Treatment variability and its relationships to outcomes among patients with Wernicke's encephalopathy: A multicenter retrospective study.

BACKGROUND: Despite guidelines and recommendations, Wernicke's encephalopathy (WE) treatment lacks evidence, leading to clinical practice variability. AIMS: Given the overall lack of information on thiamine use for WE treatment, we analyzed data from a large, well-characterized multicenter sample of patients with WE, examining thiamine dosages; factors associated with the use of different doses, frequencies, and routes; and the influence of differences in thiamine treatment on the outcome. METHODS: This retrospective study was conducted with data from 443 patients from 21 centers obtained from a nationwide registry of the Spanish Society of Internal Medicine (from 2000 to 2012). Discharge codes and Caine criteria were applied for WE diagnosis, and treatment-related (thiamine dosage, frequency, and route of administration) demographic, clinical, and outcome variables were analyzed. RESULTS: We found marked variability in WE treatment and a low rate of high-dose intravenous thiamine administration. Seventy-eight patients out of 373 (20.9%) received > 300mg/day of thiamine as initial dose. Patients fulfilling the Caine criteria or presenting with the classic WE triad more frequently received parenteral treatment. Delayed diagnosis (after 24h hospitalization), the fulfillment of more than two Caine criteria at diagnosis, mental status alterations, and folic acid deficiency were associated significantly with the lack of complete recovery. Malnutrition, reduced consciousness, folic acid deficiency, and the lack of timely thiamine treatment were risk factors for mortality. CONCLUSIONS: Our results clearly show extreme variability in thiamine dosages and routes used in the management of WE. Measures should be implemented to ensure adherence to current guidelines and to correct potential nutritional deficits in patients with alcohol use disorders or other risk factors for WE.

Crystallographic Aspects, Photophysical Properties, and Theoretical Survey of Tetrachlorometallates of Group 12 Metals [Zn(II), Cd(II), and Hg(II)] with a Triply Protonated 2,4,6-Tris(2-pyridyl)-1,3,5-triazine Ligand.

Zn(II) (complex 1), Cd(II) (complex 2), and Hg(II) (complex 3) complexes have been synthesized using a triply protonated tptz (H3tptz3+) ligand and characterized mainly by single-crystal X-ray analysis. The general formula of all of the complexes is (H3tptz)3+·Cl-·[MCl4]2-·nH2O (where n = 1, 1.5, and 1.5 for complexes 1, 2, and 3, respectively). The crystallographic analysis reveals that the anion···π, anion···π+, and several hydrogen bonding interactions play a fundamental role in the stabilization of the self-assembled architectures that in turn help to enhance the dimensionality of all of the complexes. In addition, Hirshfeld surfaces and fingerprint plots have been deployed here to visualize the similarities and differences in hydrogen bonding interactions in 1-3, which are very important in forming supramolecular architectures. A density functional theory (DFT) study has been used to analyze and rationalize the supramolecular interactions by using molecular electrostatic potential (MEP) surfaces and combined QTAIM/NCI plots. Then, the device parameters for the complexes (1-3) have been thoroughly investigated by fabricating a Schottky barrier diode (SBD) on an indium tin oxide (ITO) substrate. It has been observed that the device made from complex 2 is superior to those from complexes 1 and 3, which has been explained in terms of band gaps, differences in the electronegativities of the central metal atoms, and the better supramolecular interactions involved. Finally, theoretical calculations have also been performed to analyze the experimental differences in band gaps as well as electrical conductivities observed for all of the complexes. Henceforth, the present work combined supramolecular, photophysical, and theoretical studies regarding group 12 metals in a single frame.

Molecular insights into the in silico discovery of corilagin from Terminalia chebula as a potential dual inhibitor of SARS-CoV-2 structural proteins.

The spike (S) glycoprotein and nucleocapsid (N) proteins are the crucial pathogenic proteins of the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS CoV-2) virus during its interaction with the host. Even FDA-approved drugs like dexamethasone and grazoprevir are not able to curb the viral progression inside the host and are reported with adverse effects on body metabolism. In this context, we aim to report corilagin a novel, potential dual inhibitor of S and N proteins from Terminalia chebula. The bioactive compounds of T. chebula were subjected to a series of computational investigations including molecular docking simulations, molecular dynamics (MD) simulations, binding free energy calculations, and PASS pharmacological analysis. The results obtained from these studies revealed that corilagin was highly interactive with the S (-8.9 kcal/mol) and N (-9.2 kcal/mol) proteins, thereby showing dual inhibition activity. It was also found to be stable enough to induce biological activity inside the inhibitor binding pocket of the target enzymes throughout the dynamics simulation run for 100 ns. This is also confirmed by the changes in the protein conformations, evaluated using free energy landscapes. Outcomes from this investigation identify corilagin as the lead potential dual inhibitor of S and N proteins of SARS-CoV-2, which could be taken for biological studies in near future.Communicated by Ramaswamy H. Sarma.

Integrated approach for studying bioactive compounds from Cladosporium spp. against estrogen receptor alpha as breast cancer drug target.

Cladosporium spp. have been reported for their great diversity of secondary metabolites which represent as a prominent base material for verifying the biological activities. Several bioactive compounds which have antimicrobial, cytotoxic, quorum sensing inhibitory and phytotoxic activities have been isolated from Cladosporium species. Most of them are still needed to be explored for their anticancer properties. Therefore, the present study is focused on screening and identifying the bioactive compounds of Cladosporium spp. for their anticancer activity via the integrated approaches of Molecular Docking (MD), Molecular Dynamics Simulation (MDS) and Density Functional Theory (DFT) studies. A total of 123 bioactive compounds of Cladosporium spp. were explored for their binding affinity with the selected breast cancer drug target receptor such as estrogen receptor alpha (PDB:6CBZ). The Molecular Docking studies revealed that amongst the bioactive compounds screened, Altertoxin X and Cladosporol H showed a good binding affinity of - 10.5 kcal/mol and - 10.3 kcal/mol, respectively, with the estrogen receptor alpha when compared to the reference compound (17[Formula: see text]-Estradiol: - 10.2 kcal/mol). The MDS study indicated the stable binding patterns and conformation of the estrogen receptor alpha-Altertoxin X complex in a stimulating environment. In addition, in silico absorption, distribution, metabolism, excretion and toxicity (ADMET) study suggested that Altertoxin X has a good oral bioavailability with a high LD[Formula: see text] value of 2.375 mol/kg and did not cause any hepatotoxicity and skin sensitization. In summary, the integrated approaches revealed that Altertoxin X possesses a promising anticancer activity and could serve as a new therapeutic drug for breast cancer treatment.

Exploration of Anti-HIV Phytocompounds against SARS-CoV-2 Main Protease: Structure-Based Screening, Molecular Simulation, ADME Analysis and Conceptual DFT Studies.

The ever-expanding pandemic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has gained attention as COVID-19 and caused an emergency in public health to an unmatched level to date. However, the treatments used are the only options; currently, no effective and licensed medications are available to combat disease transmission, necessitating further research. In the present study, an in silico-based virtual screening of anti-HIV bioactive compounds from medicinal plants was carried out through molecular docking against the main protease (Mpro) (PDB: 6LU7) of SARS-CoV-2, which is a key enzyme responsible for virus replication. A total of 16 anti-HIV compounds were found to have a binding affinity greater than -8.9 kcal/mol out of 150 compounds screened. Pseudohypericin had a high affinity with the energy of -10.2 kcal/mol, demonstrating amino acid residual interactions with LEU141, GLU166, ARG188, and GLN192, followed by Hypericin (-10.1 kcal/mol). Moreover, the ADME (Absorption, Distribution, Metabolism and Excretion) analysis of Pseudohypericin and Hypericin recorded a low bioavailability (BA) score of 0.17 and violated Lipinski's rule of drug-likeness. The docking and molecular simulations indicated that the quinone compound, Pseudohypericin, could be tested in vitro and in vivo as potent molecules against COVID-19 disease prior to clinical trials.This was also supported by the theoretical and computational studies conducted. The global and local descriptors, which are the underpinnings of Conceptual Density FunctionalTheory (CDFT) have beenpredicted through successful model chemistry, hoping that they could be of help in the comprehension of the chemical reactivity properties of the molecular systems considered in this study.

Phytoconstituents of Withania somnifera unveiled Ashwagandhanolide as a potential drug targeting breast cancer: Investigations through computational, molecular docking and conceptual DFT studies.

Breast cancer is the second most common malignancy in females worldwide and poses a great challenge that necessitates the identification of novel therapeutic agents from several sources. This research aimed to study the molecular docking and molecular dynamics simulations of four proteins (such as PDB: 6CBZ, 1FDW, 5GWK and 2WTT) with the selected phytochemicals from Withania somnifera to identify the potential inhibitors for breast cancer. The molecular docking result showed that among 44 compounds, two of them, Ashwagandhanolide and Withanolide sulfoxide have the potential to inhibit estrogen receptor alpha (ERα), 17-beta-hydroxysteroid -dehydrogenase type 1 (17ß-HSD1), topoisomerase II alpha (TOP2A) and p73 tetramerization domain that are expressed during breast cancer. The molecular dynamics (MD) simulations results suggested that Ashwagandhanolide remained inside the binding cavity of four targeted proteins and contributed favorably towards forming a stable protein-ligand complex throughout the simulation. Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) properties confirmed that Ashwagandhanolide is hydrophobic and has moderate intestinal permeability, good intestinal absorption, and poor skin permeability. The compound has a relatively low VDss value (-1.652) and can be transported across ABC transporter and good central nervous system (CNS) permeability but did not easily cross the blood-brain barrier (BBB). This compound does not possess any mutagenicity, hepatotoxicity and skin sensitization. Based on the results obtained, the present study highlights the anticancer potential of Ashwagandhanolide, a compound from W. somnifera. Furthermore, in vitro and in vivo studies are necessary to perform before clinical trials to prove the potentiality of Ashwagandhanolide.

Formation Mechanism of Inter-Crosslink in DNA by Nitrogen Oxides Pollutants through A Diazonium Intermediate.

Outdoor air pollution is a mixture of multiple atmospheric pollutants, among which nitrogen oxide (NOx) stands out due to its association with several diseases. NOx reactivity can conduct to DNA damage as severe as interstrand crosslinks (ICL) formation, that in turn is able to block DNA replication and transcription. Experimental studies have suggested that the ICL formation due to NOx is realized through a diazonium intermediate (DI). In this work, we have modeled the DI structure, including a DNA double-strand composed of two base pairs GC/CG, being diazotized as one of the guanine nucleotides. The structural stability of DNA with DI lesion was essayed through 500 ns molecular dynamics simulations. It was found that the DNA structure of the oligonucleotide is stable when the DI is present since the loss of a Guanine-Cytosine hydrogen bond is replaced by the presence of two cation-π interactions. Additionally, we have studied the mechanism of formation of a crosslink between the two guanine nucleobases from the modeled DI by carrying out DFT calculations at the M06-L/DNP+ level of theory. Our results show that the mechanism is thermodynamically favored by a strong stabilization of the ICL product, and the process is kinetically viable since its limiting stage is accessible.

Insight into charge transportation in cadmium based semiconducting organic-inorganic hybrid materials and their application in the fabrication of photosensitive Schottky devices.

A coordination polymer (1) and a trinuclear complex (2) have been synthesized using a compartmental N2O2O2' donor Schiff base ligand. Both complexes are characterized using different spectroscopic techniques and their structures are determined using single crystal X-ray diffraction analyses. Energies associated with different non-covalent (S⋯O chalcogen bonds, C-H⋯H-C, C-H⋯I and C-H⋯π) interactions in the solid state of both complexes have been calculated using the Turbomole program. Investigations of electrical conductivity and photosensitivity of both complexes reveal that suitable Schottky diode devices could be fabricated from both complexes. The current vs. voltage plots of the complex based devices have been used to calculate the conductivity under dark and irradiation conditions. In both complexes the charge transportation mainly occurs through space which involves the hopping process. Standard band theory has been used to compare the experimental and theoretical results of optoelectronic measurements. The calculations confirm that both are direct band gap (2.78 and 3.30 eV) semiconductors and that complex 1 exhibits a lower band gap, in line with the experimental results (3.21 and 3.43 eV in 1 and 2, respectively).

N-((1H-Pyrrol-2-yl)methylene)-6-methoxypyridin-3-amine and Its Co(II) and Cu(II) Complexes as Antimicrobial Agents: Chemical Preparation, In Vitro Antimicrobial Evaluation, In Silico Analysis and Computational and Theoretical Chemistry Investigations.

Researchers are interested in Schiff bases and their metal complexes because they offer a wide range of applications. The chemistry of Schiff bases of heterocompounds has got a lot of attention because of the metal's ability to coordinate with Schiff base ligands. In the current study, a new bidentate Schiff base ligand, N-((1H-pyrrol-2-yl)methylene)-6-methoxypyridin-3-amine (MPM) has been synthesized by condensing 6-methoxypyridine-3-amine with pyrrole-2-carbaldehyde. Further, MPM is used to prepare Cu(II) and Co(II) metal complexes. Analytical and spectroscopic techniques are used for the structural elucidation of the synthesized compounds. Both MPM and its metal complexes were screened against Escherichia coli, Bacillus subtilis, Staphylococcus aureus and Klebsiella pneumoniae species for antimicrobial studies. Furthermore, these compounds were subjected to in silico studies against bacterial proteins to comprehend their best non-bonded interactions. The results confirmed that the Schiff base ligand show considerably higher binding affinity with good hydrogen bonding and hydrophobic interactions against various tested microbial species. These results were complemented with a report of the Conceptual DFT global reactivity descriptors of the studied compounds together with their biological scores and their ADMET computed parameters.

Conceptual DFT-Based Computational Peptidology, Pharmacokinetics Study and ADMET Report of the Veraguamides A-G Family of Marine Natural Drugs.

As a continuation of our research on the chemical reactivity, pharmacokinetics and ADMET properties of cyclopeptides of marine origin with potential therapeutic abilities, in this work our already presented integrated molecular modeling protocol has been used for the study of the chemical reactivity and bioactivity properties of the Veraguamides A-G family of marine natural drugs. This protocol results from the estimation of the conceptual density functional theory (CDFT) chemical reactivity descriptors together with several chemoinformatics tools commonly considered within the process of development of new therapeutic drugs. CP-CDFT is a branch of computational chemistry and molecular modeling dedicated to the study of peptides, and it is a protocol that allows the estimation with great accuracy of the CDFT-based reactivity descriptors and the associated physical and chemical properties, which can aid in determining the ability of the studied peptides to behave as potential useful drugs. Moreover, the superiority of the MN12SX density functional over other long-range corrected density functionals for the prediction of chemical and physical properties in the presence of water as the solvent is clearly demonstrated. The research was supplemented with an investigation of the bioactivity of the molecular systems and their ADMET (absorption, distribution, metabolism, excretion, and toxicity) parameters, as is customary in medicinal chemistry. Some instances of the CDFT-based chemical reactivity descriptors' capacity to predict the pKas of peptides as well as their potential as AGE inhibitors are also shown.

Alcoholic Liver Disease Among Patients with Wernicke Encephalopathy: A Multicenter Observational Study.

BACKGROUND: data regarding the association between Wernicke encephalopathy (WE) and alcoholic liver disease (ALD) are scarce in spite of alcohol consumption being the main risk factor for WE. AIMS: to describe the frequency of ALD in a cohort of patients diagnosed with WE and alcohol use disorders (AUDs) and to compare the characteristics of WE patients with and without ALD. METHODS: we conducted an observational study in 21 centers through a nationwide registry of the Spanish Society of Internal Medicine. WE Caine criteria were applied and demographic, clinical, and outcome variables were analyzed. RESULTS: 434 patients were included in the study, of which 372 were men (85.7%), and the mean age was 55 ± 11.8 years. ALD was present in 162 (37.3%) patients and we found a higher percentage of cases with tremor, flapping and hallucinations in the ALD group. A total of 22 patients (5.0%) died during admission (7.4% with ALD vs 3.7% without ALD; P = 0.087). Among the ALD patients, a relationship between mortality and the presence of anemia (Odds ratio [OR]=4.6 Confidence interval [CI]95% 1.1-18.8; P = 0.034), low level of consciousness (OR=4.9 CI95% 1.1-21.2; P = 0.031) and previous diagnosis of cancer (OR=10.3 CI95% 1.8-59.5; P = 0.009) was detected. Complete recovery was achieved by 27 patients with ALD (17.8%) and 71 (27.8%) without ALD (P = 0.030). CONCLUSION: the association of WE and ALD in patients with AUDs is frequent and potentially linked to differences in clinical presentation and to poorer prognosis, as compared to alcoholic patients with WE without ALD.

Virtual Screening for Potential Phytobioactives as Therapeutic Leads to Inhibit NQO1 for Selective Anticancer Therapy.

NAD(P)H:quinone acceptor oxidoreductase-1 (NQO1) is a ubiquitous flavin adenine dinucleotide-dependent flavoprotein that promotes obligatory two-electron reductions of quinones, quinonimines, nitroaromatics, and azo dyes. NQO1 is a multifunctional antioxidant enzyme whose expression and deletion are linked to reduced and increased oxidative stress susceptibilities. NQO1 acts as both a tumor suppressor and tumor promoter; thus, the inhibition of NQO1 results in less tumor burden. In addition, the high expression of NQO1 is associated with a shorter survival time of cancer patients. Inhibiting NQO1 also enables certain anticancer agents to evade the detoxification process. In this study, a series of phytobioactives were screened based on their chemical classes such as coumarins, flavonoids, and triterpenoids for their action on NQO1. The in silico evaluations were conducted using PyRx virtual screening tools, where the flavone compound, Orientin showed a better binding affinity score of -8.18 when compared with standard inhibitor Dicumarol with favorable ADME properties. An MD simulation study found that the Orientin binding to NQO1 away from the substrate-binding site induces a potential conformational change in the substrate-binding site, thereby inhibiting substrate accessibility towards the FAD-binding domain. Furthermore, with this computational approach we are offering a scope for validation of the new therapeutic components for their in vitro and in vivo efficacy against NQO1.

Ruxolitinib in severe COVID-19: Results of a multicenter, prospective, single arm, open-label clinical study to investigate the efficacy and safety of ruxolitinib in patients with COVID-19 and severe acute respiratory syndrome

Introduction: COVID-19 morbimortality is mainly associated with development of severe acute respiratory syndrome (SARS), which has been related to an augmented immune response of the host with elevated circulating cytokines. Methods: In this prospective, multicenter, single arm (compared with a historical control), add-on, experimental phase 2 study, ruxolitinib 5 mg BID was added to standard of care in COVID-19 patients. Main objective was to determine efficacy and safety of ruxolitinib in patients with COVID-19-related SARS. Results: Even though we could not show a significant reduction of COVID-19 pneumonia patients requiring intensive care unit admission and mechanical ventilation (primary endpoint), a trend to a lower mortality rate in critical ill patients receiving ruxolitinib was reported. Administered ruxolitinib dose had to be increased according to protocol in 32% of patients, without additional toxicity. Conclusion: Side effects profile was manageable, and no direct organ injury was caused by the study drug. Ruxolitinib had a fast anti-inflammatory effect, and one-third of patients felt well immediately after starting treatment.

Introducción: La morbimortalidad por COVID-19 se asocia principalmente con el síndrome respiratorio agudo severo (SARS), relacionado con una respuesta inmunitaria aumentada del huésped con aumento de los niveles circulantes de citoquinas. Métodos: En este estudio prospectivo, multicéntrico, de un solo brazo (en comparación con un control histórico), en fase 2, se agregó ruxolitinib 5 mg dos veces al día al estándar de tratamiento en pacientes con COVID-19. El objetivo principal fue determinar la eficacia y seguridad de ruxolitinib en pacientes con SARS relacionado con COVID-19. Resultados: aunque no fue posible demostrar una reducción significativa de la proporción de pacientes con neumonía por COVID-19 que requerían ingreso en la unidad de cuidados intensivos y ventilación mecánica (criterio de valoración principal), se observó una tendencia a una menor tasa de mortalidad en los pacientes críticos que recibieron ruxolitinib. La dosis de ruxolitinib administrada tuvo que aumentarse de acuerdo con el protocolo en el 32% de los pacientes, sin toxicidad adicional. Conclusión: El perfil de efectos secundarios fue manejable y el fármaco en estudio no causó lesiones orgánicas directas. El ruxolitinib tuvo un efecto antiinflamatorio rápido y un tercio de los pacientes manifestó bienestar inmediatamente después de comenzar el tratamiento.

Synthesis, Computational Pharmacokinetics Report, Conceptual DFT-Based Calculations and Anti-Acetylcholinesterase Activity of Hydroxyapatite Nanoparticles Derived From Acorus Calamus Plant Extract.

Over the years, Alzheimer's disease (AD) treatments have been a major focus, culminating in the identification of promising therapeutic targets. A herbal therapy approach has been required by the demand of AD stage-dependent optimal settings. Present study describes the evaluation of anti-acetylcholinesterase (AChE) activity of hydroxyapatite nanoparticles derived from an Acorus calamus rhizome extract (AC-HAp NPs). The structure and morphology of as-prepared (AC-HAp NPs) was confirmed using powder X-ray diffractometer (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM) and high-resolution transmission electron microscopy (HR-TEM). The crystalline nature of as-prepared AC-HAp NPs was evident from XRD pattern. The SEM analysis suggested the spherical nature of the synthesized material with an average diameter between 30 and 50 nm. Further, the TEM and HR-TEM images revealed the shape and size of as-prepared (AC-HAp NPs). The interplanar distance between two lattice fringes was found to be 0.342 nm, which further supported the crystalline nature of the material synthesized. The anti-acetylcholinesterase activity of AC-HAp NPs was greater as compared to that of pure HAp NPs. The mechanistic evaluation of such an activity carried out using in silico studies suggested that the anti-acetylcholinesterase activity of phytoconstituents derived from Acorus calamus rhizome extract was mediated by BNDF, APOE4, PKC-γ, BACE1 and γ-secretase proteins. The global and local descriptors, which are the underpinnings of Conceptual Density Functional Theory (CDFT), have been predicted through the MN12SX/Def2TZVP/H2O model chemistry to help in the comprehension of the chemical reactivity properties of the five ligands considered in this study. With the further objective of analyzing their bioactivity, the CDFT studies are complemented with the estimation of some useful computed pharmacokinetics indices, their predicted biological targets, and the ADMET parameters related to the bioavailability of the five ligands are also reported.

Association Between Preexisting Versus Newly Identified Atrial Fibrillation and Outcomes of Patients With Acute Pulmonary Embolism.

Background Atrial fibrillation (AF) may exist before or occur early in the course of pulmonary embolism (PE). We determined the PE outcomes based on the presence and timing of AF. Methods and Results Using the data from a multicenter PE registry, we identified 3 groups: (1) those with preexisting AF, (2) patients with new AF within 2 days from acute PE (incident AF), and (3) patients without AF. We assessed the 90-day and 1-year risk of mortality and stroke in patients with AF, compared with those without AF (reference group). Among 16 497 patients with PE, 792 had preexisting AF. These patients had increased odds of 90-day all-cause (odds ratio [OR], 2.81; 95% CI, 2.33-3.38) and PE-related mortality (OR, 2.38; 95% CI, 1.37-4.14) and increased 1-year hazard for ischemic stroke (hazard ratio, 5.48; 95% CI, 3.10-9.69) compared with those without AF. After multivariable adjustment, preexisting AF was associated with significantly increased odds of all-cause mortality (OR, 1.91; 95% CI, 1.57-2.32) but not PE-related mortality (OR, 1.50; 95% CI, 0.85-2.66). Among 16 497 patients with PE, 445 developed new incident AF within 2 days of acute PE. Incident AF was associated with increased odds of 90-day all-cause (OR, 2.28; 95% CI, 1.75-2.97) and PE-related (OR, 3.64; 95% CI, 2.01-6.59) mortality but not stroke. Findings were similar in multivariable analyses. Conclusions In patients with acute symptomatic PE, both preexisting AF and incident AF predict adverse clinical outcomes. The type of adverse outcomes may differ depending on the timing of AF onset.

Computer-assisted planning with 3D printing for mandibular reconstruction caused by a mandibular fracture with secondary osteomyelitis: A Case Report.

Mandibular reconstructions are complex clinical pictures that require careful planning for functional and aesthetic outcomes. Virtual surgical planning and 3D printing are ideal to achieve a predictable result. Through "hybrid techniques" (prebending plates with 3D-models) and free software, this goal is within reach for clinics with limited financial resources.

Investigation of Antifungal Properties of Synthetic Dimethyl-4-Bromo-1-(Substituted Benzoyl) Pyrrolo[1,2-a] Quinoline-2,3-Dicarboxylates Analogues: Molecular Docking Studies and Conceptual DFT-Based Chemical Reactivity Descriptors and Pharmacokinetics Evaluation.

Candida albicans, an opportunistic fungal pathogen, frequently colonizes immune-compromised patients and causes mild to severe systemic reactions. Only few antifungal drugs are currently in use for therapeutic treatment. However, evolution of a drug-resistant C. albicans fungal pathogen is of major concern in the treatment of patients, hence the clinical need for novel drug design and development. In this study, in vitro screening of novel putative pyrrolo[1,2-a]quinoline derivatives as the lead drug targets and in silico prediction of the binding potential of these lead molecules against C. albicans pathogenic proteins, such as secreted aspartic protease 3 (SAP3; 2H6T), surface protein ß-glucanase (3N9K) and sterol 14-alpha demethylase (5TZ1), were carried out by molecular docking analyses. Further, biological activity-based QSAR and theoretical pharmacokinetic analysis were analyzed. Here, in vitro screening of novel analogue derivatives as drug targets against C. albicans showed inhibitory potential in the concentration of 0.4 µg for BQ-06, 07 and 08, 0.8 µg for BQ-01, 03, and 05, 1.6 µg for BQ-04 and 12.5 µg for BQ-02 in comparison to the standard antifungal drug fluconazole in the concentration of 30 µg. Further, in silico analysis of BQ-01, 03, 05 and 07 analogues docked on chimeric 2H6T, 3N9K and 5TZ1 revealed that these analogues show potential binding affinity, which is different from the therapeutic antifungal drug fluconazole. In addition, these molecules possess good drug-like properties based on the determination of conceptual Density Functional Theory (DFT)-based descriptors, QSAR and pharmacokinetics. Thus, the study offers significant insight into employing pyrrolo[1,2-a]quinoline analogues as novel antifungal agents against C. albicans that warrants further investigation.

Semiconducting properties of pyridyl appended linear dicarboxylate based coordination polymers: theoretical prediction via DFT study.

Coordination polymers (CPs) in recent times have emerged as active constituents in many semiconductor devices like light emitting diodes (LED), field effect transistors (FET), photovoltaic devices and Schottky barrier diodes. An intelligent choice of linkers, careful selection of metal ions and post synthetic modification (PSM) can provide a better pathway for charge transportation. However, a proper understanding of the charge transport mechanism in CPs is still inadequate due to the lack of considerable experimental and theoretical work. In this paper, we address the theoretical elucidation of semiconducting properties and a probable pathway for charge transportation in three of our previously published CPs using density functional theory (DFT). These results help us to recognize the orbitals that have major contributions in the formation of the valence band and also provide the most likely pathway for optimum electronic communication. In this regard, the role of hydrogen bonding and unpaired electrons of metal d-orbitals is also established.

Cu2+, Ca2+, and methionine oxidation expose the hydrophobic α-synuclein NAC domain.

α-Synuclein is an intrinsically disordered protein whose aggregation is related to Parkinson's disease and other neurodegenerative disorders. Metal cations are one of the main factors affecting the propensity of α-synuclein to aggregate, either by directly binding to it or by catalyzing the production of reactive oxygen species that oxidize it. His50, Asp121 and several additional C-terminal α-synuclein residues are binding sites for numerous metal cations, while methionine sulfoxidation occurs readily on this protein under oxidative stress conditions. Molecular dynamics simulations are an excellent tool to obtain a microscopic picture of how metal binding or methionine sulfoxidation alter the conformational preferences of α-synuclein and, hence, its aggregation propensity. In this work, we report the first coarse-grained molecular dynamics study comparing the conformational ensembles of the native protein, the protein bound to either Cu2+ or Ca2+ at its main binding sites, and the methionine-sulfoxidized protein. Our results suggest that these events alter the transient α-synuclein intramolecular contacts, inducing a greater solvent exposure of its hydrophobic, aggregation-prone NAC domain, in full agreement with a recent experimental study on Ca2+ binding. Moreover, metal-binding residues directly participate in the long-range contacts that shield this domain and regulate α-synuclein aggregation. These results provide a molecular-level rationalization of the enhanced fibrillation experimentally observed in the presence of Cu2+ or Ca2+ and the oligomerization induced by methionine sulfoxidation.