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.

Structure-based drug design-guided identification of estrogen receptor binders.

Cancer is one of the life-threatening diseases and the second leading cause of death in the world. The estrogen receptor can be considered as one of the significant drug targets for cancer. A large number of clinically used anticancer drugs were identified from phytochemicals. Multiple literatures suggested that extracts of Datura sp. significantly inhibit estrogen receptors associated with human cancer. In the present study, all reported natural products present in Datura sp. were subjected to molecular docking against estrogen receptors. The top hits were shortlisted based on binding orientation and docking score and subjected to molecular dynamics simulation to explore the conformational stability followed by binding energy calculation. The ligand [(1S,5R)-8-Methyl-8-Azabicyclo [3.2.1] Octan-3-yl] (2R)-3-Hydroxy-2-Phenylpropanoate depicts highly acceptable MD simulations outcomes and drug-likeness profile. Knowledge-based de novo design and similar ligand screening were executed using the structural information. The designed ligand DL-50 exhibited satisfactory binding, drug-likeness profile, and well-accepted ADMET profile followed by easy synthetic accessibility which further requires experimental validation.

A Review on Artificial Intelligence Approaches and Rational Approaches in Drug Discovery.

Artificial intelligence (AI) speeds up the drug development process and reduces its time, as well as the cost which is of enormous importance in outbreaks such as COVID-19. It uses a set of machine learning algorithms that collects the available data from resources, categorises, processes and develops novel learning methodologies. Virtual screening is a successful application of AI, which is used in screening huge drug-like databases and filtering to a small number of compounds. The brain's thinking of AI is its neural networking which uses techniques such as Convoluted Neural Network (CNN), Recursive Neural Network (RNN) or Generative Adversial Neural Network (GANN). The application ranges from small molecule drug discovery to the development of vaccines. In the present review article, we discussed various techniques of drug design, structure and ligand-based, pharmacokinetics and toxicity prediction using AI. The rapid phase of discovery is the need of the hour and AI is a targeted approach to achieve this.

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.

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.

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.

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.

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.

Anti-inflammatory Potential of GSK-3 Inhibitors.

Glycogen synthase kinase-3 (GSK-3) is a protein kinase containing threonine or serine amino acid residues. GSK-3 was first discovered in 1980 as a regulatory protein kinase, Glycogen synthase (GS) enzyme, which is responsible for the conversion of glycogen from glucose with the help of uridine diphosphate glucose (UDP-Glu) residue. GSK-3 has two isoforms present in human beings, namely GSK-3 α (serine residue at 21 position) and GSK-3 ß (serine residue at 9 position). GSK-3 has two terminals, namely C- terminal and N- terminal. C-terminal of GSK-3 resembles α- helix conformation, which acts as an activator loop and is responsible for positioning residues in ATP binding and catalysis of substrates. On the other hand, the N- terminal of GSK-3 resembles ß- strand conformation, which acts as an inhibitory loop; having a tyrosine molecule at 216 positions, it is essential for the complete GSK-3 activity. N- terminal of GSK-3 is responsible for ATP binding activity and exhibits various biological activities like cell signaling, gene induction following activation of T cell receptor, apoptosis, protein translation, glycogen metabolism, and inflammatory process. Activation of GSK-3 leads to pro-inflammatory actions, i.e. an increase in the binding activity of NF-kB (pro-inflammatory genes), increase in the transactivation activity of NF-kB, increase in the phosphorylation of p105, and a decrease in the transactivation activity of C/EBPß (anti- inflammatory genes), resulting in a large number of prevalent diseases such as diabetes, cancer, neurodegenerative diseases, psychiatric diseases, mood disorders, etc. Glycogen synthase kinase inhibitors (GSK-3 inhibitors) are various chemotypes and have different mechanisms of actions. They are obtained from different sources such as natural products, synthetic ATP as well as non-ATP competitive inhibitors along with substrate-competitive inhibitors. The inhibitors of GSK3 have proven to possess very potent anti-inflammatory action. GSK-3 inhibitors are useful for treating different prevalent disorders, such as neurodegenerative diseases, including Alzheimer's disease, hyperglycemia, cancer disease, and mood disorders like depression, etc. In this review, we have highlighted the evidence regarding the description and types of GSK, inflammation process, and the factors affecting inflammation, the relationship between inflammation and GSK, GSK3 inhibitors, and finally, the impact of various natural as well as synthetic GSK3 inhibitors having anti-inflammatory activity.

In silico analysis and identification of promising hits against 2019 novel coronavirus 3C-like main protease enzyme.

The recent outbreak of the 2019 novel coronavirus disease (COVID-19) has been proved as a global threat. No particular drug or vaccine has not yet been discovered which may act specifically against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and causes COVID-19. For this highly infectious virus, 3CL-like main protease (3CLpro) plays a key role in the virus life cycle and can be considered as a pivotal drug target. Structure-based virtual screening of DrugBank database resulted in 20 hits against 3CLpro. Atomistic 100 ns molecular dynamics of five top hits and binding energy calculation analyses were performed for main protease-hit complexes. Among the top five hits, Nafarelin and Icatibant affirmed the binding energy (g_MMPBSA) of -712.94 kJ/mol and -851.74 kJ/mol, respectively. Based on binding energy and stability of protein-ligand complex; the present work reports these two drug-like hits against SARS-CoV-2 main protease.Communicated by Ramaswamy H. Sarma.

Retinopathy of prematurity in a level II neonatal care unit of a district of West Bengal: A retrospective analysis of 5 years.

Retinopathy of prematurity (ROP), particularly severe ROP is a health concern. The study is aimed to ascertain the magnitude, profile, and outcome of ROP over 5 years at a level II neonatal unit in a district of West Bengal. From 2012 to 2016, a total of 691 newborns with birth weight (BW) <2000 g and/or gestational age < 35 weeks of a district level II neonatal care unit were screened for ROP. Retrospective analysis of these screened babies was performed using the principles of descriptive and inferential statistics. Overall, 38.5% of newborns had any stage ROP and13.2% severe ROP. Two-thirds of babies with severe ROP were <1250 g of BW. About 16.2% of the ROP cases suffered from aggressive posterior ROP (APROP). Oxygen and prematurity were found as significant risk factors. Substantially high occurrence of severe ROP and APROP warrants appropriate measures. Timely screening and intervention with referral to the neonatal ROP unit can improve the scenario.

In silico design, synthesis and activity of potential drug-like chrysin scaffold-derived selective EGFR inhibitors as anticancer agents.

BACKGROUND & OBJECTIVE: Epidermal growth factor receptor (EGFR) signaling pathway is one of the promising and well-established targets for anticancer therapy. The objective of the present study was to identify new EGFR inhibitors using ligand and structure-based drug designing methods, followed by a synthesis of selected inhibitors and evaluation of their activity. METHODS: A series of C-7-hydroxyproton substituted chrysin derivatives were virtually drawn to generate a small compound library that was screened using 3D QSAR model created from forty-two known EGFR tyrosine kinase inhibitors. Next, the obtained hits with fitness score ≥ 1.0 were subjected to molecular docking analysis. Based on the predicted activity and XP glide score, three EGFR inhibitors were synthesized and characterized using 1H-NMR, 13C-NMR and MS. Finally, comparative in vitro investigation of the biological activity of synthesized inhibitors was performed with that of the parent molecule, chrysin. RESULTS: The data depicted a 3.2-fold enhanced cytotoxicity of chrysin derivative, CHM-04 against breast cancer cells as compared with chrysin as well as its binding with EGFR protein. Furthermore, the biological activity of CHM-04 was comparable to the standard EGFR inhibitor, AG1478 in increasing apoptosis and decreasing the migratory potential of triple-negative breast cancer cells as well as significantly lowering the mammosphere forming ability of breast cancer stem cells. CONCLUSION: The present study suggests CHM-04, an EGFR inhibitor possessing drug-like properties as a plausible therapeutic candidate against breast cancer.

Using complex networks towards information retrieval and diagnostics in multidimensional imaging.

We present a fresh and broad yet simple approach towards information retrieval in general and diagnostics in particular by applying the theory of complex networks on multidimensional, dynamic images. We demonstrate a successful use of our method with the time series generated from high content thermal imaging videos of patients suffering from the aqueous deficient dry eye (ADDE) disease. Remarkably, network analyses of thermal imaging time series of contact lens users and patients upon whom Laser-Assisted in situ Keratomileusis (Lasik) surgery has been conducted, exhibit pronounced similarity with results obtained from ADDE patients. We also propose a general framework for the transformation of multidimensional images to networks for futuristic biometry. Our approach is general and scalable to other fluctuation-based devices where network parameters derived from fluctuations, act as effective discriminators and diagnostic markers.

Three-dimensional quantitative structure-activity relationships and docking studies of some structurally diverse flavonoids and design of new aldose reductase inhibitors.

Aldose reductase (AR) plays an important role in the development of several long-term diabetic complications. Inhibition of AR activities is a strategy for controlling complications arising from chronic diabetes. Several AR inhibitors have been reported in the literature. Flavonoid type compounds are shown to have significant AR inhibition. The objective of this study was to perform a computational work to get an idea about structural insight of flavonoid type compounds for developing as well as for searching new flavonoid based AR inhibitors. The data-set comprising 68 flavones along with their pIC50 values ranging from 0.44 to 4.59 have been collected from literature. Structure of all the flavonoids were drawn in Chembiodraw Ultra 11.0, converted into corresponding three-dimensional structure, saved as mole file and then imported to maestro project table. Imported ligands were prepared using LigPrep option of maestro 9.6 version. Three-dimensional quantitative structure-activity relationships and docking studies were performed with appropriate options of maestro 9.6 version installed in HP Z820 workstation with CentOS 6.3 (Linux). A model with partial least squares factor 5, standard deviation 0.2482, R(2) = 0.9502 and variance ratio of regression 122 has been found as the best statistical model.

Intracorneal rhinosporidiosis managed with deep anterior lamellar keratoplasty.

A healthy 22-year-old male presented to Institutional Cornea Clinic with an intracorneal mass overlying the pupil with lobulated edges having many tiny greyish white dots. The patient had a history of trauma while swimming in a pond with subsequent removal of intracorneal foreign body in the left eye approximately a year prior to presentation. Anterior segment optical coherence tomography (OCT) confirmed that an intracorneal mass sparing deep stroma and Descemet's membrane. A deep anterior lamellar keratoplasty (DALK) was performed in left eye and the mass was sent for histology examination. Histology evaluation was suggestive of rhinosporidiosis. The patient achieved 20/60 BCVA with -1.25 Χ× 120° 1 year postoperatively without any evidence of recurrence at the graft-host interface. This unique presentation (as an 'intracorneal mass') of ocular rhinosporidiosis emphasizes that clinicians from our region of the world must consider rhinosporidiosis in the differential diagnosis especially with a history of penetrating injury while swimming in pond or river water.

Comparison of autologous in situ blood coagulum versus sutures for conjunctival autografting after pterygium excision.

Our aim was to compare the efficacy and safety of autologous in-situ blood coagulum versus sutures for attaching conjunctival limbal autografts (CAG) among patients undergoing primary pterygium excision over a period of 1 year. Thirty-two eyes of 32 patients with primary pterygium were randomly divided in into two groups: group I (16 eyes) underwent CAG with 10-0 monofilament nylon sutures and group II (16 eyes) underwent CAG with patient's own in-situ blood coagulum acting as bioadhesive or fixative followed by bandaging for 48 h. Patients were followed up postoperatively on the 2nd day, 1 week, 2 weeks, 4 weeks, and 12 months. All the surgeries were done by the same surgeon. Graft success, recurrence rate, operating time, patient comfort, graft retraction or any other complication were studied. The duration of surgery was significantly less (P < 0.001) in group II (mean duration 15 ± 2 min) than group I (mean duration 67 ± 2 min). Postoperative symptoms were fewer for group II than group I. Rate of recurrence was equal in both groups (one patient in each group, 6.25 %). But complications regarding graft failure and graft retraction were more common in group II (two patients, 12.5 %) than group I (one patient, 6.25 %); however, the difference was not statistically significant (Z = 0.61). Thus, autologous in-situ blood coagulum is a useful method for graft fixation in pterygium surgery with shorter operating time and less postoperative discomfort.

Pharmacophore modeling and 3D quantitative structure-activity relationship analysis of febrifugine analogues as potent antimalarial agent.

Febrifugine and its derivatives are effective against Plasmodium falciparum. Using PHASE algorithm, a five-point pharmacophore model with two hydrogen bond acceptor (A), one positively ionizable (P) and two aromatic rings (R), was developed to derive a predictive ligand-based statistically significant 3D-quantitative structure-activity relationship (QSAR) model (r(2) = 0.972, SD = 0.3, F = 173.4, Q(2) = 0.712, RMSE = 0.3, Person-R = 0.94, and r(2) pred = 0.8) to explicate the structural attributes crucial for antimalarial activity. The developed pharmacophore model and 3D QSAR model can be a substantial tool for virtual screening and related antimalarial drug discovery research.

A new alkaloid isolated from Abies webbiana leaf.

A new alkaloid namely 1-(4'-methoxyphenyl)-aziridine was isolated from the leaf of Abies webbiana Lindl. (Pinaceae), grown in Sikkim Himalayan region of India. Its chemical structure was elucidated on the basis of elemental and spectral analyses. This is the first experimental report of the isolation of any alkaloid from A. webbiana.