Computational analysis of bevacizumab binding with protein receptors for its potential anticancer activity.

Breast cancer poses a significant global challenge, prompting researchers to explore novel approaches for potential treatments. In this study, we investigated the binding free energy (ΔG) of bevacizumab, an anti-cancer therapy targeting angiogenesis through the inhibition of vascular endothelial growth factor (VEGF), with various proto-oncogenes including CDK4, EGFR, frizzled, IGFR, OmoMYC, and KIT. Our in-silico investigation revealed that hydrogen bonding is pivotal in inducing conformational changes within the DNA structure, impeding its replication and preventing cell death. Molecular docking results revealed the presence of crucial hydrogen bonds and supported the formation of stable bevacizumab complexes. The molecular docking scores for the tested complexes were CDK4 (Score = -7.2 kcal/mol), EGFR (Score = -8.5 kcal/mol), frizzled (Score = -6.9 kcal/mol), IGFR (Score = -7.8 kcal/mol), KIT (Score = -6.5 kcal/mol), and MYC (Score = -8.3 kcal/mol). The binding mode demonstrated vital hydrogen bonds correlated with the observed energy gap. Notably, the calculated binding free energies of the tested compounds are as follows: CDK4 (ΔG = 24275.195 ± 6411.293 kJ/mol), EGFR (ΔG = 363273.625 ± 8731.466 kJ/mol), frizzled (ΔG = 181751.990 ± 28438.515 kJ/mol), IGFR (ΔG = 162414.725 ± 10728.367 kJ/mol), KIT (ΔG = 40162.585 ± 4331.017 kJ/mol), and MYC (ΔG = 434783.463 ± 53989.676 kJ/mol). Furthermore, through extensive 100 ns MD simulations, we observed the formation of a stable bevacizumab complex structure. The simulations confirmed the stability of the bevacizumab complex with the proto-oncogenes. The results of this study highlight the potential of bevacizumab complex as a promising candidate for anticancer treatment. The identification of hydrogen bonding, along with the calculated binding free energies and molecular docking scores, provides valuable insights into the molecular interactions and stability of the bevacizumab complexes. These findings and the extensive MD simulations open new avenues for future research and development of bevacizumab as a targeted therapy for breast cancer and other related malignancies.Communicated by Ramaswamy H. Sarma.

Identification of potent COVID-19 main protease inhibitors by loading of favipiravir on Mg12O12 and Zn12O12 nanoclusters: an in silico strategy for COVID-19 treatment.

Pandemic new severe acute respiratory syndrome coronavirus (SARS-CoV-2) virus has increased throughout the world. There is no effective treatment against this virus until now. Since its appearance in Wuhan, China in December 2019, SARS-CoV-2 becomes the largest challenge the world is opposite today, including the discovery of an antiviral drug for this virus. Several viral proteins have been prioritized as SARS-CoV-2 antiviral drug targets, among them the papain-like protease (PLpro) and the main protease (Mpro). Inhibition of these proteases would target viral replication, viral maturation and suppression of host innate immune responses. Potential candidates have been identified to show inhibitory effects against Mpro, both in biochemical assays and viral replication in cells. There are different molecules such as lopinavir and favipiravir considerably inhibit the activity of Mpro in vitro. Different studies have shown that structurally improved favipiravir and other similar compounds can inhibit SARS-CoV-2 main protease. In this work, we study the interactions between favipiravir with Mg12O12 and Zn12O12 nanoclusters by density functional theory (DFT) and quantum mechanics atoms in molecules (QMAIM) methods to summarize the ability to load favipiravir onto Mg12O12 and Zn12O12 nanoclusters. Favipiravir-Mg12O12 and favipiravir-Zn12O12 lowest structures complexes were chosen to dock inside the SARS-CoV-2 main protease by molecular docking study. The molecular docking analysis revealed that the binding affinity of Mg12O12 and Zn12O12 nanoclusters inside the Mpro receptor is larger than that of favipiravir. Also, the loading of favipiravir on the surface of Mg12O12 and Zn12O12 nanoclusters increased the binding affinity against the Mpro receptor. Subsequently, 100 ns molecular dynamics simulation of the favipiravir-Mg12O12, and favipiravir-Zn12O12 docked inside the Mpro complexes established that favipiravir-Mg12O12, forms the most stable complex with the Mpro. Further molecular mechanics Poisson Boltzmann surface area (MMPBSA) analyses using the MD trajectories also demonstrated the higher binding affinity of favipiravir-Mg12O12 inside the Mpro. In summary, this study demonstrates a new way to characterize leads for novel anti-viral drugs against SARS-CoV-2, by improving the drug ability of favipiravir via loading it on Mg12O12 and Zn12O12 nanoclusters.Communicated by Ramaswamy H. Sarma.

Clinical Significance of miRNA-145 and -126 in Chronic Obstructive Pulmonary Disease with Pulmonary Embolism.

BACKGROUND: Pulmonary embolism (PE) a consequence of hypercoagulability status associated with chronic obstructive pulmonary disease (COPD) and worsens its course. Recently, microRNAs (miRNAs) have been linked to PE in COPD settings. We aimed to measure expression levels of miRNAs145 and 126 in COPD patients with and without PE. METHODS: Herein, miRNA (145 and 126) expression levels were measured in 250 COPD patients with PE by quan-titative real-time PCR, and their data were compared with 300 COPD patients without PE. RESULTS: Our results showed that miRNA-145 expression was downregulated in COPD patients with PE compared to those without PE. The reverse was observed in miRNA-126 expression that was higher in COPD patients with PE than in those without PE. miRNA-145 correlated positively with FEV1/FVC and correlated negatively with D-dimer in all patients regardless of the presence of PE. In addition, miRNA-126 positively correlated with D-dimer and negatively correlated with FEV1/FVC in all studied COPD patients. CONCLUSIONS: Lower levels of miRNA-145 and higher levels of miRNA-126 associated with worse diagnosis PE in patients with COPD. Extensive studies are mandated to bring a better understanding of the role of these miRNAs in the mechanism of thrombosis in COPD patients.

Hematological, Biochemical Properties, and Clinical Correlates of Hemoglobin S Variant Disorder: A New Insight Into Sickle Cell Trait.

Background: The sickle cell trait (SCT) disorder possesses a clinical heterogeneity ranging from a symptomless condition to sudden death. This study aimed to develop a diagnostic approach that helps the characterization and identification of SCT from normal subjects and sickle cell disease (SCD) patients, and to assess its severity. Methods: Sixty controls, 24 SCD patients and 31 SCT subjects were assessed clinically, radiologically and by laboratory investigations. Results: Of the SCT subjects, 12.8% were symptomatic (3.2% anemic, 6.4% hemolytic crisis, and 3.2% painful crises). Anemia was normocytic in 66.6%, and normochromic and polychromatic in 33.4%. Significantly lower red blood cells (RBCs), hemoglobin (Hb), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), hematocrit (Hct), Shine and Lal index (SL), and hemoglobin A (Hb A), and higher mean corpuscular hemoglobin concentration (MCHC), red cell distribution width (RDW), Ricerca index (RI), and Huber-Herklotz index (HH) were found in SCT subjects compared with the controls. Hb A and hemoglobin S (Hb S) were excellent in discriminating SCT from SCD (cut-off for SCT > 50% and < 40%) followed by Hct, MCHC, Hb, Green and King index (GK), and England and Fraser index (EF) (cut-off for SCT > 33%, > 32, > 11, < 71, and < 10, respectively). Radiologically normal findings were detected in 87% of SCT subjects; they had nearly normal liver and renal function tests (except one case each). A schematic diagnostic paradigm for SCT was proposed. Conclusion: This study allowed understanding of SCT in various aspects, i.e., clinical, hematological, biochemical and radiological. Thus, it could help prevention of the Hb S variant disorder and proper management of carriers. This might be applied in pre-marital screening, particularly in those with family history of Hb S disorder.

Can Hematological Ratios Predict Outcome of COVID-19 Patients? A Multicentric Study.

INTRODUCTION: Coronaviruses belong to a large family that leads to respiratory infection of various severity. Hematological ratios are indicators of inflammatory response widely used in viral pneumonia with affordability in developing countries. PURPOSE: Study the role of the neutrophil lymphocyte ratio (NLR), derived NLR ratio (d-NLR), platelet lymphocyte ratio (PLR), and lymphocyte monocyte ratio (LMR) in predicting the outcome of COVID-19 Egyptian patients. METHODS: A retrospective study on 496 COVID-19 Egyptian patients, managed in four tertiary centers, grouped into non-severe, severe, and critical. Patients' laboratory assessment including total leucocyte count (TLC), absolute neutrophil count (ANC), absolute lymphocyte count (ALC), absolute monocyte count (AMC), NLR, d-NLR, LMR and, PLR were reported as well as C reactive protein (CRP), D-dimer and serum ferritin. RESULTS: TLC, ANC, AMC, NLR, d-NLR and, PLR were highest in the critical group (p<0.001 for all except AMC p=0.033), while this group had the least ALC and LMR (p=0.049 and <0.001, respectively). Higher CRP and d-dimer levels were reported in the critical group (p<0.001). At the same time, higher ferritin was found in the severe group more than the critical and non-severe groups (p<0.001, p=0.005, respectively). We calculated the optimal cut-off values of the hematological ratio; NLR (3.5), d-NLR (2.86), PLR (192), and LMR (3). D-NLR had the highest specificity (89.19%), while NLR had the highest sensitivity (71.38%). By univariate logistic regression, age, DM, HTN, cardiovascular diseases, COPD, NLR, d-NLR, LMR and PLR, CRP, steroid, oxygen aids, and mechanical ventilation were associated with the severity of COVID-19. Still, only age, NLR, CRP, and oxygen aid were independent predictors in multivariate logistic regression. CONCLUSION: NLR is a predictor for severity in COVID-19. LMR, d-NLR, and PLR may assist in risk stratification.

Revisiting Autoimmunity in Chronic Lymphocytic Leukemia: Prognostic Value of Positive Direct Antiglobulin Test in a Retrospective Study and Literature Review.

INTRODUCTION: A positive direct antiglobulin test (DAT) with or without autoimmune hemolytic anemia is a frequent finding in chronic lymphocytic leukemia (CLL). The heterogenic clinical course of CLL mainly depends on different pathogenetic mechanisms which appears in a form of variable biological and clinical features. These features allow stratification of patients into subsets with different outcomes. PATIENTS AND METHODS: We evaluated the DAT as a prognostic marker in 120 CLL patients treated with chemoimmunotherapy. Clinical and laboratory features, treatment response, and survival outcomes of CLL patients were assessed in relation to their DAT test status. Additionally, the English literature was extensively reviewed regarding the prognostic impact of a positive DAT in CLL. RESULTS: DAT positivity was detected in 36 patients (30%) and was associated advanced disease staging (P = 0.03). No correlations were found with other clinical, laboratory, or biological factors such as ZAP-70 or CD38. Both a positive DAT and an Eastern Cooperative Oncology Group performance status >2 were predictors for non-response to first-line treatment in the multivariate analysis (OR = 0.3, 95% CI: 0.12-0.8 and OR = 0.2, 95% CI: 0.08-0.8, respectively). The five-year progression-free survival was significantly lower in the DAT-positive group (P = 0.004). No significant association was found with overall survival (P = 0.2). Sixteen reports analyzing more than 11,000 patients were identified in our review. CONCLUSION: In conclusion, DAT positivity in CLL patients is associated with poor response to treatment and disease progression.

Combination and tricombination therapy to destabilize the structural integrity of COVID-19 by some bioactive compounds with antiviral drugs: insights from molecular docking study.

Recently, the SARS-CoV-2 (COVID-19) pandemic virus has been spreading throughout the world. Until now, no certified drugs have been discovered to efficiently inhibit the virus. The scientists are struggling to find new safe bioactive inhibitors of this deadly virus. In this study, we aim to find antagonists that may inhibit the activity of the three major viral targets: SARS-CoV-2 3-chymotrypsin-like protease (6LU7), SARS-CoV-2 spike protein (6VYB), and a host target human angiotensin-converting enzyme 2 (ACE2) receptor (1R42), which is the entry point for the viral encounter, were studied with the prospects of identifying significant drug candidate(s) against COVID-19 infection. Then, the protein stability produced score of less than 0.6 for all residues of all studied receptors. This confirmed that these receptors are extremely stable proteins, so it is very difficult to unstable the stability of these proteins through utilizing individual drugs. Hence, we studied the combination and tricombination therapy between bioactive compounds which have the best binding affinity and some antiviral drugs like chloroquine, hydroxychloroquine, azithromycin, simeprevir, baloxavir, lopinavir, and favipiravir to show the effect of combination and tricombination therapy to disrupt the stability of the three major viral targets that are mentioned previously. Also, ADMET study suggested that most of all studied bioactive compounds are safe and nontoxic compounds. All results confirmed that caulerpin can be utilized as a combination and tricombination therapy along with the studied antiviral drugs for disrupting the stability of the three major viral receptors (6LU7, 6VYB, and 1R42). SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11224-020-01723-5.

Cytotoxic activity, molecular docking, pharmacokinetic properties and quantum mechanics calculations of the brown macroalga Cystoseira trinodis compounds.

In this study, nine compounds were isolated, eight of them were isolated for the first time from Cystoseira trinodis. The biological activity of the extract, fractions and pure compounds was evaluated. The antimicrobial activity was investigated against 3 fungi species, 3 gram + ve and 3 gram -ve bacteria. The crude extract and fractions showed moderate inhibition against some of the tested microorganisms, especially the butanol fraction exhibited the maximum inhibition zone against Salmonella typhimurium (16 ± 0.60 mm). Cytotoxicity was evaluated against HepG-2 and MCF-7 cell lines. Hexane fraction exhibited the highest cytotoxic effect against HepG-2 and MCF-7 cell lines with an IC50 value of 14.3 ± 0.8 and 19.2 ± 0.7 µg/ml, respectively with compared to other fractions. The isolates were identified as octacosanoic acid (1), glyceryl trilinoleate (2), oleic acid (3), and the epimeric mixture of saringosterols (4, 5), ß-sitosterol (6), glycoglycerolipid (7) and a mixture of kjellmanianone and loliolide (8, 9) by spectroscopic analysis. Among the all tested compounds kjellmanianone and loliolide mixture exhibited significant cytotoxic activity with an IC50 value of 7.27 µg/ml against HepG-2 cells. The major and minor constituents of the extract and fractions were identified using GC-MS analysis. Molecular docking analysis confirmed that most of the studied compounds especially compounds 8 and 9 strongly interact with TPK and VEGFR-2 with highest binding energies supported that the high cytotoxicity of these compounds against human hepatocellular cancer in the experimental part. The energetic, geometric and topological properties of compounds 8 and 9 binding with cytosine base were computed by DFT methods. Molecular properties descriptors, bioactivity score and ADMET analysis confirmed that most of the studied compounds especially compounds 8 and 9 exhibit significant biological activities and have a better chance to be developed as drug leads. Communicated by Ramaswamy H. Sarma.

Characterization and assessment of naturally mutant non-pathogenic O27 strain Escherichia coli and their potential use as poultry probiotics.

OBJECTIVE: The purpose of the current study was to evaluate the molecular characteristics of naturally mutant non-pathogenic O27 strain of Escherichia coli and its efficacy as probiotic in broilers and determine the best age at which it can be administered. MATERIALS AND METHODS: A total of 24 virulence genes using 24 sets of primers were detected using the polymerase chain reaction technique. For probiotics experiments, 60 chicks (day 1 old) were divided into three groups, 20 per group, and reared for 4 weeks. The first group was considered as a negative control. The second group was treated orally with O27 strain at first day of life for three successive days and repeated at day 21. The third group was administered orally with O27 strain at day 10 old, and repeated at day 21 old. RESULTS: The data revealed that type 1 fimbrial adhesion, salmochelin siderophore receptor, and sigma factor-binding protein were detected in O27 strain, but temperature-sensitive hemagglutinin, hemolysin secretion gene, pyelonephritis-associated Pili gene, polysaccharide capsule synthesis gene, Shiga-toxin1 gene, Shiga-toxin2 gene, Brain microvascular endothelial cell invasion, E. coli attaching and effacing gene, heat-stable enterotoxin, heat-labile enterotoxin, east 1 toxin, colicin V, verotoxin type 2, necrotizing cytotoxic factor type 1, colonization factor antigen I, colonization factor antigen III, coli surface 2, coli surface 4, serine protease pic autransporter, vacuolating autotransporter toxin, and serine protease EspP precursor were not detected in O27 strain. Group 2 performance parameters were significantly better (p < 0.01) than groups 3 and 1. Hematological and biochemical parameters did not be influenced (p > 0.05) by the administration of O27 strain. Antibody titers of infectious bursal disease virus and Newcastle disease virus in groups 2 and 3 were improved as compared to group 1. Group 2 had significantly higher titers than group 3. Histopathologically, all groups showed normal histopathological pictures. However, jejunum in groups 2 and 3 showed more tall, intact, and densely packed microvilli and more crypt depth than the control group. CONCLUSION: The O27 strain of E. coli is non-pathogenic bacteria. Its effects on growth performances and enhancement of immunity in broilers match with the same impact of probiotics, and these candidates will fit to be a good probiotic in the future. The results revealed that the effects of O27 strain at the day 1 old of life for three successive days and repeated at day 21 old are better for improving the performance and immunity of the birds. More research works about the characterized non-pathogenic E. coli strain O27 are required for field and commercial use.

The inhibitory effect of some natural bioactive compounds against SARS-CoV-2 main protease: insights from molecular docking analysis and molecular dynamic simulation.

This work aimed at evaluating the inhibitory effect of ten natural bioactive compounds (1-10) as potential inhibitors of SARS-CoV-2-3CL main protease (PDB ID: 6LU7) and SARS-CoV main proteases (PDB IDs: 2GTB and 3TNT) by molecular docking analysis. The inhibitory effect of all studied compounds was studied with compared to some proposed antiviral drugs which currently used in COVID-19 treatment such as chloroquine, hydroxychloroquine, azithromycin, remdesivir, baloxvir, lopinavir, and favipiravir. Homology modeling and sequence alignment was computed to evaluate the similarity between the SARS-CoV-2-3CL main protease and other SARS-CoV receptors. ADMET properties of all studied compounds were computed and reported. Also, molecular dynamic (MD) simulation was performed on the compound which has the highest binding affinity inside 6LU7 obtained from molecular docking analysis to study it is stability inside receptor in explicit water solvent. Based on molecular docking analysis, we found that caulerpin has the highest binding affinity inside all studied receptors compared to other bioactive compounds and studied drugs. Our homology modeling and sequence alignment showed that SARS-CoV main protease (PDB ID: 3TNT) shares high similarity with 3CLpro (96.00%). Also, ADMET properties confirmed that caulerpin obeys Lipinski's rule and passes ADMET property, which make it a promising compound to act as a new safe natural drug against SARS-CoV-2-3CL main protease. Finally, MD simulation confirmed that the complex formed between caulerpin and 3CLpro is stable in water explicit and had no major effect on the flexibility of the protein throughout the simulations and provided a suitable basis for our study. Also, binding free energy between caulerpin and 6LU7 confirmed the efficacy of the caulerpin molecule against SARS-CoV-2 main protease. So, this study suggested that caulerpin could be used as a potential candidate in COVID-19 treatment.

Destabilizing the structural integrity of COVID-19 by caulerpin and its derivatives along with some antiviral drugs: An in silico approaches for a combination therapy.

Presently, the SARS-CoV-2 (COVID-19) pandemic has been spreading throughout the world. Some drugs such as lopinavir, simeprevir, hydroxychloroquine, chloroquine, and amprenavir have been recommended for COVID-19 treatment by some researchers, but these drugs were not effective enough against this virus. This study based on in silico approaches was aimed to increase the anti-COVID-19 activities of these drugs by using caulerpin and its derivatives as an adjunct drug against SARS-CoV-2 receptor proteins: the SARS-CoV-2 main protease and the SARS-CoV-2 spike protein. Caulerpin exhibited antiviral activities against chikungunya virus and herpes simplex virus type 1. Caulerpin and some of its derivatives showed inhibitory activity against Alzheimer's disease. The web server ANCHOR revealed higher protein stability for the two receptors with disordered score (< 0.6). Molecular docking analysis showed that the binding energies of most of the caulerpin derivatives were higher than all the suggested drugs for the two receptors. Also, we deduced that inserting NH2, halogen, and vinyl groups can increase the binding affinity of caulerpin toward 6VYB and 6LU7, while inserting an alkyl group decreases the binding affinity of caulerpin toward 6VYB and 6LU7. So, we can modify the inhibitory effect of caulerpin against 6VYB and 6LU7 by inserting NH2, halogen, and vinyl groups. Based on the protein disordered results, the SARS-CoV-2 main protease and SARS-CoV-2 spike protein domain are highly stable proteins, so it is quite difficult to unstabilize their integrity by using individual drugs. Also, molecular dynamics (MD) simulation indicates that binding of the combination therapy of simeprevir and the candidate studied compounds to the receptors was stable and had no major effect on the flexibility of the protein throughout the simulations and provided a suitable basis for our study. So, this study suggested that caulerpin and its derivatives could be used as a combination therapy along with lopinavir, simeprevir, hydroxychloroquine, chloroquine, and amprenavir for disrupting the stability of SARS-CoV2 receptor proteins to increase the antiviral activity of these drugs.