New hydrazide derivatives of N-amino-11-azaartemisinin as promising epidermal growth factor receptor inhibitors for therapeutic development in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) treatments, such as DNA-damaging agents like carboplatin, pose considerable human toxicity and may contribute to cancer relapse. Artemisinin derivatives offer a less toxic alternative; however, their specific role in TNBC management remains to be established. To address this gap, computational models were employed to design and evaluate artemisinin-based prototypes as potential TNBC therapeutics, aiming to provide safer and more effective treatment options for this aggressive cancer subtype. Among the series of hydrazide derivatives of azaartemisinin (10a-l) reported herein, compound 10j emerged as the most promising, exhibiting notable cytotoxicity with IC50 values of 1.74 and 1.64 µM against MDA-MB-231 and MDA-MB-468 cells, respectively. The clinically useful drug doxorubicin provided IC50 values of 0.29 and 0.29 µM against MDA-MB-231 and MDA-MB-468 cells, while artemisinin provided IC50 values of 107.30 and 116.60 µM, respectively. Furthermore, putative interactions between the synthesized compounds and the epidermal growth factor receptor (EGFR) were identified using molecular docking studies, suggesting a possible mechanism for their anticancer effect. Additionally, to determine the thermodynamic parameters of the interactions between artemisinin, azaartemisinin, and biomolecules, isothermal titration calorimetry experiments were performed. The binding constant value on the order of 104 indicates a comparatively stronger binding affinity of azaartemisinin with human serum albumin (HSA) compared to artemisinin with HSA. These findings support the potential of azaartemisinin derivatives as promising EGFR inhibitors for therapeutic development in TNBC, offering a new avenue for less toxic and more effective cancer treatments.

Crucial Structural Understanding for Selective HDAC8 Inhibition: Common Pharmacophores, Molecular Docking, Molecular Dynamics, and Zinc Binder Analysis of selective HDAC8 inhibitors.

BACKGROUND: Overexpression of HDAC8 was observed in various cancers and inhibition of HDAC8 has emerged as a promising therapeutic approach in recent decades. OBJECTIVE: This review aims to facilitate the discovery of novel selective HDAC8 inhibitors by analyzing the structural scaffolds of 66 known selective HDAC8 inhibitors, along with their IC50 values against HDAC8 and other HDACs. METHODS: The inhibitors were clustered based on structural symmetry, and common pharmacophores for each cluster were identified using Phase. Molecular docking with all HDACs was performed to determine binding affinity and crucial interacting residues for HDAC8 inhibition. Representative inhibitors from each cluster were subjected to molecular dynamics simulation to analyze RMSD, RMSF, active site amino acid residues, and crucial interacting residues responsible for HDAC8 inhibition. The study reviewed the active site amino acid information, active site cavities of all HDACs, and the basic structure of Zn2+ binding groups. RESULTS: Common pharmacophores identified included AADHR_1, AADDR_1, ADDR_1, ADHHR_1, and AADRR_1. Molecular docking analysis revealed crucial interacting residues: HIS- 142, GLY-151, HIS-143, PHE-152, PHE-20 in the main pocket, and ARG-37, TYR-100, TYR-111, TYR-306 in the secondary pocket. The RMSD of protein and RMSF of active site amino acid residues for stable protein-ligand complexes were less than 2.4 Å and 1.0 Å, respectively, as identified from MD trajectories. The range of Molecular Mechanics Generalized Born Surface Area (MMGBSA) ΔG predicted from MD trajectories was between -15.8379 Å and -61.5017 Å kcal/mol. CONCLUSION: These findings may expedite the rapid discovery of selective HDAC8 inhibitors subject to experimental evaluation.

Parkia javanica Edible Pods Reveal Potential as an Anti-Diabetic Agent: UHPLC-QTOF-MS/MS-Based Chemical Profiling, In Silico, In Vitro, In Vivo, and Oxidative Stress Studies.

According to the World Health Organization, over 422 million people worldwide have diabetes, with the majority residing in low- and middle-income countries. Diabetes causes 1.5 million fatalities a year. The number of diabetes cases and its prevalence have progressively increased over the last few decades. This study aims to determine the phytochemicals in the edible part of Perkia javanica, predict their α-glucosidase inhibitory potential, one of the promising targets for diabetes, and then carry out in vitro and in vivo studies. The phytochemicals present in the n-butanol fraction of the methanol extract of P. javanica pods were analyzed using UHPLC-QTOF-MS/MS (Ultra-High-Performance Liquid Chromatography-Quadrupole Time-of-Flight Mass Spectrometry). The UHPLC-QTOF analysis revealed the presence of 79 different compounds in the n-butanol fraction. Among these, six compounds demonstrated excellent binding affinities with α-glucosidase, surpassing the performance of two standard inhibitors, Miglitol and Voglibose. In vitro α-glucosidase inhibitory activities were assessed by the n-butanol fraction, followed by in vivo studies. According to the in vitro study, the inhibitory efficiency against α-glucosidase was determined to have an IC50 value of 261.9 µg/mL. The in vivo findings revealed a significant reduction in blood glucose levels in Swiss albino mice treated with the same extract, decreasing from 462.66 mg/dL to 228.66 mg/dL. Additionally, the extract significantly increased the activity of the enzymes catalase and superoxide dismutase (SOD) and decreased the amount of malondialdehyde (MDA) in the liver and kidney tissue. The predicted physicochemical parameters indicated that most of the compounds would be excreted from the body after inhibition in the small intestine without being absorbed. Considering the low cost and wide availability of raw materials, P. javanica pods can serve as a good food supplement that may help prevent type 2 diabetes management.

α-Glucosidase inhibitory potential of Oroxylum indicum using molecular docking, molecular dynamics, and in vitro evaluation.

Background: According to the International Diabetes Federation, there will be 578 million individuals worldwide with diabetes by 2030 and 700 million by 2045. One of the promising drug targets to fight diabetes is α-glucosidase (AG), and its inhibitors may be used to manage diabetes by reducing the breakdown of complex carbohydrates into simple sugars. The study aims to identify and validate potential AG inhibitors in natural sources to combat diabetes. Methods: Computational techniques such as structure-based virtual screening and molecular dyncamic simulation were employed to predict potential AG inhibitors from compounds of Oroxylum indicum. Finally, in silico results were validated by in vitro analysis using n-butanol fraction of crude methanol extracts. Results: The XP glide scores of top seven hits OI_13, OI_66, OI_16, OI_44, OI_43, OI_20, OI_78 and acarbose were -14.261, -13.475, -13.074, -13.045, -12.978, -12.659, -12.354 and -12.296 kcal/mol, respectively. These hits demonstrated excellent binding affinity towards AG, surpassing the known AG inhibitor acarbose. The MM-GBSA dG binding energies of OI_13, OI_66, and acarbose were -69.093, -62.950, and -53.055 kcal/mol, respectively. Most of the top hits were glycosides, indicating that active compounds lie in the n-butanol fraction of the extract. The IC50 value for AG inhibition by n-butanol fraction was 248.1 µg/ml, and for that of pure acarbose it was 89.16 µg/ml. The predicted oral absorption rate in humans for the top seven hits was low like acarbose, which favors the use of these compounds as anti-diabetes in the small intestine. Conclusion: In summary, the study provides promising insights into the use of natural compounds derived from O. indicum as potential AG inhibitors to manage diabetes. However, further research, including clinical trials and pharmacological studies, would be necessary to validate their efficacy and safety before clinical use.

Identification of phytoconstituents from Dicliptera paniculata and study of antibacterial activity guided by molecular docking.

According to WHO, antibiotic resistance is one of the biggest healthcare challenges to the global community. Therefore, it is absolutely essential to discover new antibiotics to address the challenge. Dicliptera paniculata (ForssK.) I. Darbysh, a rare medicinal herb of Acanthaceae, is known for its noteworthy uses as a flavoring, spicing, and antibacterial agent. The primary goal of the study is to identify novel antibacterials from D. paniculata. The petroleum ether fraction of the methanol extract of D. paniculata was subjected to GC-MS and identified 14 compounds. Several bacterial target proteins were used for molecular docking. The antibacterial activity of petroleum-ether fraction was evaluated on bacteria whose target protein interacts most strongly with identified molecules. The molecules DP_02, DP_06, and DP_14 exhibited the highest docking scores with Staphylococcus aureus dihydrofolate reductase, which were - 6.283, - 7.705, and - 6.364 kcal/mol, respectively. The MM-GBSA binding energy of compounds DP_02, DP_06, and DP_14 were - 46.736, - 42.366, and - 35.734 kcal/mol, respectively. The MM-GBSA binding energy and decent docking score of the compounds DP_02 and DP_06 were both encouraging, and both of the compounds are drug-like. The finding was validated through studies on antibacterial effectiveness against S. aureus and showed encouraging results. These two molecules might serve as the building blocks for the future development of potent antibiotics.

Epidermal growth factor receptor inhibition potentiates chemotherapeutics-mediated sensitization of metastatic breast cancer stem cells.

BACKGROUND: Metastasis has been a cause of the poor prognosis and cancer relapse of triple-negative breast cancer (TNBC) patients. The metastatic nature of TNBC is contributed by the breast cancer stem cells (CSCs) which have been implicated in tumorigenesis. Higher expression of epidermal growth factor receptor (EGFR) in breast CSCs has been used as a molecular target for breast cancer therapeutics. Thus, it necessitates the design and generation of efficacious EGFR inhibitors to target the downstream signaling associated with the cellular proliferation and tumorigenesis of breast cancer. AIM: To generate efficacious EGFR inhibitors that can potentiate the chemotherapeutic-mediated mitigation of breast cancer tumorigenesis. METHODS AND RESULTS: We identified small molecule EGFR inhibitors using molecular docking studies. In-vitro screening of the compounds was undertaken to identify the cytotoxicity profile of the small-molecule EGFR inhibitors followed by evaluation of the non-cytotoxic compounds in modulating the doxorubicin-induced migration, in-vitro tumorigenesis potential, and their effect on the pro-apoptotic genes' and protein markers' expression in TNBC cells. Compound 1e potentiated the doxorubicin-mediated inhibitory effect on proliferation, migration, in-vitro tumorigenesis capacity, and induction of apoptosis in MDA-MB-231 cells, and in the sorted CD24+-breast cancer cells and CD24-/CD44+-breast CSC populations. Orthotopic xenotransplantation of the breast CSCs-induced tumors in C57BL/6J mice was significantly inhibited by the low dose of Doxorubicin in the presence of compound 1e as depicted by molecular and immunohistochemical analysis. CONCLUSION: Thus, the study suggests that EGFR inhibition-mediated sensitization of the aggressive and metastatic breast CSCs in TNBCs toward chemotherapeutics may reduce the relapse of the disease.

Identification of potential edible spices as EGFR and EGFR mutant T790M/L858R inhibitors by structure-based virtual screening and molecular dynamics.

Epidermal growth factor receptor (EGFR) tyrosine kinases are overexpressed in several human cancers and could serve as a promising anti-cancer drug target. With this in view, the main aim of the present study was to identify spices having the potential to inhibit EGFR tyrosine kinase. The structure-based virtual screening of spice database consisting of 1439 compounds with EGFR tyrosine kinase (PDB ID: 3W32) was carried out using Glide. Top scored 18 hits (XP Glide Score ≥ -10.0 kcal/mol) was further docked with three EGFR tyrosine kinases and three EGFR T790M/L858R mutants using AutodockVina, followed by ADME filtration. The best three hits were further refined by Molecular Dynamics (MD) simulation and MM-GBSA-based binding energy calculation. The overall docking results of the selected hits with both EGFR and EGFR T790M/L858R were quite satisfactory and showed strong binding compared to the three coligands. Detailed MD analysis of CL_07, AC_11 and AS_49 also showed the stability of the protein-ligand complexes. Moreover, the hits were drug-like, and MM-GBSA binding free energy of CL_07 and AS_49 was established to be far better. AC_11 was found to be similar to the known inhibitor Gefitinib. Most of the potential hits are available in Allium cepa, CL_07 and AS_49 available in Curcuma longa and Allium sativum, respectively. Therefore, these three spices could be used as a potential therapeutic candidate against cancer caused by overexpression of EGFR after validation of the observations of this study in in-vitro experiments. Further extensive work is needed to improve the scaffolds CL_07, AC_11, AC_17, and AS_49 as potential anti-cancer drugs.Communicated by Ramaswamy H. Sarma.

Potential peptidyl arginine deiminase type 4 inhibitors from Morinda citrifolia: a structure-based drug design approach.

The World Health Organization estimates that more than 23 million individuals worldwide suffer from rheumatoid arthritis (RA), a chronic systemic autoimmune disease and experts predict that the number of RA patients may double by 2030. A substantial portion of RA patients do not respond effectively to the treatment that are already available therefore there is an urgent need of innovative new drugs. Over the past several years, Peptidyl Arginine Deiminase Type 4 (PAD4) receptors have become potential therapeutic targets for the treatment of RA. The main objective of the present study is to identify potential PAD4 inhibitors from edible fruits Morinda citrifolia. Structure based virtual screening (VS) of 60 compounds from M. citrifolia were performed to identify PAD4 inhibitors. The virtual screening of compounds resulted ten hits having XP-Glide score greater than the co-ligand (XPGS: - 8.341 kcal/mol). Three hits NF_15, NF_34, and NF_35 exhibited admirable MM-GBSA dG binding energy - 52.577, - 46.777, and - 60.711 kcal/mol, respectively. These three compounds were chosen for 100 ns molecular dynamics (MD) simulations in order to evaluate the stability and interactions. The protein-ligand complex with the highest level of stability was revealed to be NF_35. Therefore, M. citrifolia fruits may be beneficial in the treatment and prevention of rheumatoid arthritis since it contains potential hits. Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-023-00147-3.

Oroxylum indicum Stem Bark Extract Reduces Tumor Progression by Inhibiting the EGFR-PI3K-AKT Pathway in an In Vivo 4NQO-Induced Oral Cancer Model.

OBJECTIVES: Oral squamous cell carcinoma (OSCC) is the predominant type of oral cancer. Its incidence is high in certain geographic regions, and it is correlated with chewing tobacco. Epidermal growth factor receptor (EGFR), induced by tobacco carcinogens, is overexpressed in OSCC, leading to poor prognosis. Thus, EGFR inhibitors are promising agents against OSCC. High cost and toxicity of existing EGFR inhibitors necessitate alternative EGFR-targeted therapy. Here, we tested the antitumor potential of ethyl acetate fraction of an ethnomedicinal tree, Oroxylum indicum stem bark extract (OIEA) in a 4-nitroquinoline-1-oxide (4NQO)-induced oral carcinogenesis model. METHODS: OIEA was prepared by solvent extraction method, and subsequently its in vitro radical scavenging activities were measured. High-performance liquid chromatography (HPLC) analysis of OIEA was done to identify the constituent active compounds. Hemolytic, trypan blue exclusion, and MTT [3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide] assays were performed in normal and cancer cells to select an optimum dose of OIEA for antitumor activity study in 4NQO-induced oral cancer in F344 rats. Measurement of tumor volume, weight, and cell count was followed by tumor cell cycle analysis and comet and annexin V/Propidium Iodide (PI) assay. Pro-apoptotic markers were detected by western blot testing. Molecular docking was done to predict the interaction between OIEA active component and EGFR or phosphatidylinositol-3-kinase (PI3K), which was further validated biologically. Finally, hepatic and renal function testing and histopathology were performed. RESULTS: OIEA reduced tumor burden and increased survivability of the tumor-bearing rats significantly as compared to untreated tumor bearers. HPLC revealed oroxylin A as the predominant bioactive component in OIEA. Molecular docking predicted significant binding between oroxylin A and EGFR as well as PI3K, which was confirmed by western blot analysis of in vivo samples. OIEA also ameliorated hepato-, renal- and myelotoxicity induced by 4NQO. CONCLUSION: OIEA reduces 4NQO-induced OSCC by modulating the EGFR/PI3K/AKT signaling cascade and also ameliorated toxicity in tumor bearers.

Phytochemical characterization of Styrax benzoin resin extract, molecular docking, ADME, and antibacterial activity study.

Styrax benzoin fumes have a spiritual aspect from ancient times, magical essence like a pleasant perfume, and are employed in religious ceremonies in India. This study aims to identify the volatile compounds in S. benzoin extract, their binding affinity to the bacterial target proteins, and study the antibacterial activity of the potential extract. The compounds obtained from GC-MS analysis of S. benzoin extract were subjected to molecular docking studies against DHFR of Staphylococcus aureus, tRNA synthetase of Escherichia coli, DHPS of Mycobacterium tuberculosis. Molecular docking studies revealed that seventeen compounds out of 20 compounds exhibited higher binding affinity than co-ligand (-7.00 kcal/mol) against the Staphylococcus aureus enzyme DHFR. Consequently, the crude extracts were evaluated for antibacterial activity against S. aureus, and the acetone extract showed promising findings. S. benzoin fumes might replace synthetic room fresheners, and promising compounds could be exploited in the cosmetics industry.

Design, synthesis and docking study of Vortioxetine derivatives as a SARS-CoV-2 main protease inhibitor.

PURPOSE: Vortioxetine an anti-depressant FDA-drug recently reported showing better in vitro efficacy against SARS-CoV-2. METHODS: In this study, we have synthesized ten new derivatives having alkenes, alkynes, benzyl, aryl, and mixed carbamate at the N-terminal of vortioxetine. Then the binding energy and interactions with the crucial amino acid residues in the binding pocket of main protease (Mpro) of SARS-CoV-2, of reported and ten newly synthesized vortioxetine derivatives (total thirty-one) in comparison with remdesivir are analyzed and presented in this paper. RESULTS: Based on the docking scores predicted by ADV and AD, most vortioxetine derivatives showed better binding efficiency towards Mpro of SARS-CoV-2 in comparison with remdesivir (an EUA approved drug against SARS-CoV-2 Mpro) and vortioxetine. CONCLUSION: This study shows that some vortioxetine derivatives can be developed into promising drugs for COVID-19 treatment.

Identification of potential edible mushroom as SARS-CoV-2 main protease inhibitor using rational drug designing approach.

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is highly pathogenic to humans and has created health care threats worldwide. This urgent situation has focused the researchers worldwide towards the development of novel vaccine or small molecule therapeutics for SARS-CoV-2. Although several vaccines have already been discovered and are in use for the masses, no therapeutic medication has yet been approved by FDA for the treatment of COVID-19. Keeping this in view, in the present study, we have identified promising hits against the main protease (Mpro) of SARS-CoV-2 from edible mushrooms. Structure-based virtual screening (VS) of 2433 compounds derived from mushrooms was performed with Mpro protein (6LU7). Four promising hits, namely, Kynapcin-12 (M_78), Kynapcin-28 (M_82), Kynapcin-24 (M_83), and Neonambiterphenyls-A (M_366) were identified based on the result of docking, Lipinski's rule, 100 ns molecular dynamics (MD) simulation and MM/PBSA binding free energy calculations. Finally, the inhibitory properties of these hits were compared with three known inhibitors, baicalein (1), baicalin (2), and biflavonoid (3). Data indicated that M_78, M_82 and M_83 compounds present in edible mushroom Polyozellus multiplex were potent inhibitors of Mproprotein (6LU7). It could be concluded that edible mushroom Polyozellus multiplex has potential activity against SARS-CoV-2 infection and identified molecules could be further explored as therapeutic inhibitors against SARS-CoV-2.

Identification of potential inhibitors of SARS-CoV-2 main protease and spike receptor from 10 important spices through structure-based virtual screening and molecular dynamic study.

The outbreak of novel coronavirus disease (COVID-19) caused by SARS-CoV-2 poses a serious threat to human health and world economic activity. There is no specific drug for the treatment of COVID-19 patients at this moment. Traditionally, people have been using spices like ginger, fenugreek and onion, etc. for the remedy of a common cold. This work identifies the potential inhibitors of the main protease (Mpro) and spike (S) receptor of SARS-CoV-2 from 10 readily available spices. These two proteins, S and Mpro, play an important role during the virus entry into the host cell, and replication and transcription processes of the virus, respectively. To identify potential molecules an in-house databank containing 1040 compounds was built-up from the selected spices. Structure-based virtual screening of this databank was performed with two important SARS-CoV-2 proteins using Glide. Top hits resulted from virtual screening (VS) were subjected to molecular docking using AutoDock 4.2 and AutoDock Vina to eliminate false positives. The top six hits against Mpro and top five hits against spike receptor subjected to 130 ns molecular dynamic simulation using GROMACS. Finally, the compound 1-, 2-, 3- and 5-Mpro complexes, and compound 17-, 18-, 19-, 20- and 21- spike receptor complexes showed stability throughout the simulation time. The ADME values also supported the drug-like nature of the selected hits. These nine compounds are available in onion, garlic, ginger, peppermint, chili and fenugreek. All the spices are edible and might be used as home remedies against COVID-19 after proper biological evaluation.

Phytochemicals of Zingiberaceae family exhibit potentiality against SARS-CoV-2 main protease identified by a rational computer-aided drug design.

Coronavirus disease 2019 (COVID-19) has created huge social, economic and human health crises globally. Discovery of specific drugs has become a new challenge to the researcher. Structure-based virtual-screening of our in-house databank containing1102 phytochemicals of Zingiberaceae family was performed with main protease(Mpro), a crucial enzyme of SARS-CoV-2. Rigorous docking and ADME study of top-scored twenty hits resulted from VS was performed. Then 100 ns molecular dynamics followed by MMPBSA binding free energy(ΔGbind) calculation of A280 and KZ133 was also performed. These two hits showed good interactions with crucial amino acid residues of Mpro HIS-41 and CYS-145, excellent ADME properties, fair ΔGbind values (> ‒188.03 kj/mol), and average protein-ligand complex RMSD < apo-protein RMSD. Therefore, the seed extracts of Alpinia blepharocalyx and rhizome extracts Kaempferia angustifolia containing A280 and KZ133, respectively, may be useful against COVID-19 after the proper biological screening. These two novel scaffolds could be exploited as potent SARS-CoV-2-Mpro inhibitors.

Mushrooms are potential foods against cancer: identified by molecular docking and molecular dynamics simulation.

Epidermal Growth Factor Receptor (EGFR) is a promising drug target for the discovery of cancer chemotherapeutics. EGFR tyrosine kinase inhibitors become resistant due to mutation after a certain period of clinical application. The objective of the present study is to identify edible mushrooms as EGFR inhibitors. Structure-based VS of mushroom compounds using Autodock Vina in PyRx, re-docking of top scored hits using Autodock 4.2 were performed. Molecular dynamics (MD) was carried out with top hits to investigate the dynamic nature of the active site followed by MMPBSA binding energy calculation and ADME study. Analysis of MD results revealed the stability of Ag_76, Ag_77, Ag_88 and Ag_340 in the active site of EGFR as potential binders. Comparison of docking and MD results with known inhibitors also claimed the effectiveness of these hits. The sources of these potential hits are Polyozellus multiplex, Sarcodon imbricatus, and Cortinarius purpurascens, which may be effective as anti-cancer food after in vitro studies.

Potentiality of Moringa oleifera against SARS-CoV-2: identified by a rational computer aided drug design method.

Coronavirus disease 2019 (COVID-19) has created a global human health crisis and economic setbacks. Lack of specific therapeutics and limited treatment options against COVID-19 has become a new challenge to identify potential hits in order to develop new therapeutics. One of the crucial life cycle enzymes of SARS-CoV-2 is main protease (Mpro), which plays a major role in mediating viral replication, makes it an attractive drug target. Virtual screening and three times repeated 100 ns molecular dynamics simulation of the best hits were performed to identify potential SARS-CoV-2 Mpro inhibitors from the available compounds of an antiviral plant Moringa oleifera. Three flavonoids isorhamnetin (1), kaempferol (2) and apigenin (3) showed good binding affinity, stable protein-ligand complexes throughout the simulation time, high binding energy and similar binding poses in comparison with known SARS-CoV-2 Mpro inhibitor baicalein. Therefore, different parts of M. oleifera may be emerged as a potential preventive and therapeutic against COVID-19.

COVID-19 X-ray image segmentation by modified whale optimization algorithm with population reduction.

Coronavirus disease 2019 (COVID-19) has caused a massive disaster in every human life field, including health, education, economics, and tourism, over the last year and a half. Rapid interpretation of COVID-19 patients' X-ray images is critical for diagnosis and, consequently, treatment of the disease. The major goal of this research is to develop a computational tool that can quickly and accurately determine the severity of an illness using COVID-19 chest X-ray pictures and improve the degree of diagnosis using a modified whale optimization method (WOA). To improve the WOA, a random initialization of the population is integrated during the global search phase. The parameters, coefficient vector (A) and constant value (b), are changed so that the algorithm can explore in the early stages while also exploiting the search space extensively in the latter stages. The efficiency of the proposed modified whale optimization algorithm with population reduction (mWOAPR) method is assessed by using it to segment six benchmark images using multilevel thresholding approach and Kapur's entropy-based fitness function calculated from the 2D histogram of greyscale images. By gathering three distinct COVID-19 chest X-ray images, the projected algorithm (mWOAPR) is utilized to segment the COVID-19 chest X-ray images. In both benchmark pictures and COVID-19 chest X-ray images, comparisons of the evaluated findings with basic and modified forms of metaheuristic algorithms supported the suggested mWOAPR's improved performance.

Identification of SARS-CoV-2 Main Protease Inhibitors Using Structure Based Virtual Screening and Molecular Dynamics Simulation of DrugBank Database.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is highly pathogenic to humans and has created an unprecedented global health care threat. Globally, intense efforts are going on to discover a vaccine or new drug molecules to control the COVID-19. However, till today, there is no effective therapeutics or treatment available for COVID-19. In this study, we aim to find out potential small molecule inhibitors for SARS-CoV-2 main protease (Mpro) from the known DrugBank database version 5.1.8. We applied structure-based virtual screening of the database containing 11875 numbers of drug candidates to identify potential hits for SARS-CoV-2 Mpro inhibitors. Seven potential inhibitors having admirable XP glide score ranging from -15.071 to -8.704 kcal/mol and good binding affinity with the active sites amino acids of Mpro were identified. The selected hits were further analyzed with 50 ns molecular dynamics (MD) simulation to examine the stability of protein-ligand complexes. The root mean square deviation and potential energy plot indicates the stability of the complexes during the 50 ns MD simulation. The MM-GBSA analysis also showed good binding energy of the selected hits (-83.2718 to -58.6618 kcal/mol). Further analysis revealed critical hydrogen bonds and hydrophobic interactions between compounds and the target protein. The compounds bind to biologically important regions of Mpro, indicating their potential to inhibit the functionality of this component.

Structure-Based Virtual Screening and Molecular Dynamics Simulation to Identify Potential SARS-CoV-2 Spike Receptor Inhibitors from Natural Compound Database.

The outbreak of respiratory disease, COVID-19 caused by SARS-CoV-2 has now been spread globally and the number of new infections is rising every moment. There are no specific medications that are currently available to combat the disease. The spike receptor of SARS-CoV-2 facilitates the viral entry into a host cell and initiation of infection. Targeting the viral entry at the initial stage has a better advantage than inhibiting it in later stages of the viral life cycle. This study deals with identification of the potential natural molecule or its derivatives from MolPort Databank as SARS-CoV-2 spike receptor inhibitors using structure-based virtual screening followed by molecular dynamics simulation. On the basis of ADME properties, docking score, MMGBSAbinding energy, 150 ns molecular docking studies, and final molecular dynamics analysis, two natural compounds - 3 (MolPort-002-535-004) docking score -9.10 kcal mol-1 and 4 (MolPort-005-910-183) docking score -8.5 kcal mol-1, are selected as potential in-silico spike receptor inhibitors. Both hits are commercially available and can be further used for in-vitro and in-vivo studies. Findings of this study can facilitate rational drug design against SARS-CoV-2 spike receptor.

Bis-indolylation of aldehydes and ketones using silica-supported FeCl3: molecular docking studies of bisindoles by targeting SARS-CoV-2 main protease binding sites.

We report herein an operationally simple, efficient and versatile procedure for the synthesis of bis-indolylmethanes via the reaction of indoles with aldehydes or ketones in the presence of silica-supported ferric chloride under grindstone conditions. The prepared supported catalyst was characterized by SEM and EDX spectroscopy. The present protocol has several advantages such as shorter reaction time, high yield, avoidance of using harmful organic solvents during the reaction and tolerance of a wide range of functional groups. Molecular docking studies targeted toward the binding site of SARS-CoV-2 main protease (3CLpro or Mpro) enzymes were investigated with the synthesized bis-indoles. Our study revealed that some of the synthesized compounds have potentiality to inhibit the SARS-CoV-2 Mpro enzyme by interacting with key amino acid residues of the active sites via hydrophobic as well as hydrogen bonding interactions.