classical description of the functionality of covalent-docking programs down to selecting the 'best' program to consult with during a virtual-screening campaign based on receptor class and covalent warhead chemistry. In addition, we made a highlight on how covalent docking could be achieved using random conventional docking software. And lastly, we raised an alert on the growing erroneous molecular docking practices with covalent targets. Our aim is to guide scientists in the rational docking pursuit when dealing with covalent targets, as this will reduce false-positive results and also increase the reliability of their work for translational research.

Pharmacophoric analogs of sotorasib-entrapped KRAS G12C in its inactive GDP-bound conformation: covalent docking and molecular dynamics investigations.

For decades, KRAS G12C was considered an undruggable target. However, in recent times, a covalent inhibitor known as sotorasib was discovered and approved for the treatment of patients with KRAS G12C-driven cancers. Ever since the discovery of this drug, several preclinical efforts have focused on identifying novel therapeutic candidates that could act as covalent binders of KRAS G12C. Despite these intensive efforts, only a few KRAS G12C inhibitors have entered clinical trials. Hence, this highlights the need to develop effective drug candidates that could be used in the treatment of KRAS G12C-driven cancers. Herein, we embarked on a virtual screening campaign that involves the identification of pharmacophores of sotorasib that could act as covalent arsenals against the KRAS G12C target. To our knowledge, this is the first computational study that involves the compilation of sotorasib pharmacophores from an online chemical database against KRAS G12C. After this library of chemical entities was compiled, we conducted a covalent docking-based virtual screening that revealed three promising drug candidates (CID_146235944, CID_160070181, and CID_140956845) binding covalently to the crucial nucleophilic side chain of Cys12 and interact with the residues that form the cryptic allosteric pocket of KRAS G12C in its inactive GDP-bound conformation. Subsequently, ADMET profiling portrayed the covalent inhibitors as lead-like candidates, while 100 ns molecular dynamics was used to substantiate their stability. Although our overall computational study has shown the promising potential of the lead-like candidates in impeding oncogenic RAS signaling, more experimental efforts are needed to validate and establish their preclinical relevance. Implication of KRAS G12C in cancer and computational approach towards impeding the KRAS G12C RAS signaling.

Immunoinformatics design of multi-epitope peptide for the diagnosis of Schistosoma haematobium infection.

Schistosoma haematobium has been identified as a significant cause of urogenital disease, as well as a risk factor for bladder cancer and HIV/AIDS. The parasites are obtained trans-dermally by swimming or wading in contaminated freshwater, and they are also transmitted to humans by freshwater snails. The organisms infect the vasculature of the gastrointestinal or genitourinary tracts. Worms live in blood vessels and lay eggs that become embedded in the bladder wall, causing chronic immune-mediated disease and squamous cell carcinoma growth. The primary goal of this research is to predict and design a novel synthetic protein containing multiple immunodominant B cell epitopes using three schistosome proteins: XP-012801068.2, XP-012801892.2, and XP-012793835.2 softwares were used to analyze the proteins' primary, secondary, and tertiary structures (BepiPred, BcPred).The B cell construct was then evaluated using I-TASSER server, and physicochemical properties, as well as homology modeling of the 3 D structure of the protein, was obtained. In silico analyses revealed regions with high immunogenicity. For XP-012801068.2, three epitopes are found between residues 292-334, 3-22, and 314-333; for XP-012801892.2, three epitopes are found in the residues 184-236, 81-100, and 329-348 for XP-012793835.2, four epitopes are found in the residues 185-222, 469-512, 649-713, and 338-357. The construct's has an average length of 308 bp, instability index of 49.96, theoretical PI of 4.2 and a C score -1.59. Furthermore, these parameters analyzed reveals that the constructed multi-epitope peptide has the potential to provide a theoretical basis for the development of a Schistosoma haematobium diagnostic kit.Communicated by Ramaswamy H. Sarma.

Integrated virtual screening and molecular dynamics simulation revealed promising drug candidates of p53-MDM2 interaction.

In the vast majority of malignancies, the p53 tumor suppressor pathway is compromised. In some cancer cells, high levels of MDM2 polyubiquitinate p53 and mark it for destruction, thereby leading to a corresponding downregulation of the protein. MDM2 interacts with p53 via its hydrophobic pocket, and chemical entities that block the dimerization of the protein-protein complex can restore p53 activity. Thus far, only a few chemical compounds have been reported as potent arsenals against p53-MDM2. The Protein Data Bank has crystallogaphic structures of MDM2 in complex with certain compounds. Herein, we have exploited one of the complexes in the identification of new p53-MDM2 antagonists using a hierarchical virtual screening technique. The initial stage was to compile a targeted library of structurally appropriate compounds related to a known effective inhibitor, Nutlin 2, from the PubChem database. The identified 57 compounds were subjected to virtual screening using molecular docking to discover inhibitors with high binding affinity for MDM2. Consequently, five compounds with higher binding affinity than the standard emerged as the most promising therapeutic candidates. When compared to Nutlin 2, four of the drug candidates (CID_140017825, CID_69844501, CID_22721108, and CID_22720965) demonstrated satisfactory pharmacokinetic and pharmacodynamic profiles. Finally, MD simulation of the dynamic behavior of lead-protein complexes reveals the stability of the complexes after a 100,000 ps simulation period. In particular, when compared to the other three leads, overall computational modeling found CID_140017825 to be the best pharmacological candidate. Following thorough experimental trials, it may emerge as a promising chemical entity for cancer therapy.

Targeting the mitochondrial permeability transition pore for drug discovery: Challenges and opportunities.

Several drug targets have been amenable to drug discovery pursuit not until the characterization of the mitochondrial permeability transition pore (MPTP), a pore with an undefined molecular identity that forms on the inner mitochondrial membrane upon mitochondrial permeability transition (MPT) under the influence of calcium overload and oxidative stress. The opening of the pore which is presumed to cause cell death in certain human diseases also has implications under physiological parlance. Different models for this pore have been postulated following its first identification in the last six decades. The mitochondrial community has witnessed many protein candidates such as; voltage-dependent anion channel (VDAC), adenine nucleotide translocase (ANT), Mitochondrial phosphate carrier (PiC), Spastic Paralegin (SPG7), disordered proteins, and F1Fo ATPase. However, genetic studies have cast out most of these candidates with only F1Fo ATPase currently under intense argument. Cyclophilin D (CyPD) remains the widely accepted positive regulator of the MPTP known to date, but no drug candidate has emerged as its inhibitor, raising concern issues for therapeutics. Thus, in this review, we discuss various models of MPTP reported with the hope of stimulating further research in this field. We went beyond the classical description of the MPTP to ascribe a 'two-edged sword property' to the pore for therapeutic function in human disease because its inhibition and activation have pharmacological relevance. We suggested putative proteins upstream to CyPD that can regulate its activity and prevent cell deaths in neurodegenerative disease and ischemia-reperfusion injury.

Novel Chalcone BDD-39 Mitigated Diabetic Nephropathy through the Activation of Nrf2/ARE Signaling.

BACKGROUND: In this study, we investigated the Nrf2/ARE signaling pathway activating capacity of Biphenyl Diester Derivative-39 (BDD-39) in diabetic nephropathy in order to elucidate the mechanism surrounding its antidiabetic potential. OBJECTIVES: Protein expressions of Nrf2, HO-1, NQO-1 and biomarkers of kidney fibrosis were executed after which mRNA levels of Nrf2, HO-1 and NQO-1 were estimated after creating the models following BBD-39 treatment. METHODS: Type 2 diabetes model was established in mice with high-fat diet feeding combined with streptozocin intraperitoneal administration. The diabetic mice were then treated with BDD-39 (15, 45mg· kg-1· d-1, ig) or a positive control drug resveratrol (45mg· kg-1·d-1, ig) for 8 weeks. Staining techniques were used to investigate collagen deposition in the glomerulus of the renal cortex and also to investigate the expression and localization of Nrf2 and extracellular matrix (ECM) proteins (collagen IV and laminin) in vitro and in vivo. Furthermore, we studied the mechanism of action of BDD-39 using RNA-mediated Nrf2 silencing technique in mouse SV40 glomerular mesangial cells (SV40 GM cells). RESULTS: We found that BDD-39 activates Nrf2/ARE signaling pathway, promotes Nrf2 nuclear translocation (Nrf2nuc/Nrf2cyt) and modulate prominent biomarkers of kidney fibrosis at the protein level. However, BDD-39 could not activate Nrf2/ARE signaling in RNA-mediated Nrf2-silenced HG-cultured SV40 GM cells. CONCLUSION: Taken together, this study demonstrates for the first time that BDD-39 ameliorates experimental DN through attenuation of renal fibrosis progression and modulation of Nrf2/ARE signaling pathway.

Dietary polyphenols mitigate SARS-CoV-2 main protease (Mpro)-Molecular dynamics, molecular mechanics, and density functional theory investigations.

The recent evolution of the SARS-like Coronavirus has ravaged the world. The deadly virus has claimed over millions of lives across the world and hence highlights the need to develop effective therapeutic drugs to contain the disease posed by this parasite. In this study, the inhibitory potential of fifty (50) dietary polyphenols against Coronavirus (SARS-CoV-2) main protease (Mpro) was conducted using the Autodock Vina Molecular docking tool. In the virtual screening process, the binding affinity of Remdesivir (-7.7 kcal/mol) currently used to treat COVID-19 patients was set as the cut-off value to screen out less probable inhibitors. Ellagic acid, Kievitone, and Punicalin were the only promising ligands with binding affinities (-8.9 kcal/mol, -8.0 kcal/mol and -7.9 kcal/mol respectively) lower than the set cut-off value. Furthermore, we validated Ellagic acid and Kievitone efficacy by subjecting them to molecular dynamics simulation and further stability was assessed at the molecular mechanics and quantum levels. The overall analysis indicates both compounds demonstrate higher stability and inhibitory potential to bind to the crucial His41 and Cys145 catalytic dyad of Mpro than the standard drug. However, further analysis of punicalin after evaluating its docking score was not conducted as the ligand pharmacokinetics properties suggests it could pose serious adverse effect to the health of participants in clinical trials. Hence, we employed a more safe approach by filtering out the compound during this study. Conclusively, while Ellagic acid and kievitone polyphenolic compounds have been demonstrated to be promising under this in silico research, further studies are needed to substantiate their clinical relevance.

Exploring the inhibitory potentials of Momordica charantia bioactive compounds against Keap1-Kelch protein using computational approaches.

The search for Keap1 inhibitors as potential Nrf2 activator is a way of increasing the antioxidant status of the human cellular environ. In this research, we used in silico methods to investigate Keap1-kelch inhibitory potential of Momordica charantia's bioactive compounds in order to predict their Nrf2 activating potential. ADMET profiling, physicochemical properties, molecular docking, molecular dynamics, and Molecular Mechanics-Poisson Boltzmann Surface Area (g_MMPBSA) free energy calculation studies were executed to drive home our aim. Out of all the bioactive compounds of Momordica charantia, catechin (CAT) and chlorogenic acid (CGA) were selected based on their ADMET profile, physicochemical properties, and molecular docking analysis. Molecular docking studies of CAT and CGA to Keap1 kelch domain showed that they have - 9.2 kJ/mol and - 9.1 kJ/mol binding energies respectively with CAT having four hydrogen bond interactions with Keap1 while CGA had three. Analysis after the 30 ns molecular dynamics simulation revealed that CAT and CGA were both stable, although with minimal conformational alterations at the kelch pocket of Keap1. Finally, MMPBSA calculation of the Gibbs free energy of each amino acid interaction with CAT and CGA revealed that CAT had a higher total binding energy than CGA. Therefore, the Keap1 inhibitory capacities and the molecular dynamic characters of CAT and CGA at the Kelch domain of Keap1 suggest a putative Nrf2 signaling activating prowess. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40203-021-00100-2.

Molecular dynamics, quantum mechanics and docking studies of some Keap1 inhibitors - An insight into the atomistic mechanisms of their antioxidant potential.

Inhibitors of Keap1 would disrupt the covalent interaction between Keap1 and Nrf2 to unleash Nrf2 transcriptional machinery that orchestrates its cellular antioxidant, cytoprotective and detoxification processes thereby, protecting the cells against oxidative stress mediated diseases. In this in silico research, we investigated the Keap1 inhibiting potential of fifty (50) antioxidants using pharmacokinetic ADMET profiling, bioactivity assessment, physicochemical studies, molecular docking investigation, molecular dynamics and Quantum mechanical-based Density Functional Theory (DFT) studies using Keap1 as the apoprotein control. Out of these 50 antioxidants, Maslinic acid (MASA), 18-alpha-glycyrrhetinic acid (18-AGA) and resveratrol stand out by passing the RO5 (Lipinski rule of 5) for the physicochemical properties and ADMET studies. These three compounds also show high binding affinity of -10.6 kJ/mol, -10.4 kJ/mol and -7.8 kJ/mol at the kelch pocket of Keap1 respectively. Analysis of the 20ns trajectories using RMSD, RMSF, ROG and h-bond parameters revealed the stability of these compounds after comparing them with Keap1 apoprotein. Furthermore, the electron donating and accepting potentials of these compounds was used to investigate their reactivity using Density Functional Theory (HOMO and LUMO) and it was revealed that resveratrol had the highest stability based on its low energy gap. Our results predict that the three compounds are potential drug candidates with domiciled therapeutic functions against oxidative stress-mediated diseases. However, resveratrol stands out as the compound with the best stability and therefore, could be the best candidate with the best therapeutic efficacy.

A secondary approach with conventional medicines and supplements to recuperate current COVID-19 status.

Novel coronavirus 2019 (COVID-19) is a zoonosis that revised the global economic and societal progress since early 2020. The SARS-CoV-2 has been recognized as the responsible pathogen for COVID-19 with high infection and mortality rate potential. It has spread in 192 countries and infected about 1.5% of the world population, and still, a proper therapeutic approach is not unveiled. COVID-19 indication starts with fever to shortness of breathing, leading to ICU admission with the ventilation support in severe conditions. Besides the symptomatic mainstay clinical therapeutic approach, only Remdesivir has been approved by the FDA. Several pharmaceutical companies claimed different vaccines with exceptionally high efficacy (90-95%) against COVID-19; how long these vaccines can protect and long-term safety with the new variants are unpredictable. After the worldwide spread of the COVID-19 pandemic, numerous clinical trials with different phases are being performed to find the most appropriate solution to this condition. Some of these trials with old FDA-approved drugs showed promising results. In this review, we have precisely compiled the efforts to curb the disease and discussed the clinical findings of Ivermectin, Doxycycline, Vitamin-D, Vitamin-C, Zinc, and cannabidiol and their combinations. Additionally, the correlation of these molecules on the prophylactic and diseased ministration against COVID-19 has been explored.