Decoding dynamic interactions between EGFR-TKD and DAC through computational and experimental approaches: A novel breakthrough in lung melanoma treatment.

In the quest for effective lung cancer treatments, the potential of 3,6-diaminoacridine-9-carbonitrile (DAC) has emerged as a game changer. While DAC's efficacy against glioblastoma is well documented, its role in combating lung cancer has remained largely untapped. This study focuses on CTX-1, exploring its interaction with the pivotal EGFR-TKD protein, a crucial target in lung cancer therapeutics. A meticulous molecular docking analysis revealed that CTX-1 exhibits a noteworthy binding affinity of -7.9 kcal/mol, challenging Erlotinib, a conventional lung cancer medication, which displayed a binding affinity of -7.3 kcal/mol. For a deeper understanding of CTX-1's molecular mechanics, this study employed rigorous 100-ns molecular dynamics simulations, demonstrating CTX-1's remarkable stability in comparison with erlotinib. The Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) method further corroborated these results, with CTX-1 showing a free binding energy of -105.976 ± 1.916 kJ/mol. The true prowess of CTX-1 was tested against diverse lung cancer cell lines, including A549, Hop-62 and H-1299. CTX-1 not only significantly outperformed erlotinib in anticancer activity but also exhibited a spectrum of therapeutic effects. It effectively diminished cancer cell viability, induced DNA damage, halted cell cycle progression, generated reactive oxygen species (ROS), impaired mitochondrial transmembrane potential, instigated apoptosis and successfully inhibited EGFR-TKD. This study not only underscores the potential of CTX-1 a formidable contender in lung cancer treatment but also marks a paradigm shift in oncological therapeutics, offering new horizons in the fight against this formidable disease.

An exploration of the binding prediction of anatoxin-a and atropine to acetylcholinesterase enzyme using multi-level computer simulations.

Acetylcholinesterase (AChE) is crucial for the breakdown of acetylcholine to acetate and choline, while the inhibition of AChE by anatoxin-a (ATX-a) results in severe health complications. This study explores the structural characteristics of ATX-a and its interactions with AChE, comparing to the reference molecule atropine for binding mechanisms. Molecular docking simulations reveal strong binding affinity of both ATX-a and atropine to AChE, interacting effectively with specific amino acids in the binding site as potential inhibitors. Quantitative assessment using the MM-PBSA method demonstrates a significantly negative binding free energy of -81.659 kJ mol-1for ATX-a, indicating robust binding, while atropine exhibits a stronger binding affinity with a free energy of -127.565 kJ mol-1. Umbrella sampling calculates the ΔGbindvalues to evaluate binding free energies, showing a favorable ΔGbindof -36.432 kJ mol-1for ATX-a and a slightly lower value of -30.12 kJ mol-1for atropine. This study reveals the dual functionality of ATX-a, acting as both a nicotinic acetylcholine receptor agonist and an AChE inhibitor. Remarkably, stable complexes form between ATX-a and atropine with AChE at its active site, exhibiting remarkable binding free energies. These findings provide valuable insights into the potential use of ATX-a and atropine as promising candidates for modulating AChE activity.

Bioinspired thiazolo-[2,3-b] quinazolin-6-one derivatives as potent anti-cancer agents targeting EGFR: their biological evaluations and in silico assessment.

Cancer is a challenging and second most deadly disease. The epidermal growth factor receptors (EGFRs) dimerize upon ligand bindings to the extracellular domain that intiates the downstream signaling cascades and activates intracellular kinase domain. Thus, activation of autophosphrylation through kinase domain results in metastasis, cell proliferation, and angiogenesis. In this study, we unravel the binding mechanism of newly synthesized thiazolo-[2,3-b] quinazolin-6-one and evaluate their anti-cancer activity against ovary and prostate carcinoma cell lines (OVCAR-3 and PC-3). Synthesized molecules exhibited promising anti-cancer activity against OVCAR-3 and PC-3 carcinoma cell lines with inhibitory concentrations ranging from 13.4 ± 0.43 to 23.6 ± 1.22 µM and 7.5 ± 0.62 to 67.5 ± 1.24 µM, respectively. These compounds induced apoptosis and resulted in cell cycle arrest at G1 and G2/M transition phases. Next, the nude mice models were taken to investigate the toxicity of the 4bi compound, and in vivo investigations revealed no effects upon examined organs (liver and kidney) treated at different concentrations. Moreover, the combined in silico approaches, molecular docking, molecular dynamics simulations, and MM/PBSA methods were performed to assess the binding affinity and stability of bioinspired synthesized congeners with the epidermal growth factor receptor tyrosine kinase (EGFR-TK). The free binding energy (ΔGbind) of the 4bi molecule was found comparable to Erlotinib drug. The test molecule could be competent for further usage to determine its efficicacy in cancer therapeutics.

Genome resequencing and genome-wide polymorphisms in mosquito vectors Aedes aegypti and Aedes albopictus from south India.

Aedes aegypti and Aedes albopictus mosquitoes spread major vector-borne viral diseases in tropical and sub-tropical regions of the globe. In this study, we sequenced the genome of Indian Ae. aegypti and Ae. albopictus and mapped to their reference genomes. Comparative genomics were performed between our strain and the reference strains. A total of 14,416,484 single nucleotide polymorphisms (SNPs) and 156,487 insertions and deletions (InDels) were found in Ae. aegypti, and 28,940,433 SNPs and 188,987 InDels in Ae. albopictus. Particular emphasis was given to gene families involved in mosquito digestion, development, and innate immunity, which could be putative candidates for vector control. Serine protease cascades and their inhibitors called serpins, play a central role in these processes. We extracted high-impact variants in genes associated with serine proteases and serpins. This study reports for the first time a high coverage genome sequence data of an Indian Ae. albopictus mosquito. The results from this study will provide insights into Indian Aedes specific polymorphisms and the evolution of immune related genes in mosquitoes, which can serve as a resource for future comparative genomics and those pursuing the development of targeted biopesticides for effective mosquito control strategies.

Exploring KRas Protein Dynamics: An Integrated Molecular Dynamics Analysis of KRas Wild and Mutant Variants.

This study employs a comprehensive approach combining protein retrieval, sequence alignment, and molecular dynamics simulations to investigate the structural dynamics and stability of wild-type KRas and its mutated variants (G12C, G12D, G12V, and G13D). The selected protein structures were retrieved from the Protein Data Bank (PDB) and prepared by using visual molecular dynamics (VMD) software. Sequence alignment using Clustal Omega provided a detailed comparison of the amino acid sequences, focusing on key mutation sites. Molecular dynamics simulations, performed with Gromacs, revealed distinct conformational changes and stability patterns in the wild-type and mutated KRas proteins over 100 ns. Clustering analysis identified higher conformational changes in the second α-helix of the mutated variants. The root-mean-square deviation (RMSD) distribution analysis showed variant-specific conformational dynamics, with G12V and G12D exhibiting slightly higher average RMSD values. Furthermore, clustering and RMSD analyses of specific amino acid residues (12, 13, 51, and 118) highlighted their roles in maintaining overall stability and influencing structural dynamics. The results indicate that mutations at positions 12 and 13 disrupt normal cycling between wild and mutated variants, leading to the persistent activation of KRas. Additionally, principal component analysis (PCA) elucidated unique conformational dynamics in mutated variants. Free energy landscape (FEL) analysis revealed alterations in the thermodynamic stability of mutated variants compared with the wild type. Overall, this study provides a detailed understanding of the structural changes associated with oncogenic mutations in KRas, offering insights crucial for targeted therapeutic strategies in KRas-driven cancers.

Design, synthesis, molecular modeling, and biological evaluations of novel chalcone based 4-Nitroacetophenone derivatives as potent anticancer agents targeting EGFR-TKD.

A series of chalcone-based 4-Nitroacetophenone derivatives were designed and synthesized by the single-step condensation method. These compounds were identified by 1H NMR,13C NMR, MS, and FTIR analysis. Further, the derivatives were evaluated against four cancer cell lines H1299, MCF-7, HepG2, and K526. The IC50 value of potent compounds NCH-2, NCH-4, NCH-5, NCH-6, NCH-8, and NCH-10 was 4.5-11.4 µM in H1299, 4.3-15.7 µM in MCF-7, 2.7-4.1 µM in HepG2 and 4.9-19.7 µM in K562. To assess the toxicity against healthy cells all potent molecules were evaluated against the HEK-293T cell line, and IC50 values exhibited by NCH-2, and NCH-3 were 77.8, 74.3, and other molecules showed IC50 values > 100 µM. The EGFR expression was determined by using rabbit anti-EGFR monoclonal antibody and significant EGFR expression was knocked down observed in H1299 treated with NCH-10 as well as erlotinib. The underlying mechanism behind cell death was investigated through bioinformatics. First, the molecules were optimized and docked to the binding site of the EGFR kinase domain. The best complexes were simulated for 100-ns and compounds NCH-2, NCH-4, and NCH-10 achieved stability similar to the erlotinib bound kinase domain. The free energy binding (ΔGbind) of NCH-10 was found to be more negative -226.616 ± 2.148 kJ/mol calculated by Molecular Mechanics Poisson Boltzmann's Surface Area (MM-PBSA) method. Both in vitro and in silico results conclude that the present class of chalcone-based 4-Nitroacetophenone derivatives are potent anti-cancer agents targeting EGFR-TKD and are 39 folds more effective against H1299, MCF-7, HepG2, and K562 carcinoma cell lines than healthy HEK-293T cell lines.Communicated by Ramaswamy H. Sarma.

Prevalence of Chronic Kidney Disease and its Association with Pesticide Exposure in Bargarh District, Odisha, India.

Background: Bargarh, a district in Odisha, is known for intense agricultural activities because of uninterrupted irrigation from the Hirakud reservoir. The number of chronic kidney disease (CKD) cases in the district is increasing rapidly. The present study assesses the prevalence of CKD and CKDu (of unknown etiology) in the district and its association with pesticide application. Materials and Methods: A door-to-door survey was conducted to find out the CKD hotspots in the different blocks of the district with the help of primary and community health centers. The prevalence of CKD in the identified hotspot villages was assessed using a random clustered sampling method along with the collection of data related to age, sex, occupation and source of drinking water. Soil and water samples collected from identified hotspot and nonhotspot villages were analyzed to assess the presence of nephrotoxic pesticide residues. Results: A total of 16 villages were identified with high CKD prevalence rates and designated as hotspot villages. Data indicate that about 21% of males under ≥ 40 years age group were found to be suffering from CKD. Cases of CKDu (85%) were more prominent in these hotspot villages. Analysis of soil and water samples demonstrated the presence of seven different nephrotoxic pesticides above the maximum residues levels (MRLs) in hotspot villages compared to nonhotspot villages. Conclusion: The presence of nephrotoxic pesticides above MRLs in the hotspot villages indicates their possible association with the onset and progression of CKD among the exposed population. Further research is needed to establish their causative association with CKDu in the study region.

Exploring binding stability of hydroxy-3-(4-hydroxyphenyl)-5-(4-nitrophenyl)-5,5a,7,8,9,9a-hexahydrothiazolo[2,3-b] quinazolin-6-one with T790M/L858R EGFR-TKD.

Cancer causes innumerable deaths every year globally. Breast cancer and non-small cell lung carcinoma are the most prevalent worldwide. EGFR-TKD is a neoplastic survival therapeutic target in a wide array of carcinoma cells. Various non-specific tyrosine kinase inhibitors lead to hyperphosphorylation and overexpression of EGFR-TKD and further mutations recognise deletion of exon 19. In this work, we study the binding affinity, binding stability, and strength of hydroxy-3-(4-hydroxyphenyl)-5-(4-nitrophenyl)-5,5a,7,8,9,9a-hexahydrothiazolo[2,3-b] quinazolin-6-one with TMLR mutated EGFR-TKD (T790M/L858R). The collective motions, residual mobility, and flexibility of TMLR mutated EGFR-TKD bound with reference and title molecule were calculated by principal component analysis. The meta-state conformations of both the simulated complexes were determined by Gibb's energy landscape analysis. The binding affinity exhibited by thiazolo-[2,3-b] quinazolinone and the reference molecule was found to be -7.95 ± 0.088 Kcal/mol and -9.13 ± 0.018 kcal/mol with TMLR mutated EGFR-TKD. The alignment of both the docked complexes was done by blosum40 matrix. Similar spatial orientations were exhibited by the synthesised ligand in the binding pocket of TMLR mutated EGFR-TKD, corresponding to the reference ligand. The ligand stability was computed for 100 ns. In addition, the radius of gyration, solvent accessible surface area, hydrogen bonds formed was calculated. The average ΔGbind of thiazolo-[2,3-b] quinazolinone was -41.212 ± 0.834 kJ/mol and for reference ligand -71.938 ± 0.367 kJ/mol, calculated by MM-PBSA. ADMET analysis concludes thiazolo-[2,3-b] quinazolinone derivative is safe. Further research work is encouraged to determine the efficacy of thiazolo-[2,3-b] quinazolinone against in vivo models.Communicated by Ramaswamy H. Sarma.

Molecular modeling and simulations of some antiviral drugs, benzylisoquinoline alkaloid, and coumarin molecules to investigate the effects on Mpro main viral protease inhibition.

Background: SARS-CoV-2 is a deadly viral disease and uncounted deaths occurs since its first appearance in the year 2019. The antiviral drugs, benzylisoquinoline alkaloids, and coumarin molecules were searched using different online engines for drug repurposing with SARS-CoV-2 and to investigate the effects on main viral protease (Mpro) upon their bindings. Methods: A database composed of antiviral drugs, benzylisoquinoline alkaloids, and Coumarin molecules was screened through a molecular docking strategy to uncover the interactions of collected molecules with SARS-CoV-2 Mpro. Further, molecular dynamics simulations (MDS) were implemented for 100 ns to calculate the stability of the best complexed molecular scaffold with Mpro. The conformations of the simulated complexes were investigated by using principal component analysis (PCA) and Gibbs energy landscape (FEL) and DSSP together. Next, free binding energy (ΔGbind) was calculated using the mmpbsa method. Results: Molecular docking simulations demonstrate 17 molecules exhibited better binding affinity out of 99 molecules present in the database with the viral protease Mpro, followed ADMET properties and were documented. The Coumarin-EM04 molecular scaffold exhibited interactions with catalytical dyad HIS41, CYS145, and neighboring amino acids SER165 and GLN189 in the catalytical site. The crucial factor RMSD was calculated to determine the orientations of Coumarin-EM04. The Coumarin-EM04 complexed with Mpro was found stable in the binding site during MDS. Furthermore, the free energy binding ΔGbind of Coumarin-EM04 was found to be -187.471 ± 2.230 kJ/mol, and for Remdesivir ΔGbind was -171.926 ± 2.237 kJ/mol with SARS-CoV-2 Mpro. Conclusion: In this study, we identify potent molecules that exhibit interactions with catalytical dyad HIS41 and CYS145 amino acids and unravel Coumarin-EM04 exhibited ΔGbind higher than Remdesivir against Mpro and thus may serve better antiviral agent against SARS-CoV-2.

Identification of anti-cyanobacterial leads targeting carbonic anhydrase from phytochemical database using in silico approach.

In cyanobacteria, carbonic anhydrase (zinc metalloenzyme) is a major enzyme that converts CO2 to HCO3- maintaining the carbon concentration around the vicinity of RuBisCo, leading to cyanobacterial biomass generation. Anthropogenic activities, disposal of leached micro nutrients effluents from industries into the aquatic environment results in cyanobacterial blooms. The harmful cyanobacteria release cyanotoxins in open-water system which on ingression through oral route causes major health issues like hepatotoxicity and immunotoxicity. A database was prepared consisting of approximately 3k phytochemicals curated from previous literatures, earlier identified by GC-MS analysis. The phytochemicals were subjected to online servers to identify the novel lead molecules which followed ADMET and drug-like candidates. The identified leads were optimized by density functional theory method using B3YLP/G* level of theory. Carbonic anhydrase chosen as target to observe the binding interaction through molecular docking simulations. From the molecules included in the database the highest binding energy exhibited by alpha-tocopherol succinate and mycophenolic acid were found to be -9.23 kcal/mol and -14.41 kcal/mol and displayed interactions with GLY A102, GLN B30, ASP A41, LYS A105 including Zn2+ and their adjacent amino acids CYS 101, HIS 98, CYS 39 in both chain A and chain A-B of carbonic anhydrase. The Identified molecular orbitals decipher computed global electrophilicity values (Energy gap, electrophilicity and Softness) of alpha-tocopherol succinate and mycophenolic acid were found to be (5.262, 1.948, 0.380) eV and (4.710, 2.805, 0.424) eV demonstrates both molecules are effective and stable. The identified leads may serve as a better anti-carbonic anhydrase agent because they accommodate in the binding site and hampers the catalytic activity of Carbonic anhydrase thus inhibiting the generation of cyanobacterial biomass. This identified lead molecules may serve as a substructure to design novel phytochemicals against carbonic anhydrase present in cyanobacteria. Further in vitro study is necessary to evaluate the efficacy of these molecules.

An exploration of binding of Hesperidin, Rutin, and Thymoquinone to acetylcholinesterase enzyme using multi-level computational approaches.

Alzheimer's disease, an intricate neurological disorder, is impacting an ever-increasing number of individuals globally, particularly among the aging population. For several decades phytochemicals were used as Ayurveda to treat both communicable and non-communicable diseases. Acetylcholinesterase (AChE) is a widely chosen therapeutic target for the development of early prevention and effective management of neurodegenerative diseases. The primary objective of the present study was to investigate the binding potential between Rutin Thymoquinone, Hesperidin and the FDA-approved drug Donepezil with AChE. Additionally, a comparative analysis was conducted. These phytochemicals were docked with the binding site of the AChE experimental complex. The molecular dockings demonstrated that the Hesperidinh showed a better binding affinity of -22.0631 kcal/mol. The ADME/T investigations revealed that the selected phytochemicals are non-toxic and drug-like candidates. Molecular dynamics simulations were implemented to determine the conformational changes of Rutin, hesperidin, Thymoquinone, and Donepezil complexed with AChE. Hesperidin and Donepezil were more stable than Rutin, Thymoquinone complexed with AChE. Next, essential dynamics and defining the secondary structure of protein were to determine the conformational changes in AChE complexed with selected phytochemicals during simulations. Overall, the MD Simulations demonstrated that all complexes in this study achieved stability until 100 ns of the simulation period was performed thrice. The structural analysis of AChE was done using multiple search engines to explore the molecular functions, biological processes, and pathways in which AChE proteins are involved and to identify potential drug targets for various diseases. This present study concludes that Hesperidin was found to be a more potent AChE inhibitors than Rutin, and further experiments are required to determine the effectivity of Hesperidin against neurodegenerative diseases.Communicated by Ramaswamy H. Sarma.

Phytochemical profiling, in vitro analysis for anti-inflammatory, immunomodulatory activities, structural elucidation and in silico evaluation of potential selective COX-2 and TNF-α inhibitor from Hydrilla verticillata (L.f.) Royle.

Hydrilla verticillata (L.f.) Royle is a perennial aquatic plant, which exhibits nutritional as well as therapeutic properties. The present study has been carried out to evaluate anti-inflammatory and immunomodulatory activities along with in silico evaluation of potential selective COX-2 and TNF-α inhibitors from methanolic extract of H. verticillata (L.f.) Royle. The potential therapeutic compounds have been identified by high-resolution GC-MS analysis. Its capacity to inhibit inflammatory responses using lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophage cells has been explored. The anti-inflammatory properties of the plant extract were investigated by inhibiting inducible nitric oxide (NO) synthase and reduced NO generation driven by LPS on stimulated RAW 264.7 macrophage cells. Further investigation for the underlying molecular mechanism of the anti-inflammatory activity of plant extract has been carried out by molecular docking and molecular dynamics simulation approaches with COX-2 and TNF-α inhibitors ability against the most potent phytocompound phytol from the plant extract. To evaluate whether the extract causes any toxicity, the cytotoxicity test has been carried out with the Human embryonic kidney cell line (Hek-293), Mouse fibroblast (L929), human mesenchyme stem cells (hMSCs) and human breast epithelial cell line (MCF-10a). Ultimately, our findings suggest that the plant extract have great potential to reduce inflammation without causing any toxicity to normal cell.Communicated by Ramaswamy H. Sarma.

Identification of potent EGFR-TKD inhibitors from NPACT database through combined computational approaches.

Cancer is the world's second leading cause of death, and there are no approved herbal therapies. The epidermal growth factor receptor tyrosine kinase (EGFR-TK) receptor is a transmembrane protein with eight domains that is found in almost every cancer type and plays an important role in abnormal cell cellular function and causes malignant outcomes. The current study aimed to virtually screen phytochemicals from the NPACT database against EGFR-TKD and also to identify potential inhibitors of this transmembrane protein among plant candidates for anticancer drug development. The docking scores of the chosen phytochemicals were compared with the control (erlotinib). Kurarinone, (2S)-2-methoxykurarnione, and Sophoraflavanone-G exhibited a stronger binding affinity of -18.102 kcal/mol, -14.243 kcal/mol, and -13.759 kcal/mol than erlotinib -12.783 kcal/mol. Moreover, several online search engines were used to predict ADME and toxicity. The drug-likeness of selected phytochemicals was higher than the reference (erlotinib). A 100 ns molecular dynamic (MD) simulation was also applied to the docked conformations to examine the stability and molecular mechanics of protein-ligand interactions. Furthermore, the calculated molecular mechanics Poisson Boltzmann surface area energy of (2S)-2-methoxykurarnione was found to be -129.555 ± 0.512 kJ/mol, which approximately corresponds to the free energy of the reference molecule -130.595 ± 0.908 kJ/mol. We identify phytoconstituents present in Sophora flavescens from the NPACT database, providing key insights into tyrosine kinase inhibition and may serve as better chemotherapeutic agents. Experimental validation is required to determine the anti-EGFR potency of the potent lead molecules discussed in this study.Communicated by Ramaswamy H. Sarma.

Novel computational and drug design strategies for inhibition of monkeypox virus and Babesia microti: molecular docking, molecular dynamic simulation and drug design approach by natural compounds.

Background: The alarming increase in tick-borne pathogens such as human Babesia microti is an existential threat to global public health. It is a protozoan parasitic infection transmitted by numerous species of the genus Babesia. Second, monkeypox has recently emerged as a public health crisis, and the virus has spread around the world in the post-COVID-19 period with a very rapid transmission rate. These two novel pathogens are a new concern for human health globally and have become a significant obstacle to the development of modern medicine and the economy of the whole world. Currently, there are no approved drugs for the treatment of this disease. So, this research gap encourages us to find a potential inhibitor from a natural source. Methods and materials: In this study, a series of natural plant-based biomolecules were subjected to in-depth computational investigation to find the most potent inhibitors targeting major pathogenic proteins responsible for the diseases caused by these two pathogens. Results: Among them, most of the selected natural compounds are predicted to bind tightly to the targeted proteins that are crucial for the replication of these novel pathogens. Moreover, all the molecules have outstanding ADMET properties such as high aqueous solubility, a higher human gastrointestinal absorption rate, and a lack of any carcinogenic or hepatotoxic effects; most of them followed Lipinski's rule. Finally, the stability of the compounds was determined by molecular dynamics simulations (MDs) for 100 ns. During MDs, we observed that the mentioned compounds have exceptional stability against selected pathogens. Conclusion: These advanced computational strategies reported that 11 lead compounds, including dieckol and amentoflavone, exhibited high potency, excellent drug-like properties, and no toxicity. These compounds demonstrated strong binding affinities to the target enzymes, especially dieckol, which displayed superior stability during molecular dynamics simulations. The MM/PBSA method confirmed the favorable binding energies of amentoflavone and dieckol. However, further in vitro and in vivo studies are necessary to validate their efficacy. Our research highlights the role of Dieckol and Amentoflavone as promising candidates for inhibiting both monkeypox and Babesia microti, demonstrating their multifaceted roles in the control of these pathogens.

Monte-Carlo method-based QSAR model to discover phytochemical urease inhibitors using SMILES and GRAPH descriptors.

Urease inhibitors are known to play a vital role in the field of medicine as well as agriculture. Special attention is attributed to the development of novel urease inhibitors with a view to treat the Helicobacter pylori infection. Amongst a number of urease inhibitors, a large number of molecules fail in vivo and in clinical trials due to their hydrolytic instability and toxicity profile. The search for potential inhibitors may require screening of large and diverse databases of small molecules and to design novel molecules. We developed a Monte-Carlo method-based QSAR model to predict urease inhibiting potency of molecules using SMILES and GRAPH descriptors on an existing diverse database of urease inhibitors. The QSAR model satisfies all the statistical parameters required for acceptance as a good model. The model is applied to identify urease inhibitors among the wide range of compounds in the phytochemical database, NPACT, as a test case. We combine the ligand-based and structure-based drug discovery methods to improve the accuracy of the prediction. The method predicts pIC50 and estimates docking score of compounds in the database. The method may be applied to any other database or compounds designed in silico to discover novel drugs targeting urease.Communicated by Ramaswamy H. Sarma.

Structural insights into conformational stability and binding of thiazolo-[2,3-b] quinazolinone derivatives with EGFR-TKD and in-vitro study.

Heterocyclic molecules are well-known drugs against various diseases including cancer. Many tyrosine kinase inhibitors including erlotinib, osimertinib, and sunitinib were developed and approved but caused adverse effects among treated patients. Which prevents them from being used as cancer therapeutics. In this study, we strategically developed heterocyclic thiazolo-[2,3-b]quinazolinone derivatives by an organic synthesis approach. These synthesized molecules were assessed against the epidermal growth factor receptor tyrosine kinase domain (EGFR-TKD) by in silico methods. Molecular docking simulations unravel derivative 17 showed better binding energy scores and followed Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) properties. The binding affinity displayed by synthetic congener and reference molecule erlotinib was found to be -8.26 ± 0.0033 kcal/mol and -7.54 ± 0.1411 kcal/mol with the kinase domain. Further, molecular dynamic simulations were conducted thrice to validate the molecular docking study and achieved significant results. Both synthetic derivative and reference molecule attained stability in the active site of the TKD. The synthetic congener and erlotinib showed free energy binding (ΔGbind) -102.975 ± 3.714 kJ/mol and -130.378 ± 0.355 kJ/mol computed by Molecular Mechanics Poison Boltzmann Surface Area (MM-PBSA) method. In addition, the motions of each sampled system including the Apo complex were determined by the principal component analysis and Gibbs energy landscape analysis. The in-vitro apoptosis study was performed using MCF-7 and H-1299 cancer cell lines. However, thiazolo-[2,3-]-quinazoline derivative 17 showed fair anti-proliferative activity against MCF-7 and H-1299. Further, the in-vivo study is necessary to determine the effectivity of the potent anti-proliferative, non-toxic molecule against TKD.

In Silico and In Vitro Evaluations of Fluorophoric Thiazolo-[2,3-b]quinazolinones as Anti-cancer Agents Targeting EGFR-TKD.

Epidermal growth factor receptor tyrosine kinase domain (EGFR-TKD) plays a pivotal role in cellular signaling, growth, and metabolism. The EGFR-TKD is highly expressed in cancer cells and was endorsed as a therapeutic target for cancer management to overcome metastasis, cell proliferation, and angiogenesis. The novel thiazolo-[2,3-b]quinazolinones series were strategically developed by microwave-assisted organic synthesis and multi dominos reactions aimed to identify the potent thiazolo-[2,3-b]quinazolinone inhibitor against EGFR-TKD. This study explores the binding stability and binding strength of newly developed series via molecular docking, molecular dynamics simulation, and MM/PBSA and MM/GBSA calculations. The binding interaction was observed to be through the functional groups on aryl substituents at positions 3 and 5 of the thiazolo-[2, 3-b]quinazolinone scaffold. The methyl substituents at position 8 of the ligands had prominent hydrophobic interactions corroborating their bindings similar to the reference FDA-approved drug erlotinib in the active site. ADMET predictions reveal that derivatives 5ab, 5aq, and 5bq are drug-like and may be effective in in vitro study. Molecular dynamics simulation for 100 ns of docked complexes revealed their stability at the atomistic level. The ΔGbinding of thiazolo-[2,3-b]quinazolinone was found to be 5ab - 22.45, 5aq - 22.23, and 5bq - 20.76 similar to standard drug, and erlotinib - 24.11 kcal/mol was determined by MM/GBSA method. Furthermore, the anti-proliferative activity of leads of thiazolo-[2,3-b]quinazolinones (n = 3) was studied against breast cancer cell line (MCF-7) and non-small lung carcinoma cell line (H-1299). The highest inhibitions in cell proliferation were shown by 5bq derivatives, and the IC50 was found to be 6.5 ± 0.67 µM against MCF-7 and 14.8 µM against H-1299. The noscapine was also taken as a positive control and showed IC50 at higher concentrations 37 ± 1 against MCF-7 and 46.5 ± 1.2 against H-1299.

Cyanobacteria in wetlands of the industrialized Sambalpur District of India.

BACKGROUND: Cyanobacteria are common components of phytoplankton communities in most freshwater ecosystems. Proliferations of cyanobacteria are often caused by high nutrient loading, and as such can serve as indicators of declining water quality. Massive industrialization in developing countries, like India, has polluted fresh water bodies, including wetlands. Many industries directly discard their effluents to nearby water sources without treatment. In the Sambalpur District of India effluents reach the reservoir of the worlds largest earthen dam i.e Hirakud Dam. This study examines cyanobacteria communities in the wetlands of Sambalpur District, Odisha, India, including areas subjected to industrial pollution. RESULT & DISCUSSION: The genera Anabaena, Oscillatoria, Chroococcus, Phormidium were dominant genera of polluted wetlands of Sambalpur districts. A positive correlation was found between total cyanobacterial species and dissolved oxygen levels, but cyanobacterial diversity was inversely related to BOD, COD, TSS, and TDS. High dissolved oxygen content was also associated with regions of lower cyanobacteria biomass. CONCLUSION: Cyanobacterial abundance was positively correlated to content of oxidisable organic matter, but negatively correlated to species diversity. Lower dissolved oxygen was correlated to decreased diversity and increased dominance by Anabaena, Oscillatoria, Chroococcus, Phormidium species, observed in regions characterized by deteriorated water quality.