Smoking and pre-existing co-morbidities as risk factors for developing severity of COVID-19 infection: Evidence from a field hospital in a rural area of Bangladesh.

Since August 2020; the International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b) in collaboration with UNICEF has been operating a COVID-19 field hospital at the Teknaf sub-district of Cox's Bazar in Bangladesh. This paper is focused on estimating the effects of a history of tobacco smoking and pre-existing co-morbidities on the severity of COVID-19 infection among adult patients admitted into the aforesaid hospital. We conducted a retrospective data analysis of COVID-19 adult patients hospitalized from August 27, 2020 to April 20, 2022. Based on inclusion criteria; a total of 788 admitted patients were included in the analysis. We conducted a Chi-squared test and Fisher's exact test for the categorical variables to see their associations. Multinomial logistic regression models were performed to explore the risk factors for the severity of COVID-19 infection. Among 788 patients, 18.4%, 18.8%, 13%, 7.1%, 3.4%, and 1.9% have had a history of smoking, hypertension, diabetes, chronic obstructive pulmonary disease (COPD), cardiovascular diseases (CVD), and asthma respectively. Overall, the mean age of the patients was 40.3 ± 16.4 years and 51% were female. In multivariate analysis, history of smoking and co-morbidities were identified as the risk factors for the severity of COVID-19 infection; the history of smoking was found linked with an increase in the risk of developing critical, severe, and moderate level of COVID-19 infection- notably 3.17 times (RRR = 3.17; 95% CI: 1.3-7.68), 2.98 times (RRR = 2.98; 95% CI: 1.87-4.76) and 1.96 times (RRR = 1.96; 95% CI: 1.25-3.08) respectively more than the patients who never smoked. It was evident that patients with at least one of the selected co-morbidities such as hypertension, diabetes, COPD, CVD, and asthma exhibited a significantly higher likelihood of experiencing severe illness of COVID-19 compared to patients without any co-morbidity. History of tobacco smoking and pre-existing co-morbidities were significantly associated with an increased severity of COVID-19 infection.

Caffeic Acid Enhances the Anti-Leukemic Effect of Imatinib on Chronic Myeloid Leukemia Cells and Triggers Apoptosis in Cells Sensitive and Resistant to Imatinib.

Among the phenolic acids tested on the K562 cell line, a model of chronic myeloid leukemia (CML), caffeic acid (CA) was biologically active on sensitive and imatinib (IM)-resistant cells at micro-molar concentration, either in terms of reduction of cell proliferation or triggering of apoptosis. The CA treatment provoked mitochondrial membrane depolarization, genomic DNA fragmentation and phosphatidylserine exposure, hallmarks of apoptosis. Cell cycle analysis following the treatment with comparable cytotoxic concentrations of IM or CA showed marked differences in the distribution profiles. The reduction of cell proliferation by CA administration was associated with increased expression of two cell cycle repressor genes, CDKN1A and CHES1, while IM at a cytotoxic concentration increased the CHES1 but not the CDKN1A expression. In addition, CA treatment affected the proliferation and triggered the apoptosis in IM-resistant cells. Taken together, these data suggested that CA induced the anti-proliferative effect and triggered apoptosis of CML cells by a different mechanism than IM. Finally, the combined administration of IM and CA at suboptimal concentrations evidenced a synergy of action in determining the anti-proliferative effect and triggering apoptosis. The ability of CA to potentiate the anti-leukemic effect of IM highlighted the nutraceutical potential of CA in CML.

Structural modification of aspirin to design a new potential cyclooxygenase (COX-2) inhibitors.

Aspirin (Asp) is one of the most important and ancient member of nonsteroidal anti-inflammatory drugs (NSAID), commonly used in medication of fever, pain and inflammation. It can inhibit the synthesis of prostaglandin by blocking the cyclooxygenase (COX). Attempts have been taken to analyze aspirin together with some of its modified derivatives applying quantum mechanical calculations in order to compare their physicochemical and biochemical properties. Density functional theory (DFT) with B3LYP/6-31G (d, p) basis set has been employed to elucidate their thermal, molecular orbital, equilibrium geometrical properties in gas phase. Molecular docking and nonbonding interactions have been performed against human cyclooxygenase-2 protein 5F1A to investigate the binding affinity and mode(s) of newly designed aspirin derivatives. ADMET prediction has been utilized to compare the absorption, metabolism, and carcinogenic properties of new derivatives with parent drug (Asp). Thermal and geometrical results support the thermochemical stability and equilibrium geometry of all the structures. From the molecular docking simulation, most of the derivatives exhibited better binding affinity than parent drug (Asp) with the receptor protein (5F1A). ADMET prediction disclosed the improved pharmacokinetic properties with lower acute oral toxicity of some derivatives. Based on quantum chemical, molecular docking and ADMET analysis, this investigation can be useful to understand the physicochemical and biochemical/biological activities of Asp and its modified derivatives to search a new antipyretic analgesic drug.

A comprehensive review on tyrosinase inhibitors.

Tyrosinase is a multi-copper enzyme which is widely distributed in different organisms and plays an important role in the melanogenesis and enzymatic browning. Therefore, its inhibitors can be attractive in cosmetics and medicinal industries as depigmentation agents and also in food and agriculture industries as antibrowning compounds. For this purpose, many natural, semi-synthetic and synthetic inhibitors have been developed by different screening methods to date. This review has focused on the tyrosinase inhibitors discovered from all sources and biochemically characterised in the last four decades.

Ab initio molecular simulations for proposing potent inhibitors to butyrylcholinesterases.

Butyrylcholinesterase (BChE) exists mainly at neuromuscular junctions and plays an important role in the hydrolyzing mechanism of neurotransmitter acetylcholine. A variety of compounds have been produced in order to inhibit the function of BChE. We here investigate the specific interactions between BChE and some ligands (Kx) with large binding affinity to BChE, using ligand-docking, classical molecular mechanics and ab initio fragment molecular orbital (FMO) methods. The binding energies between BChE and Kx evaluated by the FMO method have a correlation with the 50% inhibition concentration obtained by the previous experiments. In addition, the FMO calculations highlight that Asp70, Trp82 and Tyr128 residues of BChE contribute significantly to the binding between BChE and Kx. Based on the results, we propose some novel ligands and elucidate that one of the proposed ligands can bind strongly to BChE. The present results are useful for developing potent inhibitors to BChE.

Tyrosinase enzyme: 1. An overview on a pharmacological target.

The tyrosinase enzyme (EC 1.14.18.1) is an oxidoreductase inside the general enzyme classification and is involved in the oxidation and reduction process in the epidermis. These chemical reactions that the enzyme catalyzes are of principal importance in the melanogenesis process. This process of melanogenesis is related to the melanin formation, a heteropolymer of indolic nature that provides the different tonalities in the skin and helps to the protection from the ultraviolet radiation. However, a pigment overproduction, come up by the action of the tyrosinase, can cause different disorders in the skin related to the hyperpigmentation. Several studies mainly focused on the characteristics of the enzyme have been reported. In this work, an approximation to general aspects related to this enzyme is made. Besides, it is treated the researches that have been published in the part of the biochemical anatomy dealing with diseases associated with this protein (melanogenesis), its active place and its physiological states, the molecular mechanism, the methods carried out to detect the inhibitory activity, and the used substrates.

Flavonoid derivatives as potent tyrosinase inhibitors - a survey of recent findings between 2008-2013.

Tyrosinase (EC 1.14.18.1), also known as polyphenols oxidase, is a glycosylated multi-copper monooxygenase enzyme widely distributed in many different organisms. The enzyme is responsible for the pigmentation of skin, eyes and hair in mammals and in fruits and vegetables undesired browning. These issues have encouraged researchers all over the world to seek new, potent and safe inhibitors of the enzyme for use in foods and cosmetics. A large number of compounds from natural products have been reported as moderate to potent inhibitors of tyrosinase. Among them, many flavonoid derivatives have been revealed to be the strong inhibitors of tyrosinase. In this review, we reviewed many examples of tyrosinase inhibitors with flavonoid structure reported between 2008-2013. Our findings underline that flavonoids should continue to be the focus of tyrosinase inhibition studies as the promising compounds.

A rational workflow for sequential virtual screening of chemical libraries on searching for new tyrosinase inhibitors.

The tyrosinase is a bifunctional, copper-containing enzyme widely distributed in the phylogenetic tree. This enzyme is involved in the production of melanin and some other pigments in humans, animals and plants, including skin pigmentations in mammals, and browning process in plants and vegetables. Therefore, enzyme inhibitors has been under the attention of the scientist community, due to its broad applications in food, cosmetic, agricultural and medicinal fields, to avoid the undesirable effects of abnormal melanin overproduction. However, the research of novel chemical with antityrosinase activity demands the use of more efficient tools to speed up the tyrosinase inhibitors discovery process. This chapter is focused in the different components of a predictive modeling workflow for the identification and prioritization of potential new compounds with activity against the tyrosinase enzyme. In this case, two structure chemical libraries Spectrum Collection and Drugbank are used in this attempt to combine different virtual screening data mining techniques, in a sequential manner helping to avoid the usually expensive and time consuming traditional methods. Some of the sequential steps summarize here comprise the use of drug-likeness filters, similarity searching, classification and potency QSAR multiclassifier systems, modeling molecular interactions systems, and similarity/diversity analysis. Finally, the methodologies showed here provide a rational workflow for virtual screening hit analysis and selection as a promissory drug discovery strategy for use in target identification phase.

Dipeptide inhibitors of thermolysin and angiotensin I-converting enzyme.

Thermolysin (TLN) and other thermolysin-like zinc metalloproteinases (TLPs),are important virulence factors for pathogenesis of bacterial infections by suppressing the innate immune system of the host. Therapeutic inhibition ofTLPs is believed to be a novel strategy inthe development of a new generation antibiotics.In the present study inhibition of TLN and angiotensin I-converting enzyme (ACE) by small peptides were studied by in vitro binding assays and theoretical calculations. The capacity of the peptides to inhibitTLN induced cleavage ofthe transcription factor nuclear factor kappa beta (NF-κB) was studied by electrophoretic mobility shift assays (EMSAs).Nine peptides inhibited ACE with IC50 values in the range 0.48 (IVY) to 1408 (HF) µM, while seven inhibited TLN with IC50 values in the range 0.00034 (IY) to 95640 (FW) µM. Calculations indicated that the peptides occupied the S1' and S2' subsites of ACE, and that IY, LW and IW occupiedthe S1' and S2' subsites, while FW, WL and WV occupiedthe S1 and S1' subsites of TLN. EMSA showed that peptides inhibited TLN induced cleavage of NF-κB. The studied peptides may form as a basis for the design of new compoundstargeting TLN with a potential in the treatment of bacterial infections.

Genome analysis of the new human polyomaviruses.

Polyomaviridae is a growing family of naked, double-stranded DNA viruses that infect birds and mammals. The last few years, several new members infecting birds or primates have been discovered, including seven human polyomaviruses: KI, WU, Merkel cell polyomavirus, HPyV6, HPyV7, trichodysplasia spinulosa-associated polyomavirus, and HPyV9. In addition, DNA and antibodies against the monkey lymphotropic polyomavirus have been detected in humans, indicating that this virus can also infect man. However, little is known about the route of infection, transmission, cell tropism, and, with the exception of Merkel cell polyomavirus and trichodysplasia spinulosa-associated polyomavirus, the pathogenicity of these viruses. This review compares the genomes of these emerging human polyomaviruses with previously known polyomaviruses detected in man, reports mutations in different isolates, and predicts structural and functional properties of their viral proteins.

Structure-based analysis of the molecular recognitions between HIV-1 TAR-RNA and transcription factor nuclear factor-kappaB (NFkB).

In this paper we applied the "macromolecular docking" procedure to perform molecular modeling with the aim of screening transcription factor sequences for possible interaction to the HIV-1 TAR-RNA, employing the software Hex version 4.2. The molecular modeling data were compared with electrophoretic mobility shift assays (EMSA) and surface plasmon resonance (SPR) based biospecific interaction analysis (BIA) using an optical biosensor. Finally the specific interactions between NF-κB and RNA have been calculated utilizing the AMBER-MM and FMO calculations. The results obtained clearly indicate that (a) NF-kB p50 transcription factor can bind TAR-RNA; (b) this binding efficiency is lower than that displayed by NF-kB factor in respect to DNA sequences; (c) other structured RNAs used as controls do not bind to NF-kB; (d) TAR-RNA is capable to bind pre-formed NF-kB/DNA complexes. Despite the fact that our data do not indicate whether NF-kB/TAR-RNA complexes play a role in the early steps of HIV-1 transcriptional activation, the results presented strongly indicate that interactions between transcription factors recruited at the level of HIV-1 LTR might interact with the TAR-RNA and deserve further studies aimed to determine its role in the HIV-1 life cycle.

BK virus-associated infection in cerebrospinal fluid of neurological patients and mutation analysis of the complete VP1 gene in different patient groups.

While BK virus (BKV) is frequently associated with pathological conditions in bone marrow and renal transplant recipients, BKV infection in neurological individuals has been rarely reported. As a result of a BKV, JCV, and SV40 large T antigen-specific multiplex PCR on 2,062 cerebrospinal fluid (CSF) samples from neurological patients suspicious of JCV infection, we identified 20 subjects with at least 1 CSF specimen positive for BKV large T antigen DNA. Because VP1 protein has been suggested to influence the biological/pathological properties of BKV, we tried to sequence the entire VP1 gene in the BKV-positive neurological patients and succeeded in 14 of the 20 neurological patients. To compare the VP1 sequence of the BKV neurological strains with that of non-neurotropic strains in other clinical situations, full-length VP1 DNA was sequenced in 15 renal and 6 bone marrow transplant recipients positive to BKV-viremia, and in 8 pregnant women as non-pathological controls. An increased (respectively, decreased) tendency for mutations in the BC loop (respectively, EF loop) was observed, and no mutations were detected in the CD, GH, and HI loops. Subtype I was predominant (93%) and compared to archetypal BKV (WW), amino acid substitutions were detected in 4/14 neurological patients, 10/15 renal transplant recipients, 3/6 bone marrow transplant patients, and in all the pregnant women. Each patient group had distinctive VP1 mutations, but these unique substitutions were not present in all patients of this group. However, molecular modeling simulations of the VP1 mutants predicted changes in protein surface properties which might affect the VP1-receptor interaction.

Specific interactions and binding energies between thermolysin and potent inhibitors: molecular simulations based on ab initio molecular orbital method.

Biochemical functions of the metalloprotease thermolysin (TLN) are controlled by various inhibitors. In a recent study we identified 12 compounds as TLN inhibitors by virtual screening and in vitro competitive binding assays. However, the specific interactions between TLN and these inhibitors have not been clarified. We here investigate stable structures of the solvated TLN-inhibitor complexes by classical molecular mechanics simulations and elucidate the specific interactions between TLN and these inhibitors at an electronic level by using ab initio fragment molecular orbital (FMO) calculations. The calculated binding energies between TLN and the inhibitors are qualitatively consistent with the experimental results, and the FMO results elucidate important amino acid residues of TLN for inhibitor binding. Based on the calculated results, we propose a novel potent inhibitor having a large binding affinity to TLN.

Specific interactions and binding free energies between thermolysin and dipeptides: molecular simulations combined with ab initio molecular orbital and classical vibrational analysis.

Thermolysin (TLN) is a metalloprotease widely used as a nonspecific protease for sequencing peptide and synthesizing many useful chemical compounds by the chemical industry. It was experimentally shown that the activity and functions of TLN are inhibited by the binding of many types of amino acid dipeptides. However, the binding mechanisms between TLN and dipeptides have not been clarified at the atomic and electronic levels. In this study, we investigated the binding mechanisms between TLN and four dipeptides. Specific interactions and binding free energies (BFEs) between TLN and the dipeptides were calculated using molecular simulations based on classical molecular dynamics and ab initio fragment molecular orbital (FMO) methods. The molecular systems were embedded in solvating water molecules during calculations. The calculated BFEs were qualitatively consistent with the trend of the experimentally observed inhibition of TLN activity by binding of the dipeptides. In addition, the specific interactions between the dipeptides and each amino acid residue of TLN or solvating water molecules were elucidated by the FMO calculations.

The diterpenoid alkaloid noroxoaconitine is a Mapkap kinase 5 (MK5/PRAK) inhibitor.

The mitogen-activated protein kinase-activated protein kinase MK5 is ubiquitously expressed in vertebrates and is implicated in cell proliferation, cytoskeletal remodeling, and anxiety behavior. This makes MK5 an attractive drug target. We tested several diterpenoid alkaloids for their ability to suppress MK5 kinase activity. We identified noroxoaconitine as an ATP competitor that inhibited the catalytic activity of MK5 in vitro (IC50 = 37.5 µM; K(i) = 0.675 µM) and prevented PKA-induced nuclear export of MK5, a process that depends on kinase active MK5. MK5 is closely related to MK2 and MK3, and noroxoaconitine inhibited MK3- and MK5- but not MK2-mediated phosphorylation of the common substrate Hsp27. Molecular docking of noroxoaconitine into the ATP binding sites indicated that noroxoaconitine binds more strongly to MK5 than to MK3. Noroxoaconitine and derivatives may help in elucidating the precise biological functions of MK5 and may prove to have therapeutic values.

Alpha-glucosidase and tyrosinase inhibitors from fungal hydroxylation of tibolone and hydroxytibolones.

Sixteen new and one known metabolites 4-20 were obtained by incubation of tibolone (1) and hydroxytibolones (2 and 3) with various fungi. Their structures were elucidated by means of a homo and heteronuclear 2D NMR and by HREI-MS techniques. The relative stereochemistry was deduced by 2D NOESY experiment. Metabolites of tibolone (1) exhibited significant inhibitory activities against alpha-glucosidase and tyrosinase enzymes. Hydroxylations at C-6, C-10, C-11, C-15 positions and alpha,beta-unsaturation at C-1/C-2, C-4/C-5 showed potent inhibitory activities against these enzymes.

Ligand-based computer-aided discovery of tyrosinase inhibitors. Applications of the TOMOCOMD-CARDD method to the elucidation of new compounds.

In this review an overview of the application of computational approaches is given. Specifically, the uses of Quantitative Structure-Activity Relationship (QSAR) methods for in silico identification of new families of compounds as novel tyrosinase inhibitors are revised. Assembling, validation of models through prediction series, and virtual screening of external data sets are also shown, to prove the accuracy of the QSAR models obtained with the TOMOCOMD-CARDD (TOpological MOlecular COMputational Design-Computer-Aided Rational Drug Design) software and Linear Discriminant Analysis (LDA) as statistical technique. Together with this, a database is collected for these QSAR studies, and could be considered a useful tool in future QSAR modeling of tyrosinase activity and for scientists that work in the field of this enzyme and its inhibitors. Finally, a translation to real world applications is shown by the use of QSAR models in the identification and posterior in-vitro evaluation of different families of compounds. Several different classes of compounds from various sources (natural and synthetic) were identified. Between them, we can find tetraketones, cycloartanes, ethylsteroids, lignans, dicoumarins and vanilloid derivatives. Finally, some considerations are discussed in order to improve the identification of novel drug-like compounds based on the use of QSAR-Ligand-Based Virtual Screening (LBVS).