Practical Research on the Teaching of "Medical Interpersonal Communication" Integrate into the Red Doctor’s Spirit for Students Majoring in Public Health Management / 中国医学伦理学

The red doctor’s spirit is an important spiritual guidance for the cultivation of medical talents during the development of medical and health services in China. The teaching reform, which is oriented towards position competence, requires that students majoring in public health management should not only master solid medical knowledge and professional skills, but also possess an ability to handle medical public relations, such as shaping an excellent image of the organization, improving the medical interpersonal communication, and managing public relations crisis. Under the guidance of inheriting the red gene and innovating the medical education, the driving force of learning should be "serving the people to improve their health" led by "political firmness" , the learning goal "striving for perfection" inspired by "excellent technology" , and the working criterion "respecting patients, involving full participation and shouldering public responsibility" embodied in "making selfless dedication and helping the wounded and dying" . The article based on the characteristic culture of red medicine in the Air Force Medical University, applied the teaching method of role-playing case simulations to explore the teaching practice road of "theory-experience-practice-reflection" .

Construction of multi-epitope vaccine against the Rhipicephalus microplus tick: an immunoinformatics approach

@#Rhipicephalus microplus, known as the hard tick, is a vector for the parasites Babesia spp. and Anaplasma marginale, both of which can cause significant financial losses to the livestock industry. There is currently no effective vaccine for R. microplus tick infestations, despite the identification of numerous prospective tick vaccine candidates. As a result, the current research set out to develop an immunoinformatics-based strategy using existing methods for designing a multi-epitope based vaccination that is not only effective but also safe and capable of eliciting cellular and humoral immune responses. First, R. microplus proteins Bm86, Subolesin, and Bm95 were used to anticipate and link B and T-cell epitopes (HTL and CTL) to one another. Antigenicity testing, allergenicity assessment, and toxicity screening were just a few of the many immunoinformatics techniques used to identify potent epitopes. Multi-epitope vaccine design was chosen based on the antigenic score 0.935 that is promising vaccine candidate. Molecular docking was used to determine the nature of the interaction between TLR2 and the vaccine construct. Finally, molecular dynamic simulation was used to assess the stability and compactness of the resulting vaccination based on docking scores. The developed vaccine was shown to be stable, have immunogenic qualities, be soluble, and to have high expression by in silico cloning. These findings suggest that experimental investigation of the multi-epitope based vaccine designed in the current study will produce achievable vaccine candidates against R. microplus ticks, enabling more effective control of infestations.

Polymyxins leading to nephrotoxicity

Drug resistance gram-negative bacteria are the most hazardous type of germ because they cause life-threatening illnesses. Polymyxins are cyclic lipodecapeptide antibiotics that are effective against gram-negative bacteria like Acinetobacter, Pseudomonas, and other Enterobacteriaceae (such Klebsiella, Escherichia coli, and Serratia). Polymyxins kill bacteria by rupturing the bacterial outer membrane (OM). The main side effect of this antibiotic class is the development of kidney damage. Transposable genetic elements, such as MCR genes, can encode bacterial resistance to polymyxins. Colistin's prodrug is colistimethate sodium (CMS). Polymyxin dosage should be modified based on renal function. Polymyxins have demonstrated excellent clinical results, which have aided in the development of a better dosage regimen. Monte Carlo simulations were used to determine the most effective polymyxin dosages. Polymyxin resurgence has resulted in the eradication of multidrug resistant gram negative bacteria.

Binding interaction of laccases from Bacillus Subtilis after industrial dyes exposure: Molecular docking and molecular dynamics simulation studies

Dyes are becoming more widely used around the world wide, but there is no effective bioremediation approach for removing them completely from the environment. Several dyes are mentioned to be degraded through bacteria; however, it's still unknown how the particular enzymes act throughout the dye degradation. The behavior and function of these enzymes in the biodegradation of azo dyes (Textile dyes) had been investigated experimentally by the numbers of the researchers, however, the molecular mechanisms remain unclear. Therefore, the interaction mechanisms of textile dye (methyl orange) with laccase from B. subtilis were explored through molecular docking and molecular dynamics simulations, the three selected dyes (methyl orange, malachite green, and acid blue 62) that interact positively with laccase on the basis of their maximum binding energy, molecular docking results indicate that one of the three dyes is more stable as a target for degradation through Bacillus subtilis laccase. Therefore, subsequent research focused solely on one substrate: methyl orange. Molecular Dynamics simulation study was applied after the molecular docking to determine the interaction between laccases and methyl orange dyes. The trajectory was proved with root mean square deviation and root mean square fluctuation analysis. According to the molecular dynamics simulation results, laccase-methyl orange complexes remain stable during the catalytic reaction. So, this study demonstrates how laccase is involved in methyl orange bioremediation.

Coarse-Grained Simulation of Amyloid Nucleation under Cooperative Effects of Peptides / 医用生物力学

Objective To explore the cooperative effect from β-propensity of amyloidogenic peptides on amyloid nucleation and its related products. Methods Based on a coarse-grained model for amyloidogenic peptides containing two states ( a soluble state and a β-sheet-forming state), with the consideration of two kinds of cooperative effects on β-propensity of peptides ( inhibiting and promoting the conformational conversion of peptides), the regulation of cooperative effects from amyloidogenic peptides on amyloid nucleation was analyzed through Monte Carlo simulations. Results In the case of the cooperative effect inhibiting the conformational conversion of peptides, amyloid nucleation occurred only within a certain interval of the peptide concentration, as well as inside the oligomers with certain sizes. Besides, the coexistence of on-pathway and off-pathway oligomers was observed. In the case of the cooperative effect promoting the conformational conversion of peptides, the β-sheet protofibril could be observed at physiological concentration as low as 4 μmol / L. Conclusions In this study, a more realistic coarse-grained model for amyloidogenic peptides was developed by introducing the cooperative effects of local concentration on β-propensity of amyloidogenic peptides, with observation of some intriguing phenomena not reported in previous simulations. The research findings not only improve current understandings about the mechanism of amyloid formation, but also provide theoretic references for the therapeutic strategies for curing neurodegenerative diseases

Practical Report of the First-Year Experience Medical Students Using ICT : Trial of Online Disability Simulations / 医学教育

Tohoku Medical and Pharmaceutical University, Japan, offers “Early Exposure to Medical Practice” in the first semester for first-year medical students to learn about patient-centered care as well as the real-world conditions and issues faced in community medical practice. Owing to the COVID-19 pandemic during the past two years, we planned and implemented online training, including some disability simulations, which mostly aimed to prevent the spread of infection. The students who completed these training courses reported that the online training had certain advantages over hands-on training ; the two activities implemented were not only effective in preventing infection but also had other benefits that only an online environment could provide. Herein, we report the results and some of the merits of these practices in 2021.

Comportamiento de la amoxicilina en agua mediante métodos de solvatación implícita y explícita

El comportamiento molecular de la amoxicilina en agua fue explorado con solvatación implícita y explícita mediante dos estrategias que combinan diferentes técnicas de simulación molecular para evaluar el alcance de estos procedimientos. Con estas dos estrategias de cálculo computacional, la conformación molecular de la amoxicilina fue determinada en fase acuosa. En la primera estrategia se utilizó el generador de conformaciones Ballon-v1.8.2 y la estabilidad de las conformaciones en agua fue evaluada utilizando la energía libre de solvatación determinada con el método de solvatación implícita SMD. En la segunda estrategia, con la dinámica molecular tipo NVT fue evaluado el arreglo espacial de esta molécula en agua y, además, la interacción molecular entre la amoxicilina y el agua fue evaluada en esta simulación. Los resultados obtenidos muestran que la conformación de la amoxicilina más estable en fase acuosa es la plegada. Además, los valores de energías de solvatación de -121,42 y -14,58 kJ/mol obtenidos con solvatación implícita y dinámica molecular sugieren que esta molécula tiene una alta afinidad por el agua. Las funciones distribución radial y espacial sugieren que se forman 3 capas de solvatación alrededor de la amoxicilina y que esta molécula tiene una región altamente hidrofílica. Finalmente, la estrategia usando dinámica molecular permite obtener mejores conformaciones en equilibrio que la estrategia de simulación usando el generador de conformaciones Ballon-v1.8.2.

The molecular behavior of amoxicillin in water was explored with implicit and explicit solvation using two strategies that combine different molecular simulation techniques to assess the scope of these procedures. With these two computational calculation strategies, the molecular conformation of amoxicillin was determined in aqueous phase. In the first strategy, the conformation generator Ballon-v1.8.2 was used and the stability of the conformations in water was evaluated using the solvation free energy determined with the SMD implicit solvation method. In the second strategy, with NVT-type molecular dynamics, the spatial arrangement of this molecule in water was evaluated and, in addition, the molecular interaction between amoxicillin and water was evaluated in this simulation. The results obtained show that the most stable conformation of amoxicillin in the aqueous phase is the folded one. In addition, the solvation energy values of -121.42 and -14.58 kJ/mol obtained with implicit solvation and molecular dynamics suggest that this molecule has a high affinity for water. The radial and spatial distribution functions suggest that 3 solvation shells form around amoxicillin and that this molecule has a highly hydrophilic region. Finally, the strategy using molecular dynamics allows to obtain better equilibrium conformations than the simulation strategy using the Ballon-v1.8.2 conformation generator.

O comportamento da amoxicilina em água foi analisado com solvatação implícita e explícita mediante duas estratégias que combinam diferentes técnicas de simulação molecular para avaliar o escopo destes procedimentos. Com estas duas estratégias de cálculo computacional, a conformação molecular da amoxicilina foi determinada em fase aquosa. Na primeira estratégia, utilizou-se o gerador de conformação do software Ballon-v1.8.2 e avaliou-se a estabilidade das conformações em água a partir da energia livre de solvatação determinada pelo método de solvatação implícita SMD. Na segunda estratégia, avaliou-se o arranjo espacial da amoxicilina e sua interação com a água através de simulações de dinâmica molecular NVT. Os resultados obtidos mostram que a conformação dobrada é a mais estável em fase aquosa. Ademais, os valores de energía de solvatação de -121,42 e -14,58 kJ/mol obtidos com solvatação implícita e dinâmica molecular sugerem que esta molécula possui alta afinidade pela água. As funções de distribuição radial e espacial sugerem que se formam 3 camadas de solvatação ao redor da amoxicilina e que esta molécula possui uma região altamente hidrofílica. Finalmente, a estratégia usando dinâmica molecular permite obter melhores conformações de equilíbrio do que a estratégia de simulação usando o gerador de conformação do software Ballon-v1.8.2.

Cryptosporidiosis, a public health challenge: A combined 3D shape-based virtual screening, docking study, and molecular dynamics simulation approach to identify inhibitors with novel scaffolds for the treatment of cryptosporidiosis

Cryptosporidiosis is a neglected tropical disease caused by the protozoan parasite Cryptosporidium parvum. Limited therapeutic options, limitation in in vitro parasite culture, and lack of a reliable animal model of parasite for replication of in vivo life cycle and drug testing demand alternative methods for drug development. The in silico methods of drug discovery prove a crucial process in such conditions.Recent research reported a limited number of small molecules for drug development. Purine nucleotide biosynthesis in Cryptosporidium species is dependent on the IMPDH (CpIMPDH) enzyme, so distortion of parasite IMPDH has been pursued as a compelling strategy for curbing Cryptosporidium infection due to its different kinetics from the host enzyme. Our study's primary aim was to discover novel ligand molecules with noticeable activity against Cryptosporidium parvum IMPDH. For this purpose, we selected 18 previously discovered ligands to understand the interaction feature between ligand and receptor, and their shape and electronic features are employed as a template for shape-based virtual screening of the ZINC database (drug-like subset) search approach via Schrodinger-2019 (Maestro 11.9). The obtained hits were subsequently subjected to structure-based screening, quantum polarized ligand docking (QPLD), and molecular dynamics simulations to fetch potential small molecules with the highest binding affinity for CpIMPDH protein. Further ligand binding energy and pharmacokinetic analysis were also taken into consideration as filtering criteria for selecting the most promising drug-like compounds. On this experimentation analysis, three top-ranked (ZINC24855054, ZINC58171263, and ZINC08000072) molecules were found to have appropriate pharmacokinetic properties along with surpassing in silico inhibitory potential towards the CpIMPDH compared to known inhibitors. The molecular docking and molecular dynamics simulation analysis results satisfactorily confirmed the inhibitory action. Therefore, these new scaffolds deduced by the presented computational methodology could recommend lead molecules for designing promising anti-cryptosporidial drugs targeting CpIMPDH protein.

Structurally defined tandem-responsive nanoassemblies composed of dipeptide-based photosensitive derivatives and hypoxia-activated camptothecin prodrugs against primary and metastatic breast tumors

Substantial progress in the use of chemo-photodynamic nano-drug delivery systems (nano-DDS) for the treatment of the malignant breast cancer has been achieved. The inability to customize precise nanostructures, however, has limited the therapeutic efficacy of the prepared nano-DDS to date. Here, we report a structurally defined tandem-responsive chemo-photosensitive co-nanoassembly to eliminate primary breast tumor and prevent lung metastasis. This both-in-one co-nanoassembly is prepared by assembling a biocompatible photosensitive derivative (pheophorbide-diphenylalanine peptide, PPA-DA) with a hypoxia-activated camptothecin (CPT) prodrug [(4-nitrophenyl) formate camptothecin, N-CPT]. According to computational simulations, the co-assembly nanostructure is not the classical core-shell type, but consists of many small microphase regions. Upon exposure to a 660 nm laser, PPA-DA induce high levels of ROS production to effectively achieve the apoptosis of normoxic cancer cells. Subsequently, the hypoxia-activated N-CPT and CPT spatially penetrate deep into the hypoxic region of the tumor and suppress hypoxia-induced tumor metastasis. Benefiting from the rational design of the chemo-photodynamic both-in-one nano-DDS, these nanomedicines exhibit a promising potential in the inhibition of difficult-to-treat breast tumor metastasis in patients with breast cancer.

Practical Research on the Teaching of "Medical Interpersonal Communication" Integrate into the Red Doctor’s Spirit for Students Majoring in Public Health Management / 中国医学伦理学

The red doctor’s spirit is an important spiritual guidance for the cultivation of medical talents during the development of medical and health services in China. The teaching reform, which is oriented towards position competence, requires that students majoring in public health management should not only master solid medical knowledge and professional skills, but also possess an ability to handle medical public relations, such as shaping an excellent image of the organization, improving the medical interpersonal communication, and managing public relations crisis. Under the guidance of inheriting the red gene and innovating the medical education, the driving force of learning should be "serving the people to improve their health" led by "political firmness" , the learning goal "striving for perfection" inspired by "excellent technology" , and the working criterion "respecting patients, involving full participation and shouldering public responsibility" embodied in "making selfless dedication and helping the wounded and dying" . The article based on the characteristic culture of red medicine in the Air Force Medical University, applied the teaching method of role-playing case simulations to explore the teaching practice road of "theory-experience-practice-reflection" .

Computational approaches towards the discovery and optimisation of cruzain inhibitors

The need to develop safer and more efficacious drugs to treat Chagas disease has motivated the search for cruzain inhibitors. Cruzain is the recombinant, truncated version of cruzipain, a cysteine protease from Trypanosoma cruzi with important roles during the parasite life cycle. Several computational techniques have been applied to discover and optimise cruzain inhibitors, providing a molecular basis to guide this process. Here, we review some of the most recent computational studies that provided important information for the design of cruzain inhibitors. Moreover, we highlight the diversity of applications of in silico techniques and their impact.

Theoretical Study of the Function of the IP3 Receptor/BK Channel Complex in a Single Neuron / Estudio Teórico de la Función del Complejo Receptor-IP3/Canales BK en Neurona Única

ABSTRACT Large conductance calcium-activated potassium (BK) channels carry out many functions in the central nervous system. These channels open in response to increased cytosolic calcium ([Ca2+]cyt) concentration. The influx of calcium ions to the cytosol can occur through voltage-gated calcium channels (VGCCs) on the plasma membrane and/ or through IP3 receptors (IP3-Rs) and ryanodine receptors (RyRs) on the endoplasmic reticulum membrane. The BK channel/IP3-R/RyR interaction has been widely reported in smooth muscle but scarcely investigated in relation to neurons. The aim of this study was to theoretically explore the function of the BK/IP3-R complex by means of a computational model of a neuron that replicates the interaction between the release of Ca2+ from the endoplasmic reticulum (through IP3-Rs) and the opening of the BK channels. The mathematical models are based on the Hodgkin-Huxley formalism and the Goldbeter model. These models were implemented on Visual Basic® and differential equations were solved numerically. Distinct conditions were contemplated for BK conductance and the efflux of endoplasmic Ca2+ to the cytosol. An abrupt rise in [Ca2+]cyt (≥ 5 μM) and short duration (spark) was found to activate BK channels and either pause or stop the action potential train.

RESUMEN Los canales de potasio activados por calcio de gran conductancia (canales BK) cumplen múltiples funciones en el sistema nervioso central. Estos canales se abren en respuesta al incremento de la concentración de calcio citosólico ([Ca2+]cyt). La entrada de Ca2+ puede ocurrir a través de canales de calcio dependientes de voltaje (VGCCs) localizados en la membrana plasmática y por eflujo de Ca2+ del retículo endoplásmico (ER) causado por 1,4,5-Trifosfato (IP3) o rianodina (RyR). La interacción BK/IP3/RyR ha sido ampliamente estudiada en músculo liso, pero escasamente en neuronas. El objetivo de este estudio fue explorar teóricamente la función del complejo BK/IP3-R mediante un modelo computacional de una neurona que replica la interacción entre la liberación de Ca2+ del retículo endoplásmico (a través de IP3-Rs) y la apertura de los canales BK. Los modelos matemáticos se basan en el formalismo de Hodgkin-Huxley y el modelo de Goldbeter. Estos modelos fueron implementados en Visual Basic® y las ecuaciones diferenciales fueron resueltas por métodos numéricos. Se contemplaron distintas condiciones para la conductancia del canal BK y la salida de Ca2+ endoplásmico al citosol. Los resultados muestran que un incremento abrupto de [Ca2+] cyt (≥ 5 μM) y de corta duración (spark) activa los canales BK y producen una pausa o detiene el tren de potenciales de acción.

Percepción estudiantil sobre el modelo educativo basado en la simulación / Student perception of the educational model based on simulation

Objetivo: evaluar la percepción de los estudiantes sobre un modelo educativo basado en simulación, en una escuela de medicina privada ubicada en Medellín, Colombia, respecto a su capacidad para desempeñarse en escenarios clínicos reales. Materiales y métodos: estudio transversal. La muestra fueron estudiantes de medicina del IV al XIII período académico. Los datos se recolectaron en fuentes primarias, mediante el diseño y aplicación de un cuestionario. Resultados: la muestra incluyó 300 estudiantes durante sus prácticas clínicas y pasantías y la edad promedio fue de 21,9 años. El 68,3% (n = 205) de la muestra eran mujeres. Se evaluó el nivel de satisfacción con la experiencia de usar simulación clínica; el 65,3% (n = 196) describió la experiencia como satisfactoria, el 2% (n = 6) y el 23% (n = 69) como insatisfactoria y moderadamente satisfactoria respectivamente; los participantes restantes 9,7% (n = 29) describieron la experiencia como totalmente satisfactoria. En cuanto a la percepción de las competencias desarrolladas bajo el modelo educativo se destacan el razonamiento clínico, 98% (n = 294) y la toma de decisiones, 95% (n = 285). Conclusión: los estudiantes encuestados percibieron que la simulación facilita el aprendizaje al posibilitar el desarrollo de habilidades como el trabajo en equipo y la comunicación, lo que genera un alto grado de satisfacción en los estudiantes con respecto a su proceso de formación..(Au)

Objective: to assess perception of the students on a simulation-based educational model, in a private medical school located at the municipality of Medellín, Colombia, regarding with their ability to perform in real clinical scenarios. Materials and methods: a cross sectional study. Sample were medical students from IV to the XIII academic period. Data was collected from primary sources, through the design and application of a questionnaire. Results: the sample included were 300 students during their clinical practices and clerkship, the mean age was 21.9 years. 68.3% (205) of the sample were female. We assess the level of satisfaction with the experience of using clinical simulation; 65.3% (n=196) described the experience as satisfactory, 2% (n=6) and 23% (n=69) as unsatisfactory and moderately satisfactory respectively; remaining participants described the experience as full satisfactory. Regarding the perception of the competences developed under the simulation-based education model, the main ones were 98% (n=294) clinical reasoning and 95% (n=285) decision making. Conclusion: surveyed students perceived that simulation facilitates learning by making possible the development of skills such as teamwork and communication, which generates a high degree of satisfaction in students regarding their training process..(Au)

Computation-aided design of the flexible region of zearalenone hydrolase improves its thermal stability / 生物工程学报

The zearalenone hydrolase (ZHD101) derived from Clonostachys rosea can effectively degrade the mycotoxin zearalenone (ZEN) present in grain by-products and feed. However, the low thermal stability of ZHD101 hampers its applications. High throughput screening of variants using spectrophotometer is challenging because the reaction of hydrolyzing ZEN does not change absorbance. In this study, we used ZHD101 as a model enzyme to perform computation-aided design followed by experimental verification. By comparing the molecular dynamics simulation trajectories of ZHD101 at different temperatures, 32 flexible sites were selected. 608 saturated mutations were introduced into the 32 flexible sites virtually, from which 12 virtual mutants were screened according to the position specific score and enzyme conformation free energy calculation. Three of the mutants N156F, S194T and T259F showed an increase in thermal melting temperature (ΔTm>4 °C), and their enzyme activities were similar to or even higher than that of the wild type (relative enzyme activity 95.8%, 131.6% and 169.0%, respectively). Molecular dynamics simulation analysis showed that the possible mechanisms leading to the improved thermal stability were NH-π force, salt bridge rearrangement, and hole filling on the molecular surface. The three mutants were combined iteratively, and the combination of N156F/S194T showed the highest thermal stability (ΔTm=6.7 °C). This work demonstrated the feasibility of engineering the flexible region to improve enzyme performance by combining virtual computational mutations with experimental verification.

Las simulaciones de pacientes politraumatizados mejoran el conocimiento y el criterio de aplicación de triaje en estudiantes de sexto año de la facultad de medicina de la Universidad Francisco Marroquín / Simulations of polytraumatized patients improve the knowledge and application criteria of triage in sixth-year students of the faculty of medicine of the Francisco Marroquín University

Introducción y objetivos: Las simulaciones han sido una estrategia que se ha desarrollado para prevenir los errores médicos ya que proporcionan un ambiente seguro para el aprendizaje, donde los errores no son fatales. Triaje se define como la clasificación de pacientes según la severidad de sus lesiones con el propósito de salvar la mayor cantidad de vidas con los recursos disponibles. El objetivo del estudio es determinar si las simulaciones de pacientes politraumatizados mejoran el conocimiento y criterio de aplicación de triaje. Métodos: Este fué un estudio descriptivo prospectivo donde se realizó un examen antes y al finalizar las simulaciones de pacientes politraumatizados. esultados: El puntaje promedio fue de 50.73 y 59.44 antes y después de la simulaciones espectivamente. El 53 % de los pacientes fueron sobreclasificados, el 40% fue clasificado correctamente y el 6% fueron subclasificados en el examen previo a las simulaciones, el 40% de los pacientes fue sobreclasificado y el 60% fue clasificado correctamente en el examen al finalizar las simulaciones. Discusión: Aunque se presentó un escenario con todos los recursos necesarios, los estudiantes analizaron los casos en base a la realidad de Guatemala, por lo que sobre clasificaron a los pacientes. Sin embargo, se evidenció una mejoría en el puntaje y en la correcta clasificación de los pacientes. (AU)

Introduction and objectives: Simulations have been developed as a strategy to prevent medical errors, because they provide a safe environment to learn from mistakes and the mistakes are not fatal. Triage is defined as the classification of patients according to the severity of their injuries in order to save as many lives with the available resources. The objective of the study is to determine if simulations of polytraumatized patients improve the knowledge and criteria of triage application. Methods: This was a prospective descriptive study where a test was performed before and at the end of the simulations of solytraumatized patients. Results: The average results were 50.73 and 59.44 before and after the simulations respectively. They overclassified 53% of the patients, 40% was correctly classified and 6% were subclassified in the pre-simulation test, in the test at the end of the simulations 40% were overclassified and 60% were correctly classified. Discussion: Although the scenario was presented with all the necessary resources, the students analyzed the cases based on the reality of Guatemala, so they had the tendency to over-classified the patients. However, there was an improvement in the score and in the correct classification of patients. (AU)

Identification of a repurposed drug as an inhibitor of Spike protein of human coronavirus SARS-CoV-2 by computational methods

Severe acute respiratory syndrome coronavirus (SARS-CoV-2) is an emerging new viral pathogen that causessevere respiratory disease. SARS-CoV-2 is responsible for the outbreak of COVID-19 pandemic worldwide.As there are no confirmed antiviral drugs or vaccines currently available for the treatment of COVID-19,discovering potent inhibitors or vaccines are urgently required for the benefit of humanity. The glycosylatedSpike protein (S-protein) directly interacts with human angiotensin-converting enzyme 2 (ACE2) receptorthrough the receptor-binding domain (RBD) of S-protein. As the S-protein is exposed to the surface and isessential for entry into the host, the S-protein can be considered as a first-line therapeutic target for antiviraltherapy and vaccine development. In silico screening, docking, and molecular dynamics simulation studieswere performed to identify repurposing drugs using DrugBank and PubChem library against the RBD ofS-protein. The study identified a laxative drug, Bisoxatin (DB09219), which is used for the treatment ofconstipation and preparation of the colon for surgical procedures. It binds nicely at the S-protein–ACE2interface by making substantial p-p interactions with Tyr505 in the ‘Site 1’ hook region of RBD andhydrophilic interactions with Glu406, Ser494, and Thr500. Bisoxatin consistently binds to the proteinthroughout the 100 ns simulation. Taken together, we propose that the discovered molecule, Bisoxatin may bea promising repurposable drug molecule to develop new chemical libraries for inhibiting SARS-CoV-2 entryinto the host.

Analyzing The Role Of Phytochemicals In Targeting Drug Transporter Protein Abcc6 Using Molecular Docking And Molecular Dynamics Simulations

Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype that lacks hormonal receptors. This reduces the therapeutic options for TNBC patients creating more focus on chemotherapy. Drug resistance has posed as a major hurdle in treating TNBC patients. Deregulation of drug transporter proteins is one of major factors that cause resistance to chemotherapeutic drugs. In this study, ABCC6 a drug transporter protein that is found dysregulated in several resistant cancer cells has been docked with natural compounds or phytochemicals with known anti-cancer activities. Subtrifloralactone G, a withanolide extracted from Deprea subtriflora is found to show highest binding energy with ABCC6 protein. Molecular dynamics simulations further prove the stability of the ABCC6 protein- Subtrifloralactone G ligand complex. ADMET analysis shows that phytochemical Subtrifloralactone G can be used as an anti-cancer therapeutic drug in treating resistant cancer cells. The study mainly focuses on the role of phytochemicals in treating resistant TNBC cells.

In-silico analysis of Porcine and recombinant Insulin activity on Glycogen

The study focuses on the anti-diabetic activity by molecular simulation of Recombinant Insulin, PorcineInsulin, and Glycogen. The sequence of these three molecules was retrieved, and 3D structures weremodeled. A total of two different molecular simulations were carried out. The simulations were done usingAutodock software. Initially, the downloaded PDB structures were docked with glycogen and the secondbetween the active site peptide models of both insulin molecules based on castP prediction with glycogenmolecule. The results were analyzed by Ramachandran plot for model prediction, and the binding energywas set as criteria to determine the best-docked model. The binding energy of recombinant insulin, porcineinsulin with glycogen was 0.32 and -1.09 respectively. Similarly, the binding energy for peptide modelswith glycogen molecule was found to be +1.09 and +6.76 respectively. Based on the results, it wasconcluded that the recombinant insulin has higher affinity than the porcine insulin.

An in silico investigation of phytochemicals as potential inhibitors against non-structural protein 1 from dengue virus 4

Dengue fever has emerged as a big threat to human health since the last decade owing to high morbidity with considerable mortalities. The proposed study aims at the in silico investigation of the inhibitory action against DENV4-NS1 of phytochemicals from two local medicinal plants of Pakistan. Non-Structural Protein 1 of Dengue Virus 4 (DENV4-NS1) is known to be involved in the replication and maturation of viron in the host cells. A total of 129 phytochemicals (50 from Tanacetum parthenium and 79 from Silybum marianum) were selected for this study. The tertiary structure of DENV4-NS1 was predicted based on homology modelling using Modeller 9.18 and the structural stability was evaluated using molecular dynamics simulations. Absorption, distribution, metabolism, excretion and toxicity (ADMET) along with the drug-likeness was also predicted for these phytochemicals using SwissADME and PreADMET servers. The results of ADMET and drug-likeness predictions exhibited that 54 phytochemicals i.e. 25 from Tanacetum parthenium and 29 from Silybum marianum showed effective druglikeness. These phytochemicals were docked against DENV4-NS1 using AutoDock Vina and 18 most suitable phytochemicals with binding affinities ≤ -6.0 kcal/mol were selected as potential inhibitors for DENV4-NS1. Proposed study also exploits the novel inhibitory action of Jaceidin, Centaureidin, Artecanin, Secotanaparthenolide, Artematin, Schizolaenone B, Isopomiferin, 6, 8-Diprenyleriodictyol, and Anthraxin against dengue virus. It is concluded that the screened 18 phytochemicals have strong inhibition potential against Dengue Virus 4.

Novel ligand-based docking; molecular dynamic simulations; and absorption, distribution, metabolism, and excretion approach to analyzing potential acetylcholinesterase inhibitors for Alzheimer's disease / 药物分析学报

Acetylcholinesterase (AChE) plays an important role in Alzheimer's disease (AD). The excessive activity of AChE causes various neuronal problems, particularly dementia and neuronal cell deaths. Generally, anti- AChE drugs induce some serious neuronal side effects in humans. Therefore, this study sought to identify alternative drug molecules from natural products with fewer side effects than those of conventional drugs for treating AD. To achieve this, we developed computational methods for predicting drug and target binding affinities using the Schrodinger suite. The target and ligand molecules were retrieved from established databases. The target enzyme has 539 amino acid residues in its sequence alignment. Ligand molecules of 20 bioactive molecules were obtained from different kinds of plants, after which we performed critical analyses such as molecular docking; molecular dynamic (MD) simulations; and absorption, distribution, metabolism, and excretion (ADME) analysis. In the docking studies, the natural compound rutin showed a superior docking score of -12.335 with a good binding energy value of -73.313 kcal/mol. Based on these findings, rutin and the target complex was used to perform MD simulations to analyze rutin stability at 30 ns. In conclusion, our study demonstrates that rutin is a superior drug candidate for AD. Therefore, we propose that this molecule is worth further investigation using in vitro studies.