In-silico study: docking simulation and molecular dynamics of peptidomimetic fullerene-based derivatives against SARS-CoV-2 Mpro.

COVID-19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, has become a global pandemic resulting in significant morbidity and mortality. This study presents 12 new peptidomimetic fullerene-based derivatives in three groups that are investigated theoretically as SARS-CoV-2 Mpro inhibitors to increase the chance of treating COVID-19. Studied compounds are designed and optimized at B88-LYP/DZVP method. Molecular descriptors results show the stability and reactivity of the compounds with Mpro, especially in the 3rd group (Ser compounds). However, Lipinski's Rule of Five values indicates that the compounds are not suitable as oral drugs. Furthermore, molecular docking simulations are carried out to investigate the binding affinity and interaction modes of the top five compounds (compounds 1, 9, 11, 2, and 10) with the Mpro protein, which have the lowest binding energy. Molecular dynamics simulations are also performed to evaluate the stability of the protein-ligand complexes with compounds 1 and 9 and compare them with natural substrate interaction. The analysis of RMSD, H-bonds, Rg, and SASA indicates that both compounds 1 (Gly-α acid) and 9 (Ser-α acid) have good stability and strong binding affinity with the Mpro protein. However, compound 9 shows slightly better stability and binding affinity compared to compound 1.

Evaluation of the expression of the stromal cell-derived factor-1 alpha (CXCL 12) in psoriatic patients after treatment with Methotrexate.

BACKGROUND: CXCL12 has an important role in skin homeostasis and inflammation. OBJECTIVE: In this work, the expression of CXCL12 was evaluated in psoriasis vulgaris, psoriatic arthritis (PsA) patients in relation to disease activity and methotrexate (MTX) therapy. METHODS: Skin biopsies were obtained from 10 psoriasis vulgaris patients, 10 PsA patients, and 20 controls. The biopsies were repeated 6 weeks after MTX therapy. The biopsies were stained immunohistochemically by stromal dermal factor 1 alpha (CXCL 12) antibody. RESULTS: Psoriatic arthritis showed significantly more expression of CXCL 12 than psoriasis vulgaris patients before treatment but not after treatment. There was significant decrease in CXCL 12 expression in the keratinocytes of psoriasis vulgaris patients after MTX therapy than before treatment, P-value was 0.009. There was no significant difference between pre- and post-treatment in the CXCL 12 expression of keratinocytes of PsA patients, P-value was 0.093. The percentage decrease of PASI score after treatment showed a moderate correlation with the percentage decrease of CXCL12 expression of the keratinocytes of the total psoriasis patients, r = 0.484, P-value was 0.015. CONCLUSION: CXCL12 might be involved in the progression of psoriasis vulgaris to PsA. MTX therapy downregulated the expression of CXCL12 of the keratinocytes of psoriasis patients. This downregulation was paralleled by decrease in the PASI score. CXCL12 can be used as a biological marker of disease severity of psoriasis patients.

Novel inhibitors against wild-type and mutated HCV NS3 serine protease: an in silico study.

In 2011, the FDA approved boceprevir as a hepatitis C virus (HCV) NS3 serine protease inhibitor. The sustained virological response rate for treatment with this approved compound is considerably low. Patients have not responded as much as expected to boceprevir therapy. In this in silico study, modified boceprevir compounds are suggested and tested on wild-type HCV NS3 protease and 19 mutated HCV NS3 proteases using molecular docking. Results reveal the superiority of two of the proposed modified compounds to boceprevir. One of which appears to be more potent than boceprevir itself concerning activity against wild-type NS3 and most of the examined mutated NS3 proteases.

Structure-based drug design of novel peptidomimetic cellulose derivatives as HCV-NS3 protease inhibitors.

Hepatitis C Virus (HCV) represents a global health threat not only due to the large number of reported worldwide HCV infections, but also due to the absence of a reliable vaccine for its prevention. HCV NS3 protease is one of the most important targets for drug design aiming at the deactivation of HCV. In the present work, molecular docking simulations are carried out for suggested novel NS3 protease inhibitors applied to the Egyptian genotype 4. These inhibitors are modifications of dimer cellulose by adding a hexa-peptide to the cellulose at one of the positions 2, 3, 6, 2', 3' or 6'. Results show that the inhibitor compound with the hexa-peptide at position 6 shows significantly higher simulation docking score with HCV NS3 protease active site. This is supported by low total energy value of docking system, formation of two H-bonds with HCV NS3 protease active site residues, high binding affinity and increased stability in the interaction system.

Cathelicidin (LL-37) level in the scalp hair of patients with tinea capitis.

Antimicrobial peptides (AMPs) are considered an important first line of defense against pathogens. Cathelicidin LL-37 was upregulated in response to fungal infection. In this work we aimed to evaluate cathelicidin LL-37 in the hair of tinea capitis and compare it to normal controls. Hair samples were collected from 30 children and 30 controls aged from 2 to10 years old, and the level of cathelicidin LL-37 in the hair was detected by quantitative real-time PCR. The 30 patients were further subdivided into three subgroups according to their clinical type. Ten patients were scaly type, 10 patients were black dots type, and 10 patients were kerion type. Cathelicidin level in patients ranged from 6.0 to 17.5 with mean ± SD (11.3 ± 2.3) and in control ranged from 1.02 to 6.2, with mean ± SD (2.8 ± 1.5). There was a significant difference between the patients and controls regarding the cathelicidin level; P value was 0. The mean cathelicidin level was lowest in the kerion type10.73 ± 2.6 and highest in the black dot type 12.05 ± 2.76. However, there was no significant difference between the cathelicidin level of the different clinical types of tinea capitis; P value was 0.58. In conclusion, the level of cathelicidin LL-37 in hair specimens of human tinea capitis was significantly higher than controls.

The QSAR and docking calculations of fullerene derivatives as HIV-1 protease inhibitors.

The inhibition of HIV-1 protease is considered as one of the most important targets for drug design and the deactivation of HIV-1. In the present work, the fullerene surface (C60) is modified by adding oxygen atoms as well as hydroxymethylcarbonyl (HMC) groups to form 6 investigated fullerene derivative compounds. These compounds have one, two, three, four or five O atoms+HMC groups at different positions on phenyl ring. The effect of the repeating of these groups on the ability of suggested compounds to inhibit the HIV protease is studied by calculating both Quantitative Structure Activity Relationship (QSAR) properties and docking simulation. Based on the QSAR descriptors, the solubility and the hydrophilicity of studied fullerene derivatives increased with increasing the number of oxygen atoms+HMC groups in the compound. While docking calculations indicate that, the compound with two oxygen atoms+HMC groups could interact and binds with HIV-1 protease active site. This is could be attributed to the active site residues of HIV-1 protease are hydrophobic except the two aspartic acids. So that, the increase in the hydrophilicity and polarity of the compound is preventing and/or decreasing the hydrophobic interaction between the compound and HIV-1 protease active site.

QSAR analysis and molecular docking simulation of suggested peptidomimetic NS3 protease inhibitors.

Based on the N-terminal hexapeptide product of hydrolysis (EDVVCC) at HCV NS5A/5B junction, three modified groups of compounds are built. The first group contains linear peptides while the second and third groups contain P1-P3 and P2-P4 macrocyclic structures, respectively. Quantitative Structure Activity Relationship (QSAR) characterization and docking simulations are performed in order to investigate the potential of these compounds as HCV NS3/4A protease inhibitors. Based on the QSAR properties, the three most stable compounds due to their lowest total energy are P1-P3 and P2-P4 macrocycles of azahexapeptide sequence (DDIVP vinyl amino cyclopropane) and P2-P4 macrocycle of azahexapeptide sequence (DDIVP norvaline). They also have high surface area, solvent accessible surface area, volume, molar refractivity and polarizabilty. They have moderately low dipole moment and good log P values, as well. The docking scores of the best two P2-P4 macrocycles are just acceptable. The two compounds 5A/5B hexapeptide sequence (DDIVP vinyl amino cyclopropane) and P2-P4 macrocycle of azapentapeptide sequence (DIVP vinyl amino cyclopropane) yielded the best docking scores.

Hexapeptide functionality of cellulose as NS3 protease inhibitors.

Two novel groups of hexapeptide inhibitors for NS3 serine protease of the hepatitis C virus (HCV) are designed. The hexapeptide is an amino acid sequence of NS5A/NS5B substrate (Glu-Asp-Val-Val-Cys-Cys). In the first group, the hexapeptide binds to a cellulose monomer at the positions 2, 3 or 6 while in the second group, the hexapeptide binds to a cellulose dimmer at the positions 2, 3, 6, 2', 3' or 6'. Molecular modeling semiemprical PM3 calculations are used to optimize the geometry and calculate the electronic properties of the suggested inhibitors compared to that of natural substrate. Computational results show that the second group has the maximum stability and reactivity indicating that it would be considered as a promising HCV NS3 protease inhibitor.

Knowledge about the association between periodontal diseases and diabetes mellitus: contrasting dentists and physicians.

BACKGROUND: There is a strong body of evidence that supports the relationship between periodontal diseases and diabetes mellitus (DM). Many patients are unaware of the effects of diabetes on oral health. Whether health care providers are applying the information about the link between DM and periodontal diseases in their practices depends on the levels of their knowledge of such valuable information. Therefore, the aims of this study are to evaluate the knowledge of dental and medical practitioners concerning the effects of diabetes on periodontal health and to find out if the practitioners are aware of the bidirectional relationship between periodontal diseases and DM. METHODS: This was a cross-sectional survey of randomly selected general practitioners practicing in Kuwait. Participants were asked about specific periodontal complications that they believed patients diagnosed with diabetes were more susceptible to, and their awareness of the bidirectional relationship between diabetes and periodontal diseases was evaluated. RESULTS: A total of 510 general practitioners (232 physicians and 278 dentists) participated in the study. There were no significant differences between the two groups regarding mean ages, sex distributions, and years in practice. Only 50% of all study participants believed that patients with diabetes were more susceptible to tooth loss because of periodontal diseases than were individuals without diabetes. Dentists were significantly more aware of gingival bleeding, tooth mobility, and alveolar bone resorption than were physicians. Factors significantly associated with having knowledge about the effects of diabetes on periodontal health in logistic regression analyses were older age, female sex, and the dental profession. CONCLUSION: The knowledge about the association between periodontal diseases and DM should be increased among dental and medical practitioners to effectively prevent, manage, and control diabetes and periodontal diseases.

Structural and electronic properties of new fullerene derivatives and their possible application as HIV-1 protease inhibitors.

Density functional theory (DFT) calculations have been carried out at the hybrid Becke 3-Lee-Yang-Parr; B3LYP/3-21G** level of theory to study two series of hydroxy-chalca-acetic acid-(4-pyrrolidin-1-yl-phenyl) ester [C(60)-C(2)H(4)N-(4-XCOCH(2)OH)C(6)H(4)] and hydroxy-chalcoacetic acid-[2-(2-hydroxy-acetylchalcanyl)-4-pyrrolidin-1-yl-phenyl] ester[C(60)-C(2)H(4)N-(3,4-XCOCH(2)OH)C(6)H(4)]. The X atom is O, S or Se for the two series. The vibrational spectra, physical, chemical, thermodynamics and Quantitative Structure Activity Relationship (QSAR) properties of the studied molecules are calculated and discussed. We have evaluated these molecules as HIV-1 protease inhibitors based on the hydrogenation interaction between the hydroxymethylcarbonyl (HMC) groups and the two aspartic acid of the HIV-1 protease active site. Results show that some of the investigated fullerene-based derivatives can be considered promising as HIV-1 protease inhibitors.

Duodenal dearterialization and stapling for severe hemorrhage from duodenal varices with portal vein thrombosis.

BACKGROUND: Hemorrhage from duodenal varices is a rare but frequently fatal cause of gastrointestinal bleeding. Portal vein thrombosis may worsen the bleeding and prevent access for reduction of variceal pressure. METHODS: A technique to control bleeding and reduce inflow pressure to the varices is described. It includes ligation of the gastroduodenal and splenic arteries, splenectomy, stapling of the duodenum, and gastroenterostomy. RESULTS: Three patients, hemodynamically unstable from duodenal hemorrhage, underwent the procedure. No further bleeding was encountered. One patient died of fungal sepsis and liver failure, but 2 are alive without further problems 21 and 24 months later. CONCLUSIONS: Reduction in arterial inflow, direct variceal ligation, reversal of hypersplenism, and food stream diversion are elements of this procedure that may have contributed the control of severe hemorrhage from duodenal varices associated with portal vein thrombosis.