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Comparative binding pose of the docked ligand guggulsterone (green) to the native pose of the reference crystallized ligand ADP ribose (red) within the active binding site of the viral ARP enzyme.
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Coronavirus Disease-2019 (COVID-19) is a highly contagious disease caused by Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2). The World Health Organization (WHO) classified the disease a as global public health hazard on 11 March 2020. Currently, there are no adequate measures to combat viral infections, including COVID-19, and the med...
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... analysis of the obtained screening results with the reported viral ARP inhibitor ZINC82673 showed that the screened herbal lead guggulsterone had a much higher binding affinity for the target receptor (ARP). The comparative binding pose of guggulsterone with respect to the native pose of the reference crystallized ligand (ADP ribose) is shown in Figure 3. ...
Citations
... The individual conformational search for its local conformational space, discovering local minima and then proceed this information to later generations is performed by "Lamarckian" aspect, which is its additional feature. The binding energy of the small molecules with macromolecular targets is predicted by using the semiempirical force field (Agrawal et al. 2021;Kciuk et al. 2022;Fidan and Mujwar 2024). AutoDock 4.2 tool was also used for the calculation of inhibition constants (K i ) for hit molecules . ...
Human body odor is a result of the bacterial biotransformation of odorless precursor molecules secreted by the underarm sweat glands. In the human axilla, Staphylococcus hominis is the predominant bacterial species responsible for the biotransformation process of the odorless precursor molecule into the malodorous 3M3SH by two enzymes, a dipeptidase and a specific C-S lyase. The current solutions for malodor, such as deodorants and antiperspirants are known to block the apocrine glands or disrupt the skin microbiota. Additionally, these chemicals endanger both the environment and human health, and their long-term use can influence the function of sweat glands. Therefore, there is a need for the development of alternative, environmentally friendly, and natural solutions for the prevention of human body malodor. In this study, a library of secondary metabolites from various plants was screened to inhibit the C-S lyase, which metabolizes the odorless precursor sweat molecules, through molecular docking and molecular dynamics (MD) simulation. In silico studies revealed that tannic acid had the strongest affinity towards C-S lyase and was stably maintained in the binding pocket of the enzyme during 100-ns MD simulation. We found in the in vitro biotransformation assays that 1 mM tannic acid not only exhibited a significant reduction in malodor formation but also had quite low growth inhibition in S. hominis, indicating the minimum inhibitory effect of tannic acid on the skin microflora. This study paved the way for the development of a promising natural C-S lyase inhibitor to eliminate human body odor and can be used as a natural deodorizing molecule after further in vivo analysis.
... In several clinical trials, oral guggulsterone resulted in only minor side effects, including gastrointestinal and skin eruption, without any major side effects [83]. Given the evidence of guggulsterone safety in clinical trials [84], this compound might serve as an important lead for future clinical investigations. ...
Recently, we have shown that guggulsterone is the principal constituent responsible for protective effects of Commiphora wightii against elastase-induced chronic obstructive pulmonary disease (COPD)-linked inflammation/emphysema. Given that cigarette smoke (CS) exposure is a primary risk factor for COPD and beneficial effects of guggulsterone have not been investigated in CS-induced COPD-linked lung inflammation. The present work was designed to validate the potential of guggulsterone in amelioration of COPD-linked lung inflammation by using a CS-based mouse model of the condition. Male BALB/c mice were exposed to 9 cigarettes/day with 1 h interval for 4 days daily. Guggulsterone was administered daily at a dose of 10 mg/kg orally for 4 consecutive days, 1 h before initiation of CS exposure. Mice were subjected to measurement of lung function followed by procurement of bronchoalveolar lavage fluid (BALF)/lung tissue. BALF was analyzed for inflammatory cells and pro-inflammatory cytokines. Lung tissue was subjected to RT-PCR for gene expression analysis. Data showed that CS exposure resulted in a significant increase in total BALF cells, predominantly neutrophils, and macrophages. Interestingly, guggulsterone administration significantly blunted CS-induced inflammation as reflected by reduced neutrophil and macrophage count. Further, the compound inhibited CS-induced gene expression of pro-inflammatory mediators TNF-α/ IL-1β/ G-CSF/and KC in lungs along with the production of pro-inflammatory mediators TNF-α/ IL-1β/ IL-6/ G-CSF/ KC/and MCP-1 in BALF. Further, guggulsterone improved the lung function parameters upon CS exposure. Analysis of mRNA expression of matrix metalloproteinase (MMP)-9 and tissue inhibitor of matrix metalloproteinase (TIMP)-1 suggests that guggulsterone may restore the fine balance between matrix-degrading proteases and its inhibitor in lung tissue upon CS exposure, which may contribute in the development of emphysema at later stages. Overall, our data show that guggulsterone protects against CS-induced COPD-linked lung inflammation by modulating relevant molecular players. Based on the potential effects of guggulsterone in the amelioration of CS-induced lung inflammation, we speculate that guggulsterone might alter chronic CS-induced emphysema.
... Especially, in the pandemic area, computational-aided drug discovery could provide an unreplaceable method to accelerate the pace of drug discovery. During the COVID-19 pandemic, a lot of investigation and progress has been made using this approach [56][57][58] . Most importantly, the mutation and variant of interest could also be deeply investigated using the computational repurposing method 59,60 . ...
The pandemic of coronavirus disease 2019 (COVID-19) caused by the infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a significant impact on the economy and public health worldwide. Therapeutic options such as drugs and vaccines for this newly emerged disease are eagerly desired due to the high mortality. Using the U.S. Food and Drug Administration (FDA) approved drugs to treat a new disease or entirely different diseases, in terms of drug repurposing, minimizes the time and cost of drug development compared to the de novo design of a new drug. Drug repurposing also has some other advantages such as reducing safety evaluation to accelerate drug application on time. Carvedilol, a non-selective beta-adrenergic blocker originally designed to treat high blood pressure and manage heart disease, has been shown to impact SARS-CoV-2 infection in clinical observation and basic studies. Here, we applied computer-aided approaches to investigate the possibility of repurposing carvedilol to combat SARS-CoV-2 infection. The molecular mechanisms and potential molecular targets of carvedilol were identified by evaluating the interactions of carvedilol with viral proteins. Additionally, the binding affinities of in vivo metabolites of carvedilol with selected targets were evaluated. The docking scores for carvedilol and its metabolites with RdRp were − 10.0 kcal/mol, − 9.8 kcal/mol (1-hydroxyl carvedilol), − 9.7 kcal/mol (3-hydroxyl carvedilol), − 9.8 kcal/mol (4-hydroxyl carvedilol), − 9.7 kcal/mol (5-hydroxyl carvedilol), − 10.0 kcal/mol (8-hydroxyl carvedilol), and − 10.1 kcal/mol (O-desmethyl carvedilol), respectively. Using the molecular dynamics simulation (100 ns) method, we further confirmed the stability of formed complexes of RNA-dependent RNA polymerase (RdRp) and carvedilol or its metabolites. Finally, the drug-target interaction mechanisms that contribute to the complex were investigated. Overall, this study provides the molecular targets and mechanisms of carvedilol and its metabolites as repurposed drugs to fight against SARS-CoV-2 infection.
... In vitro, guggulsterone promotes ACE2 down-regulation, thus reducing susceptibility of host cells to SARS-CoV-2 infection [69]. Furthermore, a computational study suggests that guggulsterone might inhibit SARS-CoV-2 ADP ribose phosphate (ARP), enzyme fundamental for viral metabolism, thus affecting virus' replication [103]. ...
... Fig. 1 shows the vital milestones in the journey of vaccine development. It became vital to develop vaccinations at an incredible speed and in abundance following the appearance of the severe acute respiratory syndrome coronavirus 2 [12] virus at the end of 2019 and realizing its potential for worldwide spread, causing the COVID-19 disease [13]. In this devastating endemic to treat people with vaccines it was made clear that those in phase III clinical trials that were found to be safe and effective may hit the market by giving them an emergency use status [14]. ...
One of the most significant medical advancements in human history is the development of vaccines. Progress in vaccine development has always been greatly influenced by scientific human innovation. The main objective of vaccine development would be to acquire sufficient evidence of vaccine effectiveness, immunogenicity, safety, and/or quality to support requests for marketing approval. Vaccines are biological products that enhance the body's defenses against infectious diseases. From the first smallpox vaccine to the latest notable coronavirus disease 2019 nasal vaccine, India has come a long way. The development of numerous vaccines, driven by scientific innovation and advancement, combined with researcher's knowledge, has helped to reduce the global burden of disease and mortality rates. The Drugs and Cosmetics Rules of 1945 and the New Drugs and Clinical Trials Rules of 2019 specify the requirements and guidelines for CMC (chemistry, manufacturing, and controls) for all manufactured and imported vaccines, including those against coronavirus infections. This article provides an overview of the regulation pertaining to the development process, registration, and approval procedures for vaccines, particularly in India, along with their brief history.
... Molecular docking involves simulating the optimal conformation based on complementarity and preorganization, enabling us to predict and obtain the binding affinity and interaction mode between the ligand and the receptor (Gupta et al., 2022b(Gupta et al., , 2022cMorris and Lim-Wilby, 2008). To validate the results of the CoMFA and CoMSIA contour maps, a molecular docking study was performed using AutoDock 4.2 (Gupta et al., 2023;Kciuk et al., 2022b;Norgan et al., 2011;Shah et al., 2019b;Sharma et al., 2023;Shinu et al., 2022). In order to observe the ligand-protein interaction and eliminate water molecules, Discovery 2020 was used ("Free Download: BIOVIA Discovery Studio Visualizer -Dassault Systèmes,"). ...
The overexpression of cyclooxygenase-2 (COX-2) was clearly associated with carcinogenesis, andCOX-2 as a possible target has long been exploited for cancer therapy. A group of 29 derivatives of 1,5-diarylpyrazole was used to study its structural requirements using three-dimensional quantitativestructure-activity relationship (3D-QSAR), the density functional theory method, molecular docking,and molecular dynamics. Four 3D-QSAR models were developed, and the predictive capability of thefour selected models was also successfully tested using different validation methods. The contributioncontours of the comparative molecular field analysis (CoMFA) and comparative molecular similarityindex analysis (CoMSIA) models effectively illustrate the relationships between the various chemicalcharacteristics and their biological activities. Using the density functional theory method with the 6-31G(d, p) basis set and the Becke, 3-parameter, Lee-Yang-Parr (B3LYP) function to evaluate chemicalreactivity properties, the results obtained from energy gaps of 3.431, 3.446, and 2.727 ev for moleculesnumbers 21, 22, and 23 indicate that these three molecules have good chemical stability and reactivityand select the most reactive regions in the three molecules studied. Molecular docking results revealedthat the active sites of the COX-2 protein (PDB code: 3PGH) were residues ARG222, THR212, HIS386,HIS207, TYR148, and ASP382, in which the most active ligands and now ligands can inhibit the COX-2enzyme. Based on the various results obtained by molecular modeling, four new compounds (N1, N2,N3, and N4) were proposed with significant predicted activity by different 3D-QSAR models. Amolecular docking study and molecular dynamics simulations of the proposed new molecules (N1 andN2) and the most active molecule over 100 ns revealed that all three molecules establish multiplehydrogen interactions with several residues and also exhibit frequent stability throughout the simulationperiod. As a result, it is strongly recommended to consider the two newly proposed molecules, N1 andN4, as promising candidates for novel anti-cancer agents specifically designed to target COX-2inhibition.
... The five protein-ligand complexes were selected from the IFD protocol based on the refined pose produced by the protocol. The MDS was run for a time frame of 100 nanoseconds (ns) at a constant temperature of 300K and constant pressure (Fidan et al., May 2022;Gahtori et al., 2020;Kciuk, Mujwar, Rani, et al., 2022;Kciuk, Mujwar, Szymanowska, et al., 2022;Kciuk et al. 2023;Kikiowo et al., 2022;Petersen, 1995;Posch et al., 1986;Rani et al., 2022;Shinu et al., 2022;Toukan & Rahman, 1985). The Desmond module of Schr€ odinger Maestro was employed to perform MDS using the OPLS3e force field and solvating in an orthorhombic box of size 10 Â 10 Â 10 Å (Manandhar et al., 2022). ...
Dipeptidyl peptidase-4 (DPP4) inhibitors are a potent therapeutic treatment for type 2 diabetes mellitus (T2DM). There is a family of compounds used as DPP4 inhibitors (DPP4Is) called gliptins. They bind tightly to DPP4 to form an inactive protein-ligand complex. However, there remains a need to identify novel DPP4Is that are more efficacious and safer due to the increasing prevalence of T2DM and the undesirable side effects of gliptins. To identify potential DPP4Is, we screened over 1800 novel compounds in a comparative study with gliptins. We performed dual-factor molecular docking to assess the binding affinity of the compounds to DPP4 and found four compounds with a higher binding affinity to DPP4 than currently used gliptins. The newly identified compounds interacted with the dyad glutamate (GLU205 and GLU206) and tyrosine (TYR662 and TYR666) residues in DPP4's active site. We performed molecular dynamics simulations to determine the stability of the protein-ligand complexes formed by the compounds and DPP4. Furthermore, we examined the toxicity and pharmacological profile of the compounds. The compounds are drug-like, easy to synthesize, and relatively less toxic than gliptins. Collectively, our results suggest that the novel compounds are potential DPP4Is and should be considered for further studies to develop novel antidiabetics.Communicated by Ramaswamy H. Sarma.
... TIP3P explicit water model was used to create an orthorhombicshaped simulation box with a 10 Å gap between the wall of the box and the ligand-protein complex. [50][51][52][53][54][55][56][57] The simulation box's isosmotic environment was created by adding counter ions with 0.15 M NaCl to neutralize the existing charge. The system's energy was minimized by running 2,000 iterations using a 1 kcal/mol merging threshold. ...
A series of oxadiazole-based five-membered heterocyclic derivatives was designed and synthesized with the intent of exclusive cyclo-oxygenase-2 (COX-2) inhibition to acquire anti-inflammatory activity without the presence of gastric toxicity. Oxadiazole-based novel analogs were designed by using bioisosteric substitutions and were screened against the macromolecular target by using docking-based virtual screening to identify their potential inhibitors. These selective COX-2 inhibitors were further evaluated for their stability within the binding cavity of macromolecular complex by performing molecular dynamic simulation for 100 ns. Selected compounds were synthesized by using Naphthalene-2-yl-acetic acid as a starting material based on the fundamental structure of naphthalene. The naphthalene ring and methylene bridge of naphthalene-2-yl-acetic acid were retained in the rational molecular design by replacing the carboxyl group with biologically significant groups like 1,3,4-oxadiazoles, with the goal of obtaining a novel, superior, and relatively safe anti-inflammatory molecule with better efficacy and optimized pharmacokinetics. Anti-inflammatory as well as analgesic properties of the compounds were evaluated experimentally for their pharmacological efficiency.
... In 2019, the unprecedented COVID-19 was caused by the new coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has become a global public health concern (Kciuk et al., 2022;Murali et al., 2022). BA has been shown to inhibit SARS-CoV-2 RNA-dependent RNA polymerase activity and exhibited significant antiviral activity against SARS-CoV-2 in vitro (Zandi et al., 2021). ...
Background: Respiratory diseases are common and frequent diseases. Due to the high pathogenicity and side effects of respiratory diseases, the discovery of new strategies for drug treatment is a hot area of research. Scutellaria baicalensis Georgi (SBG) has been used as a medicinal herb in China for over 2000 years. Baicalin (BA) is a flavonoid active ingredient extracted from SBG that BA has been found to exert various pharmacological effects against respiratory diseases. However, there is no comprehensive review of the mechanism of the effects of BA in treating respiratory diseases. This review aims to summarize the current pharmacokinetics of BA, baicalin-loaded nano-delivery system, and its molecular mechanisms and therapeutical effects for treating respiratory diseases. Method: This review reviewed databases such as PubMed, NCBI, and Web of Science from their inception to 13 December 2022, in which literature was related to "baicalin", "Scutellaria baicalensis Georgi", "COVID-19", "acute lung injury", "pulmonary arterial hypertension", "asthma", "chronic obstructive pulmonary disease", "pulmonary fibrosis", "lung cancer", "pharmacokinetics", "liposomes", "nano-emulsions", "micelles", "phospholipid complexes", "solid dispersions", "inclusion complexes", and other terms. Result: The pharmacokinetics of BA involves mainly gastrointestinal hydrolysis, the enteroglycoside cycle, multiple metabolic pathways, and excretion in bile and urine. Due to the poor bioavailability and solubility of BA, liposomes, nano-emulsions, micelles, phospholipid complexes, solid dispersions, and inclusion complexes of BA have been developed to improve its bioavailability, lung targeting, and solubility. BA exerts potent effects mainly by mediating upstream oxidative stress, inflammation, apoptosis, and immune response pathways. It regulates are the NF-κB, PI3K/AKT, TGF-β/Smad, Nrf2/HO-1, and ERK/GSK3β pathways. Conclusion: This review presents comprehensive information on BA about pharmacokinetics, baicalin-loaded nano-delivery system, and its therapeutic effects and potential pharmacological mechanisms in respiratory diseases. The available studies suggest that BA has excellent possible treatment of respiratory diseases and is worthy of further investigation and development.
... Some carotenoids, such as crocin, which has the highest binding affinity for the SARS-CoV-2 replication complex, have been reported to be possibly beneficial for patients of COVID-19 because of their powerful antioxidant capabilities and also have the potential to be used as alternative treatments and dietary supplements for the prevention and treatment of COVID-19. 4 The structural and molecular design of the SARS-CoV-2 genome has been accurately understood using bioinformatics techniques and various software programs. The primary three methods used in in silico research are computer aided drug design (CADD), next-generation sequencing, and genome-wide association (GWA)studies. ...
ChAdOx1 nCoV-19 (AZD1222) is a replication-deficient chimpanzee adenovirus vectored vaccine developed by Oxford and AstraZeneca for a disease we all know as Coronavirus, or COVID-19. Ongoing clinical studies reveal that the ChAdOx1 nCoV-19 vaccine has a tolerable safety profile and is effective against symptomatic COVID-19. This vaccine may prove crucial in boosting herd immunity, averting life threatening illness, and relieving the current pandemic. In this mini review, we performed a thorough literature search through PubMed and Google Scholar and reported various case reports associated with complications of the adenovirus-vectored COVID-19 vaccine. Various adverse effects of the ChAdOx1 nCoV-19 vaccine were reported around the globe, which were often serious but rare and developed
into life-threatening pathologies such as GBS, thrombocytopenia, demyelinating neuropathies, progressive dementia, cerebral infarction, IgA vasculitis, hemophagocytic lymphohistiocytosis, herpes zoster, cutaneous reactions, and vein thrombosis. These worldwide reported complications, which are usually rare and severe, will aid clinicians in understanding and managing unforeseen situations. There is a need for more research to find out more about these complications and their etiopathogenesis.
However, the benefits of these vaccinations for stopping the spread of the outbreak and lowering the fatality rate outweigh the potential risk of the uncommon complications.
