QSAR and DFT Studies of Some Tacrine-Hydroxamate Derivatives as Inhibitors of Cholinesterase (AChEs) in the Treatment of Alzheimer's Disease

Introduction: This work was devoted to an in silico investigation conducted on twenty-eight Tacrine-hydroxamate derivatives as a potential treatment for Alzheimer's disease using DFT and QSAR modeling techniques. Method(s): The data set was randomly partitioned into a training set (22 compounds) and a test set (6 compounds). Then, fourteen models were built and were used to compute the predicted pIC50 of compounds belonging to the test set. Result(s): Al built models were individualy validated using both internal and external validation methods, including the Y-Randomization test and Golbraikh and Tropsha's model acceptance criteria. Then, one model was selected for its higher R2, R2test, and Q2cv values (R2 = 0.768, R2adj = 0.713, MSE = 0.304, R2test=0.973, Q2cv = 0.615). From these outcomes, the activity of the studied compounds toward the main protease of Cholinesterase (AChEs) seems to be influenced by 4 descriptors, i.e., the total dipole moment of the molecule (mu), number of rotatable bonds (RB), molecular topology radius (MTR) and molecular topology polar surface area (MTPSA). The effect of these descriptors on the activity was studied, in particular, the increase in the total dipole moment and the topological radius of the molecule and the reduction of the rotatable bond and topology polar surface area increase the activity. Conclusion(s): Some newly designed compounds with higher AChEs inhibitory activity have been designed based on the best-proposed QSAR model. In addition, ADMET pharmacokinetic properties were carried out for the proposed compounds, the toxicity results indicate that 7 molecules are nontoxic.Copyright © 2023 Bentham Science Publishers.

Just Keep Swimming...Just Keep Swimming

History: We present a 15-year-old right hand dominant high school swimmer with no significant past medical history, who complains of right elbow pain along the distal biceps' tendon for a 2 months. Pain was insidious in onset, sharp, intermittent, and described as a 0 to 6 out of 10. The patient has been swimming more frequently over the last few months to prepare for competition and noticed progressive pain with swimming. He went on vacation and then was diagnosed with a COVID-19 infection and took an additional 2 weeks off due to fatigue. He returned to sport without re-integration and increased his swimming intensity to 1 to 2 hours daily, which worsened his pain. Performing the butterfly and breaststroke provoke symptoms and cessation of activity reduces the pain. Denies pain at rest. He took Advil which did not reduce his pain. Denies acute trauma, prior injuries, or paresthesias. Physical Exam: Inspection of right elbow: no swelling or signs of discoloration. Palpation: Tenderness at the distal biceps tendon but can hook the tendon without pain. No shoulder or wrist tenderness. Active Range of Motion: Elbow extension 0 degrees, elbow flexion 130 degrees, supination and pronation normal. Normal shoulder and wrist ROM. Muscle strength: 5/5 grip, wrist extension, and wrist flexion. Pain elicited with resisted elbow flexion at the distal humerus. Maneuvers: pain with distal humerus squeeze. Negative Maudsley and negative Cozen test. Differential Diagnosis: 36. Distal Biceps Tendonitis/Tear 37. Stress Reaction of the Distal Humerus 38. Medial Epicondyle Apophysitis 39. Capitellar Osteochondritis Dissecans 40. Radiocapitellar Plica Syndrome Test Results: x-ray right elbow: AP and Lateral views indicate no abnormalities to the bones, alignment, or soft tissue structures. MRI right elbow No IVCON: Biceps tendon intact. There is periosteal edema and endosteal aspect marrow edema along the medial aspect of the distal diaphysis and metaphysis of the humerus. Several small foci of increased cortical signal. No fractures, joint effusion, or chondral defects. Findings comparable to Fredrickson grade 4a distal humerus diametaphysis stress injury. Final Diagnosis: Right Elbow Supracondylar Grade 4a Stress Reaction. Discussion(s): Actives that involve repetitive motion are susceptible to overuse injuries. Cases of upper extremity stress reactions in swimmers have been documented along the inferior angle of the scapula, upper ribs, and olecranon. Stress reactions along the distal humerus in swimmers is not well documented. This pathology has been seen in baseball players, cricket bowlers, and tennis players. In swimming, the butterfly technique requires significant endurance and athletic strength. During a sprint, fast synchronized upper extremity revolutions occurring up to 60 cycles perminute counterforcewater surface area friction leading to excessive loading forces even at 50 meter distances. Outcome(s): The patient was withheld from upper body work outs and swimming for 6 weeks. VitaminDand Calcium levels were drawn revealing a normal calcium level (10.2), but a vitamin D level of 28.1. Patient was started on 600 IU of Vitamin D and 1300 mg of Calcium daily. The patient started a return to swim program and returned to full competition at 7 months post presentation. Follow-Up: At 6 weeks, started an upper extremity low impact non-aquatic physical therapy program. Then a slow progressive return to swimming was initiated at 50% effort for 4 weeks. At 10 weeks, a return to sport plan including 200 m all strokes except butterfly, progressed to 250 m at week 2, 300 m at week 3, and 350 m at week 4. Finally, initiated speed work in =0 to 100 m increments and elbow loading workouts.

Molecular Docking study of Severe Acute Respiratory Syndrome Coronavirus 2 Spike Glycoprotein with Celastroid Triterpenoid Inhibitors

Bagchi et al.: Screening of Severe Acute Respiratory Syndrome Coronavirus 2 inhibitors Severe acute respiratory syndrome coronavirus 2 poses a huge threat to humans. The beta genus Severe acute respiratory syndrome coronavirus 2 has four structural proteins: Spike, envelope, membrane and nucleocapsid protein. Among them, spike plays an important role in the host cell attachment and fusion. The S1 subunit of the spike is responsible for bonding to the host and hence is the most crucial target for finding appropriate inhibitors. Molecular docking calculations at the receptor binding domain of S1 subunit have been carried out with twenty celastroid triterpenoids and found that they have very good binding energies. The interactions of these compounds with important amino acid residues were also thoroughly investigated. The docking poses were further validated by the farPPI web server.

Valorization of biomass ash for the effective removal of dipyrone from water: an efficient and low-cost option

Background: In order to propose a destination for the bottom ash generated from biomass burning, its morphology, functional groups and mineral phases were studied. Dipyrone has been extensively used as an antipyretic, increased due to cases of COVID-19, and due to excretion by urine, incorrect disposal and industrial effluents has been destined to wastewater, being harmful to human and animal life. The present study proposes using biomass ash for the adsorption of dipyrone. Result(s): The characterization of biomass ash shows a sufficient surface area size for adsorption, and a mainly amorphous structure with some peaks of quartz, calcite and other mineral phases. The results show that the kinetic model which best describes the adsorption is the pseudo-first-order model. The Langmuir model best fits at 25 degreeC, and the Freundlich model best describes the adsorption at 35 and 45 degreeC. The thermodynamic parameters indicated that the process is endothermic with a maximum adsorptive capacity of 65.27 mg g-1. In addition, the adsorption is spontaneous, disordered and chemical. The ionic strength study reveals that the adsorbent is promising for real effluent treatment and there is evidence that electrostatic interaction is not the primary adsorptive mechanism, agreeing with the result obtained from pH testing. The proposed mechanism for dipyrone removal involves hydrogen bonds, pi bonds and electron donor-acceptor complex. Conclusion(s): The results are promising in comparison with recent literature and solve two environmental problems: biomass bottom ash disposal and pharmaceutical removal in aqueous medium. The ash may be regarded as a low-cost and environmentally friendly adsorbent. © 2023 Society of Chemical Industry (SCI).

The emerging Omicron variant spike mutation: the relative receptor-binding domain affinity and molecular dynamics

This study aims to fill a knowledge gap in our understanding of Omicron variant receptor-binding domain (RBD) interactions with host cell receptor, angiotensin-converting enzyme 2 (ACE2). Protein-protein docking, scoring, and filtration were all performed using the HDOCK server. A coarse-grained prediction of the changes in binding free energy caused by point mutations in Omicron RBD was requested from the Binding Affinity Changes upon Mutation (BeAtMuSiC) tools. GROMACS was utilized to perform molecular dynamics simulations (MD). Within the 15 mutations in Omicron RBD, several mutations have been linked to increased receptor affinity, immunological evasion, and inadequate antibody response. Wild-type (wt) SARS-CoV-2 and its Omicron variant have 92.27% identity. Nonetheless, Omicron RBD mutations resulted in a slight increase in the route mean square deviations (RMSD) of the Omicron structural model during protein-protein docking, as evidenced by RMSDs of 0.47 and 0.85 A for the wt SARS-CoV-2 and Omicron RBD-ACE2 complexes, respectively. About five-point mutations had essentially an influence on binding free energy, namely G6D, S38L, N107K, E151A, and N158Y. The rest of the mutations were expected to reduce the binding affinity of Omicron RBD and ACE2. The MD simulation supports the hypothesis that Omicron RBD is more stably bound to ACE2 than wt SARS-CoV-2 RBD. Lower RMSD and greater radius of gyration (Rg) imply appropriate Omicron structure 3D folding and stability. However, the increased solvent accessible surface area (SASA) with a greater Omicron shape may have a different interaction with receptor binding and regulate virus entrance. Omicron RBD's mutations help it maintain its structural stability, compactness, ACE2 binding, and immune evasion.Copyright © 2022 AEPress, s.r.o.. All rights reserved.

Facile fabrication of phenylenediamine residue derived N, O co-doped hierarchical hyperporous carbon for high-efficient chloroxylenol removal

The chloroxylenol (PCMX) has shown well virucidal efficacy against COVID-19, but the large-scale utilization of which will undoubtedly pose extra environmental threaten. In the present study, the recycled industrial phenylenediamine residue was used and an integrated strategy of "carbonization-casting-activation" using super low-dose of activator and templates was established to achieve in-situ N/O co-doping and facile synthesis of a kind of hierarchical hyperporous carbons (HHPC). The sample of HHPC-1.25-0.5 obtained with activator and template to residue of 1.25 and 0.5 respectively shows super-high specific surface area of 3602 m2/g and volume of 2.81 cm3/g and demonstrates remarkable adsorption capacity of 1475 mg/g for PCMX in batch and of 1148 mg/g in dynamic column adsorption test. In addition, the HHPC-1.25-0.5 exhibits excellent reusability and tolerance for PCMX adsorption under various ionic backgrounds and real water matrix conditions. The combined physio-chemistry characterization, kinetic study and DFT calculation reveal that the enhanced high performances originate from the hierarchical pore structure and strong electrostatic interaction between PCMX and surface rich pyridinic-N and carbonyl groups.

Integrated smart analytics of nucleic acid amplification tests via paper microfluidics and deep learning in cloud computing

Pandemics such as COVID-19 have exposed global inequalities in essential health care. Here, we proposed a novel analytics of nucleic acid amplification tests (NAATs) by combining paper microfluidics with deep learning and cloud computing. Real-time amplifications of synthesized SARS-CoV-2 RNA templates were performed in paper devices. Information pertained to on-chip reactions in time-series format were transmitted to cloud server on which deep learning (DL) models were preloaded for data analysis. DL models enable prediction of NAAT results using partly gathered real-time fluorescence data. Using information provided by the G-channel, accurate prediction can be made as early as 9 min, a 78% reduction from the conventional 40 min mark. Reaction dynamics hidden in amplification curves were effectively leveraged. Positive and negative samples can be unbiasedly and automatically distinguished. Practical utility of the approach was validated by cross-platform study using clinical datasets. Predicted clinical accuracy, sensitivity and specificity were 98.6%, 97.6% and 99.1%. Not only the approach reduced the need for the use of bulky apparatus, but also provided intelligent, distributable and robotic insights for NAAT analysis. It set a novel paradigm for analyzing NAATs, and can be combined with the most cutting-edge technologies in fields of biosensor, artificial intelligence and cloud computing to facilitate fundamental and clinical research.Copyright © 2023 Elsevier Ltd

Molecularly imprinted polymer-modified carbon paste electrodes (MIP-CPE): A review on sensitive electrochemical sensors for pharmaceutical determinations

Recent years have been associated with the development of various sensor-based technologies in response to the undeniable need for the rapid and precise analysis of an immense variety of pharmaceuticals. In this regard, special attention has been paid to the design and fabrication of sensing platforms based on electrochemical detection methods as they can offer many advantages, such as portability, ease of use, relatively cheap instruments, and fast response times. Carbon paste electrodes (CPEs) are among the most promising conductive electrodes due to their beneficial properties, including ease of electrode modification, facile surface renewability, low background currents, and the ability to modify with different analytes. However, their widespread use is affected by the lack of sufficient selectivity of CPEs. Molecularly imprinted polymers (MIPs) composed of tailor-made cavities for specific target molecules are appealing complementary additives that can overcome this limitation. Accordingly, adding MIP to the carbon paste matrix can contribute to the required selectivity of sensing platforms. This review aims to present a categorized report on the recent research and the outcomes in the combinatory fields of MIPs and CPEs for determining pharmaceuticals in complex and simple matrices. CPEs modified with MIPs of various pharmaceutical compounds, including analgesic drugs, antibiotics, antivirals, cardiovascular drugs, as well as therapeutic agents affecting the central nervous system (CNS), will be addressed in detail.Copyright © 2023 Elsevier B.V.

Life threatening non-accidental burns, pandemic dependent telemedicine, and successful use of cultured Zurich Skin in a neonate - A case report

Life threatening burns of non-accidental origin in neonates are extremely rare. Their management represents a great challenge, particularly since necrosectomy of deep burns and grafting at this young age are technically very demanding. Thus, a strategic surgical master plan is mandatory to achieve rapid and definitive autologous coverage and avoidance of undue risks and iatrogenic burden for the fragile neonatal patient. We present the case of a four day-old neonate who sustained non-accidental deep burns involving 40 % of its total body surface area (TBSA) and the successful application of a laboratory grown, autologous dermo-epidermal skin analogue, termed Zurich Skin (also named denovoSkin), within a clinical trial sub-study. Due to COVID-19 pandemic restrictions, a telemedicine-based approach was installed and a total of 260 cm2 Zurich Skin were transplanted, video assisted, on a wound bed previously prepared with a dermal substitute, thereby covering 20 % TBSA. Take of Zurich Skin was excellent on the chest, good to moderate on the abdomen, and poor on other small areas, where we observed a prolonged healing. After maturation, Zurich Skin showed a close to natural skin coverage without need for further reconstructive surgery. This unique case delivers the proof of concept that Zurich Skin can be successfully applied in early life and even under most adverse medical and paramedical circumstances, provided a carefully crafted masterplan properly addressing the key issues can be executed by joint forces of committed partner institutions.Copyright © 2023 The Authors

Bike Sharing and Health

Civil Aviation is a vital sector of the global economy. The US National Airspace System (NAS) provides a network of airspace, air navigation facilities, equipment, services, airports, technical information, and personnel needed for the operation of civil aviation in the United States. The capacity of the airspace in the current system is primarily limited by the ability of the air traffic controllers to maintain situational awareness and provide separation services to the aircraft. Currently, there is an unprecedented decline of between 56% and 60% in air traffic demand due to the outbreak of corona virus (COVID-19) pandemic in China and its rapid spread to the rest of the world. Before the pandemic, the 2020 FAA forecast predicted the air traffic demand to grow over the next 20 years with an annual growth rate of about 2%. This anticipated increase in traffic will put a further strain on the airports and the airspace;it will result in large delays, airline schedule breakdown, and adverse environmental impact. The system needs to address developments and anticipated explosive growth in low speed and low-cost urban air mobility vehicles. This article provides an overview of Air Traffic Management (ATM) in the United States, brief review of current aviation operations, research under development, and technology and infrastructure upgrades currently being deployed to enable the current aviation system to meet the needs of future aviation systems. Air traffic operations need to be harmonized across all parts of the globe to achieve standardization and efficiency of operations. © 2021 Elsevier Ltd. All rights reserved

D155Y substitution of SARS-CoV-2 ORF3a weakens binding with Caveolin-1.

The clinical manifestation of the recent pandemic COVID-19, caused by the novel SARS-CoV-2 virus, varies from mild to severe respiratory illness. Although environmental, demographic and co-morbidity factors have an impact on the severity of the disease, contribution of the mutations in each of the viral genes towards the degree of severity needs a deeper understanding for designing a better therapeutic approach against COVID-19. Open Reading Frame-3a (ORF3a) protein has been found to be mutated at several positions. In this work, we have studied the effect of one of the most frequently occurring mutants, D155Y of ORF3a protein, found in Indian COVID-19 patients. Using computational simulations we demonstrated that the substitution at 155th changed the amino acids involved in salt bridge formation, hydrogen-bond occupancy, interactome clusters, and the stability of the protein compared with the other substitutions found in Indian patients. Protein-protein docking using HADDOCK analysis revealed that substitution D155Y weakened the binding affinity of ORF3a with caveolin-1 compared with the other substitutions, suggesting its importance in the overall stability of ORF3a-caveolin-1 complex, which may modulate the virulence property of SARS-CoV-2.

A review on production and application of activated carbon from discarded plastics in the context of ‘waste treats waste'

In the post-COVID scenario, the annual increase in plastic waste has taken an upsurge due to the disposal of plastic masks, gloves and other protective equipment. To reduce the plastic load ending up in landfills and oceans or dumped at roadsides, the potential of using plastic polymers in different sectors has been investigated over the years leading to their potential application in pavement laying, concrete industry, fuel generation and production of carbon-based compounds among which activated carbons (AC) is a prime example. As one of the most recommended adsorbents for removing contaminants from water and adsorbing greenhouse gases, AC creates a potential sector for using discarded plastic to further treat pollutants and approach closer to a circular economy for plastics. This paper analyses the production process, the effect of production parameters on AC characteristics and properties that aid in adsorption. The interdependence of these factors determines the surface area, porosity, relative micropore and mesopore volume, thereby defining the utility for removing contaminant molecules of a particular size. Furthermore, this work discusses the application of AC along with a summary of the earlier works leading to the existing gaps in the research area. Production costs, formation of by-products including toxic substances and adsorbate selectivity are the major issues that have restricted the commercial application of this process towards its practical use. Research aimed at valorization of plastic waste into ACs would minimize the solid waste burden, along with treating other pollutants. © 2022 Elsevier Ltd

Surface control approach for growth of cerium oxide on flower-like molybdenum disulfide nanosheets enables superior removal of uremic toxins

Due to the high incidence of kidney disease, there is an urgent need to develop wearable artificial kidneys. This need is further exacerbated by the coronavirus disease 2019 pandemic. However, the dialysate regeneration system of the wearable artificial kidney has a low adsorption capacity for urea, which severely limits its application. Therefore, nanomaterials that can effectively remove uremic toxins, especially urea, to regenerate dialysate are required and should be further investigated and developed. Herein, flower-like molybdenum disulphide (MoS2) nanosheets decorated with highly dispersed cerium oxide (CeO2) were prepared (MoS2/CeO2), and their adsorption performances for urea, creatinine, and uric acid were studied in detail. Due to the open interlayer structures and the combination of MoS2 and CeO2, which can provide abundant adsorption active sites, the MoS2/CeO2 nanomaterials present excellent uremic toxin adsorption activities. Further, uremic toxin adsorption capacities were also assessed using a self-made fixed bed device under dynamic conditions, with the aim of developing MoS2/CeO2 for the practical adsorption of uremic toxins. In addition, the biocompatibility of MoS2/CeO2 was systematically analyzed using hemocompatibility and cytotoxicity assays. Our data suggest that MoS2/CeO2 can be safely used for applications requiring close contact with blood. Our findings confirm that novel 2-dimensional nanomaterial adsorbents have significant potential for dialysis fluid regeneration. © 2022

Sarcopenia in Children with Liver Disease: A Pilot Study

Background and Aims Sarcopenia can be defined as loss of muscle mass, strength and function and has been shown to be associated with increased morbidity and mortality in the adult population. Sarcopenia has been assessed by decreased psoas muscle surface area (PMSA) on Computer tomography (CT) and has been validated in paediatric studies. The impact of Sarcopenia in children with end stage liver disease and oncological conditions is now being recognised. There is scarce literature on the effect of sarcopenia on motor function. CT imaging exposes children to radiation and hence is done in a select group of children at the time of transplant assessment. The aim of this audit was to assess the prevalence of Sarcopenia in children undergoing liver transplant assessment and its relationship on laboratory variables, functional activity and clinical outcomes. Methods Retrospective single centre case review of patients with liver disease undergoing transplant assessment and CT imaging between 2018-2020. Psoas muscle was analysed at the level of L4/L5. The z-Scores were calculated using ageand gender-specific reference values. Sarcopenia was defined as tPMA z score less than -2. We assessed the relationship of Sarcopenia to the biochemical parameters, nutritional status, effect on motor delay/physical abilities (assessed by a range of age appropriate standardised developmental and physical assessments due to COVID pandemic isolation restrictions) and post-transplant complications. Results Thirty one children that met the inclusion criteria were included. Sarcopenia was prevalent in 17 children (6 males: 11 females), with a median age of 3.5 years (SD = 4.9). The common conditions were biliary atresia (n= 11, 35%), hepatoblastoma (n=6, 19%), Autoimmune hepatitis (n=3) etc. Twenty- four patients required additional nutritional support (77% nasogastric feeding, 13% PN and 6% oral supplementation). Mean tPMA z-score was -2.27. Data for the assessment of physical abilities/functional activity was available in 21 children. Impairment of motor skills/physical abilities was overall noted in 14/21 children (67%);9/13 (69%) in the sarcopenic group (6 significant impairment) vs 5/8 (63%) in non sarcopenic group (4 significant impairment). Sarcopenia was associated with increased complications (27 vs 7, p = 0.005) and hypoalbuminaemia (p=0.01), but was not statistically significant (p> 0.05) for the overall length of stay (total and intensive care). Discussion Sarcopenia was commonly identified in children with liver diseases undergoing transplant assessment. Reduction in physical abilities/functional activity was observed in both groups which may be a consequence of loss of muscle mass in children secondary to liver diseases or underlying oncological conditions leading to delay in gross motor skills. Although there was no statistical difference in the duration of stay or impairment of motor skills, complications were higher in the sarcopenic group. Conclusion In this pilot study, sarcopenia is prevalent in children being assessed for liver transplantation and was associated with increased complications. Better non-invasive methods (aside from CT scan) of assessing sarcopenia needs to be developed and validated for the paediatric age group, which would help to better characterise the true incidence and prevalence of sarcopenia in children with chronic liver disease. There is a need to offer nutritional support and assess physical function early in the pre transplant period in order to initiate appropriate physiotherapy interventions to halt and even reverse the progression of sarcopenia.

An investigation into the aging of disposable face masks in landfill leachate

Due to the excessive use of disposable face masks during the COVID-19 pandemic, their accumulation has posed a great threat to the environment. In this study, we explored the fate of masks after being disposed in landfill. We simulated the possible process that masks would experience, including the exposure to sunlight before being covered and the contact with landfill leachate. After exposure to UV radiation, all three mask layers exhibited abrasions and fractures on the surface and became unstable with the increased UV radiation duration showed aging process. The alterations in chemical groups of masks as well as the lower mechanical strength of masks after UV weathering were detected to prove the happened aging process. Then it was found that the aging of masks in landfill leachate was further accelerated compared to these processes occurring in deionized water. Furthermore, the carbonyl index and isotacticity of the mask samples after aging for 30 days in leachate were higher than those of pristine materials, especially for those endured longer UV radiation. Similarly, the weight and tensile strength of the aged masks were also found lower than the original samples. Masks were likely to release more microparticles and high concentration of metal elements into leachate than deionized water after UV radiation and aging. After being exposed to UV radiation for 48 h, the concentration of released particles in leachate was 39.45 muL/L after 1 day and then grew to 309.45 muL/L after 30 days of aging. Seven elements (Al, Cr, Cu, Zn, Cd, Sb and Pb) were detected in leachate and the concentration of this metal elements increased with the longer aging time. The findings of this study can advance our understanding of the fate of disposable masks in the landfill and develop the strategy to address this challenge in waste management. Copyright © 2023 Elsevier B.V.

Multi-ligand molecular docking, simulation, free energy calculations and wavelet analysis of the synergistic effects between natural compounds baicalein and cubebin for the inhibition of the main protease of SARS-CoV-2.

Combination drugs have been used for several diseases for many years since they produce better therapeutic effects. However, it is still a challenge to discover candidates to form a combination drug. This study aimed to investigate whether using a comprehensive in silico approach to identify novel combination drugs from a Chinese herbal formula is an appropriate and creative strategy. We, therefore, used Toujie Quwen Granules for the main protease (Mpro) of SARS-CoV-2 as an example. We first used molecular docking to identify molecular components of the formula which may inhibit Mpro. Baicalein (HQA004) is the most favorable inhibitory ligand. We also identified a ligand from the other component, cubebin (CHA008), which may act to support the proposed HQA004 inhibitor. Molecular dynamics simulations were then performed to further elucidate the possible mechanism of inhibition by HQA004 and synergistic bioactivity conferred by CHA008. HQA004 bound strongly at the active site and that CHA008 enhanced the contacts between HQA004 and Mpro. However, CHA008 also dynamically interacted at multiple sites, and continued to enhance the stability of HQA004 despite diffusion to a distant site. We proposed that HQA004 acted as a possible inhibitor, and CHA008 served to enhance its effects via allosteric effects at two sites. Additionally, our novel wavelet analysis showed that as a result of CHA008 binding, the dynamics and structure of Mpro were observed to have more subtle changes, demonstrating that the inter-residue contacts within Mpro were disrupted by the synergistic ligand. This work highlighted the molecular mechanism of synergistic effects between different herbs as a result of allosteric crosstalk between two ligands at a protein target, as well as revealed that using the multi-ligand molecular docking, simulation, free energy calculations and wavelet analysis to discover novel combination drugs from a Chinese herbal remedy is an innovative pathway.

Insight into free energy and dynamic cross-correlations of residue for binding affinity of antibody and receptor binding domain SARS-CoV-2.

SARS-CoV-2 virus continues to evolve and mutate causing most of the mutated variants resist to many of the therapeutic monoclonal antibodies (mAbs). Despite several mAbs retained neutralizing capability for Omicron BA.1 and BA.2, reduction in neutralization potency was reported. Hence, effort of searching for mAb that is broader in neutralization breadth without losing the neutralizing ability is continued. MW06 was reported with capability in neutralizing most of the variants of concern (VOC) and it binds to the conserved region (left flank) near epitope mAb sotrovimab (S309). In this study, binding affinity of mAb MW06 and its cocktail formulation with MW05 for receptor binding domain (RBD) SARS-CoV-2 virus was investigated under molecular dynamics simulations (MDs). Binding free energies computed by Molecular Mechanics Generalised Born Surface Area (MM-GBSA) algorithm predicted the binding affinity of MW06 for RBD BA.1 (-53 kcal/mol) as strong as RBD wildtype (-58 kcal/mol) while deterioration was observed for RBD BA.2 (-43 kcal/mol). Alike S309 and MW06, simulated cocktail mAb (MW05 and MW06)-RBD interactions suggested the neutralizing capability of the cocktail formulation for RBD BA.1 and BA.2 reduced. Meanwhile, residue pairs that favour the communication between the mAb and RBD have been identified by decomposing the free energy per pairwise residue basis. Apart from understanding the effects of mutation occurred in the RBD region on human angiotensin-converting enzyme 2 (hACE2) binding, impact of heavily mutated RBD on mAb-RBD interactions was investigated in this study as well. In addition to energetic profile obtained from MDs, plotting the dynamics cross-correlation map of the mAb-RBD complex under elastic network model (ENM) was aimed to understand the cross-correlations between residue fluctuations. It allows simple and rapid analysis on the motions or dynamics of the protein residues of mAbs and RBD in complex. Protein residues having correlated motions are normally part of the structural domains of the protein and their respective motions and protein function are related. Motion of mutated RBD residues and mAb residues was less correlated while their respective interactions energy computed to be higher. The combined techniques of MDs and ENM offered simplicity in understanding dynamics and energy contribution that explain binding affinity of mAb-RBD complexes.

Multi-level scoring approach to discover multi-targeting potency of medicinal plant phytochemicals against protein targets in SARS-CoV-2 and human ACE-2 receptor

SARS-CoV-2 pandemic has become a major threat to human healthcare and world economy. Due to the rapid spreading and deadly nature of infection, we are in a situation to develop quick therapeutics to combat SARS-CoV-2. In this study, we have adopted a multi-level scoring approach to identify multi-targeting potency of bioactive compounds in selected medicinal plants and compared its efficacy with two reference drugs, Nafamostat and Acalabrutinib which are under clinical trials to treat SARS-CoV-2. In particular, we employ molecular docking and implicit solvent free energy calculations (as implemented in the Molecular Mechanics-Generalized Born Surface Area approach) and QM fragmentation approach for validating the potency of bioactive compounds from the selected medicinal plants against four different viral targets and one human receptor (Angiotensin-converting enzyme 2-ACE-2) which facilitates the SARS-CoV-2 entry into the cell. The protein targets considered for the study are viral 3CL main protease (3CLpro), papain-like protease (PLpro), RNA dependent RNA polymerase (RdRp), and viral spike protein-human hACE-2 complex (Spike:hACE2) including human protein target (hACE-2). Herein, there liable multi-level scoring approach was used to validate the mechanism behind the multi-targeting potency of selected phytochemicals from medicinal plants. The present study evidenced that the phytochemicals Chebulagic acid, Stigmosterol, Repandusinic acid and Geranin exhibited efficient inhibitory activity against PLpro while Chebulagic acid was highly active against 3CLpro. Chebulagic acid and Geranin also showed excellent target specific activity against RdRp. Luteolin, Quercetin, Chrysoeriol and Repandusinic acid inhibited the interaction of viral spike protein with human ACE-2 receptor. Moreover, Piperlonguminine and Piperine displayed significant inhibitory activity against human ACE-2 receptor. Therefore, the identified compounds namely Chebulagic acid, Geranin and Repandusinic acid can serve as potent multi-targeting phytomedicine for treating COVID-19. © 2022, National Institute of Science Communication and Policy Research. All rights reserved.

Structural and Functional Analyses of SARS COV-2 RNA-dependent RNA Polymerase Protein and Complementary vs. Synthetic Drugs against COVID-19 and the Exploration of Binding Sites for Docking, Molecular Dynamics Simulation, and Density Functional Theory Studies

Background: RNA-dependent RNA polymerase (RdRp) contributes to the transcription cycle of the SARS-CoV-2 virus with the possible assistance of nsp-7-8 cofactors. Objective(s): The study aims to investigate the viral protective effects of complementary drugs in computational approaches that use viral proteins. Method(s): For the in silico studies, the identified compounds were subjected to molecular docking with RdRp protein followed by structural and functional analyses, density functional theory (DFT), and molecular dynamics (MD) simulation. The 3D structure of RdRp (6m71 PDB ID) was obtained from the protein databank as a target receptor. After reviewing the literature, 20 complementary and synthetic drugs were selected for docking studies. The top compounds were used for DFT and MD simulation at 200 ns. DFT of the compounds was calculated at B3LYP/6-311G (d, p) based on chemical properties, polarizability, and first-order hyperpolarizability. Results were analyzed using USCF Chimera, Discovery Studio, LigPlot, admetSAR, and mCule. Result(s): Computational studies confirmed the potent interaction of the complementary drugs forsythi-aside A, rhoifolin, and pectolinarin with RdRp. Common potential residues of RdRp (i.e., Thr-556, Tyr-619, Lys-621, Arg-624, Asn-691, and Asp-760) were observed for all three docking complexes with hydrogen bonding. Docking analysis showed strong key interactions, hydrogen bonding, and binding affinities (-8.4 to -8.5 kcal/mol) for these ligands over the FDA-approved drugs (-7.4 to -7.6 kcal/mol). Docking and simulation studies showed these residues in the binding domains. Conclusion(s): Significant outcomes of novel molecular interactions in docking, simulation, DFT, and binding domains in the structural and functional analyses of RdRp were observed. Copyright © 2022 Bentham Science Publishers.

Development of Android-Controlled Ultraviolet Floor Sanitizer Robot

Ultraviolet (UV) light radiation is very dangerous as it can irritate human skin and eyes in which long and direct exposure can lead to skin and eyes cancer. However, Ultraviolet C (UVC) light with a wavelength between 207nm-222nm could sanitize in which inactivate the bacteria such as superbug (the pathogen that already built immunity against chemical sanitizer) and contribute to the fight against Covid-19 viruses. Therefore, this development of UV sanitizer is to sanitize surface area effectively with a human alert system in which will activate the buzzer, turn off the UV light and stop moving when human motion is detected. The notification also will be sent to the user whenever a human motion is detected as a 360° sanitization area to inactivate pathogens. The precaution to avoid any accident. The device is equipped with one UVC light which provides, the body has ultrasonic sensors to detect obstacles and provide autonomous movement to the device while the PIR sensor is used to detect human motion and activate the human alert system. As the result, the UVC light effectiveness is determined based on the bacteria growth in the petri dish. After the sanitization process, the bacteria are significantly reduced and killed effectively in low areas such as floors but reduce their efficiency to the high area. Thus, this device is time efficient and able to reduce the cost of sanitization compared to chemical sanitizer. © 2022 IEEE.