Computer-aided Design Approach Research Articles

In Silico Design of Potential Small-Molecule Antibiotic Adjuvants against Salmonella typhimurium Ortho Acetyl Sulphydrylase Synthase to Address Antimicrobial Resistance

The inhibition of O-acetyl sulphydrylase synthase isoforms has been reported to represent a promising approach for the development of antibiotic adjuvants. This occurs via the organism developing an unpaired oxidative stress response, causing a reduction in antibiotic resistance in vegetative and swarm cell populations. This consequently increases the effectiveness of conventional antibiotics at lower doses. This study aimed to predict potential inhibitors of Salmonella typhimurium ortho acetyl sulphydrylase synthase (StOASS), which has lower binding energy than the cocrystalized ligand pyridoxal 5 phosphate (PLP), using a computer-aided drug design approach including pharmacophore modeling, virtual screening, and in silico ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) evaluation. The screening and molecular docking of 4254 compounds obtained from the PubChem database were carried out using AutoDock vina, while a post-screening analysis was carried out using Discovery Studio. The best three hits were compounds with the PubChem IDs 118614633, 135715279, and 155773276, possessing binding affinities of −9.1, −8.9, and −8.8 kcal/mol, respectively. The in silico ADMET prediction showed that the pharmacokinetic properties of the best hits were relatively good. The optimization of the best three hits via scaffold hopping gave rise to 187 compounds, and they were docked against StOASS; this revealed that lead compound 1 had the lowest binding energy (−9.3 kcal/mol) and performed better than its parent compound 155773276. Lead compound 1, with the best binding affinity, has a hydroxyl group in its structure and a change in the core heterocycle of its parent compound to benzimidazole, and pyrimidine introduces a synergistic effect and consequently increases the binding energy. The stability of the best hit and optimized compound at the StOASS active site was determined using RMSD, RMSF, radius of gyration, and SASA plots generated from a molecular dynamics simulation. The MD simulation results were also used to monitor how the introduction of new functional groups of optimized compounds contributes to the stability of ligands at the target active site. The improved binding affinity of these compounds compared to PLP and their toxicity profile, which is predicted to be mild, highlights them as good inhibitors of StOASS, and hence, possible antimicrobial adjuvants.

Exploring Lead-Like Molecules of Traditional Chinese Medicine for Treatment Quest against Aliarcobacter butzleri: In Silico Toxicity Assessment, Dynamics Simulation, and Pharmacokinetic Profiling

Background. Aliarcobacter butzleri is a Gram-negative, curved or spiral-shaped, microaerophilic bacterium and causes human infections, specifically diarrhea, fever, and sepsis. The research objective of this study was to employ computer-aided drug design techniques to identify potential natural product inhibitors of a vital enzyme in this bacterium. The pyrimidine biosynthesis pathway in its core genome fraction is crucial for its survival and presents a potential target for novel therapeutics. Hence, novel small molecule inhibitors were identified (from traditional Chinese medicinal (TCM) compound library) against it, which may be used for possible curbing of infection by A. butzleri. Methods. A comprehensive subtractive genomics approach was utilized to identify a key enzyme (orotidine-5′-phosphate decarboxylase) cluster conserved in the core genome fraction of A. butzleri. It was selected for inhibitor screening due to its vital role in pyrimidine biosynthesis. TCM library (n>36,000 compounds) was screened against it using pharmacophore model based on orotidylic acid (control), and the obtained lead-like molecules were subjected to structural docking using AutoDock Vina. The top-scoring compounds, ZINC70454134, ZINC85632684, and ZINC85632721, underwent further scrutiny via a combination of physiological-based pharmacokinetics, toxicity assessment, and atomic-scale dynamics simulations (100 ns). Results. Among the screened compounds, ZINC70454134 displayed the most favorable characteristics in terms of binding, stability, absorption, and safety parameters. Overall, traditional Chinese medicine (TCM) compounds exhibited high bioavailability, but in diseased states (cirrhosis, renal impairment, and steatosis), there was a significant decrease in absorption, Cmax, and AUC of the compounds compared to the healthy state. Furthermore, MD simulation demonstrated that the ODCase-ZINC70454134 complex had a superior overall binding affinity, supported by PCA proportion of variance and eigenvalue rank analysis. These favorable characteristics underscore its potential as a promising drug candidate. Conclusion. The computer-aided drug design approach employed for this study helped expedite the discovery of antibacterial compounds against A. butzleri, offering a cost-effective and efficient approach to address infection by it. It is recommended that ZINC70454134 should be considered for further experimental analysis due to its indication as a potential therapeutic agent for combating A. butzleri infections. This study provides valuable insights into the molecular basis of biophysical inhibition of A. butzleri through TCM compounds.

Optimizing the Biosynthesis of Dihydroquercetin from Naringenin in Saccharomyces cerevisiae.

Dihydroquercetin (DHQ), known for its varied physiological benefits, is widely used in the food, chemical, and pharmaceutical industries. However, the efficiency of the DHQ synthesis is significantly limited by the substantial accumulation of intermediates during DHQ biosynthesis. In this study, DHQ production was achieved by integrating genes from various organisms into the yeast chromosome for the expression of flavanone-3-hydroxylase (F3H), flavonoid-3'-hydroxylase, and cytochrome P450 reductase. A computer-aided protein design approach led to the development of optimal F3H mutant P221A, resulting in a 1.67-fold increase in DHQ yield from naringenin (NAR) compared with the control. Subsequently, by analysis of the enzyme reaction and optimization of the culture medium composition, 637.29 ± 20.35 mg/L DHQ was synthesized from 800 mg/L NAR. This corresponds to a remarkable conversion rate of 71.26%, one of the highest reported values for DHQ synthesis from NAR to date.

Design of new small molecules derived from indolin-2-one as potent TRKs inhibitors using a computer-aided drug design approach

Tropomyosin receptor kinase (TRKs) enzymes are responsible for cancers associated with the neurotrophic tyrosine kinase receptor gene fusion and are identified as effective targets for anticancer drug discovery. A series of small-molecule indolin-2-one derivatives showed remarkable biological activity against TRKs enzymatic activity. These small molecules could have an excellent profile for pharmaceutical application in the treatment of cancers caused by TRKs activity. The aim of this study is to modify the structure of these molecules to obtain new molecules with improved TRK inhibitory activity and pharmacokinetic properties favorable to the design of new drugs. Based on these series, we carried out a 3D-QSAR study. As a result, robust and reliable CoMFA and CoMSIA models are developed and applied to the design of 11 new molecules. These new molecules have a biological activity superior to the most active molecule in the starting series. The eleven designed molecules are screened using drug-likeness, ADMET proprieties, molecular docking, and MM-GBSA filters. The results of this screening identified the T1, T3, and T4 molecules as the best candidates for strong inhibition of TRKs enzymatic activity. In addition, molecular dynamics simulations are performed for TRK free and complexed with ligands T1, T3, and T4 to evaluate the stability of ligand-protein complexes over the simulation time. On the other hand, we proposed experimental synthesis routes for these newly designed molecules. Finally, the designed molecules T1, T2, and T3 have great potential to become reliable candidates for the conception of new drug inhibitors of TRKs. Communicated by Ramaswamy H. Sarma

Improving Press Bending Production Quality through Finite Element Simulation: Integration CAD and CAE Approach

Efficient operations and output of outstanding quality distinguish superior manufacturing sectors. The manufacturing process production of bending sheet metal is a form of fabrication in the industry of manufacture in which the plate is bent using punches and dies to the angle of the work design. Product quality is influenced by plate material selection, which includes thickness, type, dimensions, and material. Because no prior research has concentrated on this methodology, this research aims to determine V-bending capacity limits utilizing the press bending method. The inquiry employed finite element analysis (FEA), along with Solidworks was the tool of choice to develop drawings of design and simulations. The ASTM E290 standard guides this study. The software in this package may combine CAD (Computer-Aided Design) and CAE (Computer-Aided Engineering) without requiring extra design applications. This study tested SPCC and SPHC plate materials with five thickness variations. The findings embrace the number of failure risks associated with press bending exhibited on the von Mises stress diagram, which is directly proportional to showing the thickness limit of each material type throughout the bending process. The study's findings lay the groundwork for improving manufacturing quality by lowering the number of faulty goods produced by trial and error. Because the maximum allowable die width is 12 mm, the thickness limit of the press bending process is 2 mm. However, due to the greater intensity of the SPCC material, it has a reduced defect rate compared to SPHC material.

Dual Targeting of DNA Damage Response Proteins Implicated in Cancer Radioresistance.

Ionizing radiation can induce different types of DNA lesions, leading to genomic instability and ultimately cell death. Radiation therapy or radiotherapy, a major modality in cancer treatment, harnesses the genotoxic potential of radiation to target and destroy cancer cells. Nevertheless, cancer cells have the capacity to develop resistance to radiation treatment (radioresistance), which poses a major obstacle in the effective management of cancer. It has been shown that administration of platinum-based drugs to cancer patients can increase tumor radiosensitivity, but despite this, it is associated with severe adverse effects. Several lines of evidence support that activation of the DNA damage response and repair machinery in the irradiated cancer cells enhances radioresistance and cellular survival through the efficient repair of DNA lesions. Therefore, targeting of key DNA damage repair factors would render cancer cells vulnerable to the irradiation effects, increase cancer cell killing, and reduce the risk of side effects on healthy tissue. Herein, we have employed a computer-aided drug design approach for generating ab initio a chemical compound with drug-like properties potentially targeting two proteins implicated in multiple DNA repair pathways. The findings of this study could be taken into consideration in clinical decision-making in terms of co-administering radiation with DNA damage repair factor-based drugs.

Identification of potential inhibitors targeting Ebola virus VP35 protein: a computational strategy

Ebola virus (EBOV) poses a severe threat as a highly infectious pathogen, causing devastating hemorrhagic fever in both humans and animals. The EBOV virus VP35 protein plays a crucial role in viral replication and exhibits the ability to suppress the host interferon cascade, leading to immune system depletion. As a potential drug target, VP35 protein inhibition holds promise for combating EBOV. To discover new drug candidates, we employed a computer-aided drug design approach, focusing on compounds capable of inhibiting VP35 protein replication. In this connection, a pharmacophore model was generated using molecular interactions between the VP35 protein and its inhibitor. ZINC and Cambridge database were screened using validated pharmacophore model. Further the compounds were filtered based on Lipinski’s rule of five and subjected to MD simulation and relative binding free energy calculation. Six compounds manifest a significant docking score and strong binding interaction towards VP35 protein. MD simulations further confirmed the remarkable stability of these six complexes. Relative binding free energy calculations also showed significant ΔG value in the range of −132.3 and −49.3 kcal/mol. This study paves the way for further optimization of these compounds as potential inhibitors of VP35, facilitating subsequent experimental in vitro studies. Communicated by Ramaswamy H. Sarma

An Exploration of the Inhibitory Mechanism of Rationally Screened Benzofuran-1,3,4-Oxadiazoles and-1,2,4-Triazoles as Inhibitors of NS5B RdRp Hepatitis C Virus through Pharmacoinformatic Approaches.

Benzofuran, 1,3,4-oxadiazole, and 1,2,4-triazole are privileged heterocyclic moieties that display the most promising and wide spectrum of biological activities against a wide variety of diseases. In the current study, benzofuran-1,3,4-oxadiazole BF1-BF7 and benzofuran-1,2,4-triazole compounds BF8-BF15 were tested against HCV NS5B RNA-dependent RNA polymerase (RdRp) utilizing structure-based screening via a computer-aided drug design (CADD) approach. A molecular docking approach was applied to evaluate the binding potential of benzofuran-appended 1,3,4-oxadiazole and 1,2,4-triazole BF1-BF15 molecules. Benzofuran-1,3,4-oxadiazole scaffolds BF1-BF7 showed lesser binding affinities (-12.63 to -14.04 Kcal/mol) than benzofuran-1,2,4-triazole scaffolds BF8-BF15 (-14.11 to -16.09 Kcal/mol) against the HCV NS5B enzyme. Molecular docking studies revealed the excellent binding affinity scores exhibited by benzofuran-1,2,4-triazole structural motifs BF-9 (-16.09 Kcal/mol), BF-12 (-15.75 Kcal/mol), and BF-13 (-15.82 Kcal/mol), respectively, which were comparatively better than benzofuran-based HCV NS5B inhibitors' standard reference drug Nesbuvir (-15.42 Kcal/mol). A molecular dynamics simulation assay was also conducted to obtain valuable insights about the enzyme-compounds interaction profile and structural stability, which indicated the strong intermolecular energies of the BF-9+NS5B complex and the BF-12+NS5B complex as per the MM-PBSA method, while the BF-12+NS5B complex was the most stable system as per the MM-GBSA calculation. The drug-likeness and ADMET studies of all the benzofuran-1,2,4-triazole derivatives BF8-BF15 revealed that these compounds possessed good medicinal chemistry profiles in agreement with all the evaluated parameters for being drugs. The molecular docking affinity scores, MM-PBSA/MM-GBSA and MD-simulation stability analysis, drug-likeness profiling, and ADMET study assessment indicated that N-4-fluorophenyl-S-linked benzofuran-1,2,4-triazole BF-12 could be a future promising anti-HCV NS5B RdRp inhibitor therapeutic drug candidate that has a structural agreement with the Nesbuvir standard reference drug.

Antibreast cancer activities of phytochemicals from Anonna muricata using computer-aided drug design (CADD) approach

Abstract Antibreast cancer activities of 131 phytochemicals from Annona muricata (Soursop) were investigated against human placental aromatase (PDB ID: 3S7S), a prominent target receptor in breast cancer therapy using computer aided-drug design approach. An antibreast cancer drug (tamoxifen) was used for comparison. The result of this work flourishes caffeoquinic acid (−8.4 kcal/mol), roseoside (−8.3 kcal/mol), chlorogenic acid (−8.2 kcal/mol), feruloylglycoside (−8.1 kcal/mol), citroside A (−8.0 kcal/mol), and coreximine (−7.8 kcal/mol), as probable inhibitors of human placental aromatase. This is due to their excellent binding affinities (ΔG), coupled with outstanding druglike, absorption, distribution, metabolism, excretion, and toxicity profiles, bioavailability and oral-bioavailability properties, and the interactions of important residues with the active pocket of human placental aromatase. All the results obtained were similar to that of the standards tamoxifen (−8.0 kcal/mol) but could be better when optimized. Thus, lead optimization, molecular dynamics, and in vivo investigations are thereby recommended on the identified potent compounds in the quest of developing new therapeutic agents against breast cancer.

Mur ligase F as a new target for the flavonoids quercitrin, myricetin, and (-)-epicatechin.

MurC, D, E, and F are ATP-dependent ligases involved in the stepwise assembly of the tetrapeptide stem of forming peptidoglycan. As highly conserved targets found exclusively in bacterial cells, they are of significant interest for antibacterial drug discovery. In this study, we employed a computer-aided molecular design approach to identify potential inhibitors of MurF. A biochemical inhibition assay was conducted, screening twenty-four flavonoids and related compounds against MurC-F, resulting in the identification of quercitrin, myricetin, and (-)-epicatechin as MurF inhibitors with IC50 values of 143 µM, 139 µM, and 92 µM, respectively. Notably, (-)-epicatechin demonstrated mixed type inhibition with ATP and uncompetitive inhibition with D-Ala-D-Ala dipeptide and UM3DAP substrates. Furthermore, in silico analysis using Sitemap and subsequent docking analysis using Glide revealed two plausible binding sites for (-)-epicatechin. The study also investigated the crucial structural features required for activity, with a particular focus on the substitution pattern and hydroxyl group positions, which were found to be important for the activity. The study highlights the significance of computational approaches in targeting essential enzymes involved in bacterial peptidoglycan synthesis.

Analysing potent biomarkers along phytochemicals for breast cancer therapy: an in silico approach

PurposeThis research focused on the identification of herbal compounds as potential anti-cancer drugs, especially for breast cancer, that involved the recognition of Notch downstream targets NOTCH proteins (1–4) specifically expressed in breast tumours as biomarkers for prognosis, along with P53 tumour antigens, that were used as comparisons to check the sensitivity of the herbal bio-compounds.MethodsAfter investigating phytochemical candidates, we employed an approach for computer-aided drug design and analysis to find strong breast cancer inhibitors. The present study utilized in silico analyses and protein docking techniques to characterize and rank selected bio-compounds for their efficiency in oncogenic inhibition for use in precise carcinomic cell growth control.ResultsSeveral of the identified phytocompounds found in herbs followed Lipinski’s Rule of Five and could be further investigated as potential medicinal molecules. Based on the Vina score obtained after the docking process, the active compound Epigallocatechin gallate in green tea with NOTCH (1–4) and P53 proteins showed promising results for future drug repurposing. The stiffness and binding stability of green tea pharmacological complexes were further elucidated by the molecular dynamic simulations carried out for the highest scoring phytochemical ligand complex.ConclusionThe target-ligand complex of green tea active compound Epigallocatechin gallate with NOTCH (1–4) had the potential to become potent anti-breast cancer therapeutic candidates following further research involving wet-lab experiments.

Tailored nanofibrous molecularly imprinted polymers for selective removal of di(2-ethylhexyl) phthalate: A computer-aided design and synthesis approach

This study aimed to develop molecularly imprinted polymer nanofibers (MIP-NFs) for the selective removal of di(2-ethylhexyl) phthalate (DEHP). Fifteen commonly used monomers were screened using computational calculations to determine the most suitable functional monomer for MIP-NFs synthesis. Methyl methacrylate (MMA) was selected based on its high binding energy (104.254 kJ mol−1) and strong hydrophobic interaction with DEHP in acetonitrile. The MIP-NFs were synthesized via a precipitation polymerization reaction using MMA as the functional monomer, ethylene glycol dimethacrylate (EGDMA) as the crosslinker, DEHP as the molecule template, and benzoyl peroxide (BPO) as the initiator. The resulting MIP-NFs exhibited a highly porous and fibrous structure with a larger surface area, pore volume, and pore diameter size compared to non-imprinted polymer nanofibers (NIP-NFs) and PAN-NFs. The Freundlich isotherm model was found to be the most suitable for describing the DEHP adsorption process by MIP-NFs, and the imprinting factor (IF) >1 indicated that MIP-NFs had a higher affinity for DEHP than NIP-NFs. The pseudo-second-order model better explained the adsorption process of MIP-NFs, and selectivity studies demonstrated that DEHP could selectively adsorb onto MIP-NFs. These results suggest that MIP-NFs have great potential in various applications such as water treatment and environmental remediation.

Costs Comparison of Teaching and Learning Strategies in a South African University Fashion Design Programme

The use of manual teaching and learning (T&L) strategies for creative design, as well as technical drawing modules, continues in South African university fashion design programmes with few computer-aided design (CAD) T&L strategies being employed. Given the global developments in technological T&L strategies using CAD approach, this comparative study assessed the cost-effectiveness of manual T&L strategies against CAD T&L strategies for Creative Design and Technical drawing modules in a South African fashion design programme. A case study design was used to collect data (documents) on manual and CAD T&L strategies from procurement, budget documents and the in-house university printing department. The results showed that manual T&L strategies expenditure was over 70% to 318% compared to the budget, while CAD T&L strategies were below 60% compared to the budget for creative design ii, creative design iii, technical drawing ii, and technical drawing iii. The findings indicated that CAD T&L strategies are sustainable for the implicated university and the South African government as they fund free higher education with decreasing budgets. The paper concluded that technologically driven T&L strategies like CAD can reduce tuition fees for the programme, improve the sustainability of the university, widen access to government funding for free higher education, as well as improve the contribution of fashion design education programmes towards Sustainable Development Goals 8, 9, and 12. This paper contributes to the ongoing research on developing and implementing sustainable strategies to support the constitutional mandate and the #FeesMustFall campaign and the funding sustainability of South African higher education. This paper’s contribution is a comparison of the cost-effectiveness of manual and CAD T&L strategies. Keywords: Computer-aided Design, clothing industry, fashion design education programme, technology in universities.

Design and development of fused deposition modeling (FDM) 3D-Printed Orthotic Insole by using gyroid structure

The orthotic insole is a device that is placed between the bottom of the foot and the sole of the shoe. It bears the body weight and directly influences the biomechanics of the foot and the body. These insoles are used to minimize the stress by reducing plantar pressure between support points hence minimizing the pressure. Such customized insoles have usually been produced by either handmade or subtractive methods. Fused deposition modeling (FDM) has opened innovative ways for the manufacture of orthotic insoles. In recent studies, no specific computer-aided design (CAD) tools are available to design and manufacture the insole, which is the primary focus. This work aims to evaluate established CAD techniques for designing and fabricating insoles utilizing different manufacturing processes. The evaluation is based on a prior analysis of the possibilities for functionalizing insole materials and structures. In this study, multiple software tools are utilized for designing custom insoles, considering pressure points and a three-dimensional (3D) foot scan of an individual. The research highlights how the implementation of software enables a significant level of customization by integrating pressure mapping data into the insole design process. A novel CAD approach for designing an orthotic insole has been provided in this work. Soft poly-lactic acid (PLA) is used to fabricate an insole using FDM technology. The gyroid and solid samples were evaluated following ASTM standards. When compared to the solid construction, the gyroid structure has a high specific energy absorption capability, which is used to create the orthotic insole. The results of the experiment suggest that the selection of the structure for customized insole design is significantly affected by the infill density parameter.

Medicinal and toxicological investigation of some common NSAIDs; A computer-aided drug design approach

Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used for the treatment of pain, fever, and inflammation. Their consumption rises some crucial side effects like gastrointestinal, cardiovascular, and renal injury because of the non-selective reduction of prostaglandin synthesis, with differences in the extent of inhibition of the cyclooxygenase. Attempts have been taken for a comparative biochemical, medicinal, and toxicological investigation to raise awareness of the consumption of NSAIDs. In-silico methods were incorporated to investigate their physicochemical, spectral, medicinal, pharmacological, and toxicological properties. Molecular docking and non-bonding calculations were performed against the human prostaglandin synthase protein to reveal their binding affinity and interactions with the amino acid residues of the receptor protein. Further, molecular dynamics simulation was conducted to validate the binding mode and drug-protein stability at the inhibiting binding pocket. The physical and chemical analysis supports their geometries and spectral results confirming the presence of essential functional groups at the core structure. From ADMET and PASS prediction, all the drugs are non-carcinogenic (except IBP), and nonselective NSAIDs showed relatively higher adverse effects compared to selective agents. Based on the above studies, this report can be helpful to understand more deeply the medicinal, and toxicological effects of the reported NSAIDs.

Discovery of thiazolo[5,4-c]isoquinoline based compounds as acetylcholinesterase inhibitors through computational target prediction, molecular docking and bioassay

A computer-aided drug design (CADD) approach was developed for a focused chemical library comprising a series of sixteen thiazolo[5,4-c]isoquinoline derivatives. Little is known about this group of heteroaromatic compounds, both from the point of view of their synthesis and their biological properties. First, our CADD approach included target prediction by Mondrian conformal prediction with the ChEMBL database. The acetylcholinesterase (AChE) was identified as having a high probability of thiazolo[5,4-c]isoquinolines being active against it. Secondly, the molecular docking predictions revealed four promising thiazoloisoquinolines (2, 7, 13 and 14) according to their prominent ligand-protein energy scores and relevant binding affinities with the AChE pocket residues. The subsequent in vitro evaluation of promising hits and related ones revealed a set of novel AChE inhibitors. Therefore, the findings reported herein may provide a new strategy for discovering novel AChE inhibitors.

Breakdown Characteristics of Ga2O3-on-SiC Metal-Oxide-Semiconductor Field-Effect Transistors

Ultra-wide bandgap semiconductor gallium oxide (Ga2O3) features a breakdown strength of 8 MV/cm and bulk mobility of up to 300 cm2V−1s−1, which is considered a promising candidate for next-generation power devices. However, its low thermal conductivity is reckoned to be a severe issue in the thermal management of high-power devices. The epitaxial integration of gallium oxide thin films on silicon carbide (SiC) substrates is a possible solution for tackling the cooling problems, yet premature breakdown at the Ga2O3/SiC interface would be introduced due to the relatively low breakdown strength of SiC (3.2 MV/cm). In this paper, the on-state properties as well as the breakdown characteristics of the Ga2O3-on-SiC metal-oxide-semiconductor field-effect transistor (MOSFET) were investigated by using the technology computer-aided design (TCAD) approach. Compared with the full-Ga2O3 MOSFET, the lattice temperature of the Ga2O3-on-SiC MOSFET was decreased by nearly 100 °C thanks to the high thermal conductivity of SiC. However, a breakdown voltage degradation of >40% was found in an unoptimized Ga2O3-on-SiC MOSFET. Furthermore, by optimizing the device structure, the breakdown voltage degradation of the Ga2O3-on-SiC MOSFET is significantly relieved. As a result, this work demonstrates the existence of premature breakdown in the Ga2O3-on-SiC MOSFET and provides feasible approaches to further enhance the performance of hetero-integrated Ga2O3 power devices.

Identification of novel inhibitors of P13K/AKT pathways: an integrated in-silico study towards the development of a new therapeutic agent against ovarian cancer

Abstract Ovarian cancer is a crucial gynaecological unmet medical disease with a high mortality rate. According to recent research, the phosphoinositol 3 kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathways are hyper-activated in the majority of ovarian cancer patients, necessitating the use of inhibitors. Over the years, phytochemicals have been used as alternative sources of therapeutic agents due to their reported biological activities and limited side effects. Curcuma longa (Tumeric), a reported ayurvedic medicine has also been noted for its anti-cancer properties. Thus, 155 phytochemicals from this plant and 2 reference drugs were evaluated for their inhibitory prowess against P13K/AKT receptor using a computer-aided drug design approach. The binding scores and inhibiting efficiencies were obtained via virtual screening. Molinspiration Chemoinformatics and SwissADME tools were used to investigate the drug-likeness properties and oral bioavailability of the compounds selected, while the ADMET SAR-2 website was used to conduct the Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) analysis. Other analyses performed on the selected compounds include bioactivity, activity spectra for substances (PASS) prediction, binding mode, and molecular interaction. The results revealed that Hopenone 1 (−8.8 kcal mol−1) and Epriprocurcumenol (−7.8 kcal mol−1) are potent inhibitors of the P13K receptor, while Epiprocurcumenol (−9.0 kcal mol−1), Procurcuminol (−8.6 kcal mol−1) and Curlone (−8.3 kcal mol−1) are potential inhibitors of AKT receptor. In comparison to Topotecan and Melphalan, they have better binding affinities, oral bioavailability, drug-likeness characteristics, ADMET properties, bioactivities, PASS properties, binding mechanism, and also interact well with the active site of the target receptor. As a result, this preliminary investigation suggests that these chemicals should be studied further for the design of novel ovarian cancer therapeutics.

Pharmacophore-based virtual screening, molecular docking and molecular dynamics simulation for identification of potential ERK inhibitors

As the downstream component of the mitogen-activated protein kinases (MAPK) pathway, the extracellular signal-regulated kinase (ERK) is responsible for phosphorylating a broad range of substrates in cell proliferation, differentiation, and survival. Direct targeting the ERK proteins by the piperidinopyrimidine urea-based inhibitors has been demonstrated to be an effective way to block the MAPK signaling pathway in inhibiting tumor growth. In order to discover better inhibitors, a computer-aided drug design (CADD) approach was employed to reveal the pharmacological characteristics and mechanisms of action. The pharmacophore model was generated on the basis of the compounds with eight features, i.e., four hydrogen bond acceptor atoms, one hydrogen bond donor atom, and three hydrophobic centers. A total of 14 hit compounds were obtained through virtual screening. Two potential inhibitors, namely VS01 and VS02, have been identified by molecular docking and molecular dynamics simulations. Both compounds are capable of attaching to the ERK pocket precisely. The binding free energies of VS01 and VS02 are about 15 kJ/mol and 4 kJ/mol stronger than that of the clinic Ulixertinib because of the characteristic hydrogen bonding, electrostatic, and hydrophilic interactions. The present theoretical investigations shed new light on the rational design of the potential ERK inhibitors to stimulate further experimental tests. Communicated by Ramaswamy H. Sarma

Key ingredients in Verbena officinalis and determination of their anti-atherosclerotic effect using a computer-aided drug design approach.

Lipid metabolism disorders may considerably contribute to the formation and development of atherosclerosis (AS). Traditional Chinese medicine has received considerable attention in recent years owing to its ability to treat lipid metabolism disorders using multiple components and targets. Verbena officinalis (VO), a Chinese herbal medicine, exhibits anti-inflammatory, analgesic, immunomodulatory, and neuroprotective effects. Evidence suggests that VO regulates lipid metabolism; however, its role in AS remains unclear. In the present study, an integrated network pharmacology approach, molecular docking, and molecular dynamics simulation (MDS) were applied to examine the mechanism of VO against AS. Analysis revealed 209 potential targets for the 11 main ingredients in VO. Further, 2698 mechanistic targets for AS were identified, including 147 intersection targets between VO and AS. Quercetin, luteolin, and kaempferol were considered key ingredients for the treatment of AS based on a potential ingredient target-AS target network. GO analysis revealed that biological processes were primarily associated with responses to xenobiotic stimuli, cellular responses to lipids, and responses to hormones. Cell components were predominantly focused on the membrane microdomain, membrane raft, and caveola nucleus. Molecular functions were mainly focused on DNA-binding transcription factor binding, RNA polymerase II-specific DNA-binding transcription factor binding, and transcription factor binding. KEGG pathway enrichment analysis identified pathways in cancer, fluid shear stress, and atherosclerosis, with lipid and atherosclerosis being the most significantly enriched pathways. Molecular docking revealed that three key ingredients in VO (i.e., quercetin, luteolin, and kaempferol) strongly interacted with three potential targets (i.e., AKT1, IL-6, and TNF-α). Further, MDS revealed that quercetin had a stronger binding affinity for AKT1. These findings suggest that VO has beneficial effects on AS via these potential targets that are closely related to the lipid and atherosclerosis pathways. Our study utilized a new computer-aided drug design to identify key ingredients, potential targets, various biological processes, and multiple pathways associated with the clinical roles of VO in AS, which provides a comprehensive and systemic pharmacological explanation for the anti-atherosclerotic activity of VO.