Computer-aided Design Methods Research Articles

Novel 1,3,4-oxadiazole derivatives of naproxen targeting EGFR: Synthesis, molecular docking studies, and cytotoxic evaluation.

The close association between inflammation and cancer inspired the synthesis of a series of 1,3,4-oxadiazole derivatives (compounds H4-A-F) of 6-methoxynaphtalene. The chemical structures of the new compounds were validated utilizing Fourier-transform infrared, proton nuclear magnetic resonance, and carbon-13 nuclear magnetic resonance spectroscopic techniques and CHN analysis. Computer-aided drug design methods were used to predict the compounds biological target, ADMET properties, toxicity, and to evaluate the molecular similarities between the design compounds and erlotinib, a standard epidermal growth factor receptor (EGFR) inhibitor. The antiproliferative effects of the new compounds were evaluated by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay, cell cycle analysis, apoptosis detection by microscopy, quantitative reverse transcription-polymerase chain reaction, and immunoblotting, and EGFR enzyme inhibition assay. In silico analysis of the new oxadiazole derivatives indicated that these compounds target EGFR, and that compounds H4-A, H4-B, H4-C, and H4-E show similar molecular properties to erlotinib. Additionally, the results indicated that none of the synthesized compounds are carcinogenic, and that compounds H4-A, H4-C, and H4-F are nontoxic. Compound H4-A showed the best-fit score against EGFR pharmacophore model, however, the in vitro studies indicated that compound H4-C was the most cytotoxic. Compound H4-C caused cytotoxicity in HCT-116 colorectal cancer cells by inducing both apoptosis and necrosis. Furthermore, compounds H4-D, H4-C, and H4-B had potent inhibitory effect on EGFR tyrosine kinase that was comparable to erlotinib. The findings of this inquiry offer a basis for further investigation into the differences between the synthesized compounds and erlotinib. However, additional testing will be needed to assess all of these differences and to identify the most promising compound for further research.

The Power of Molecular Dynamics Simulations and Their Applications to Discover Cysteine Protease Inhibitors.

A large family of enzymes with the function of hydrolyzing peptide bonds, called peptidases or cysteine proteases (CPs), are divided into three categories according to the peptide chain involved. CPs catalyze the hydrolysis of amide, ester, thiol ester, and thioester peptide bonds. They can be divided into several groups, such as papain-like (CA), viral chymotrypsin-like CPs (CB), papain-like endopeptidases of RNA viruses (CC), legumain-type caspases (CD), and showing active residues of His, Glu/Asp, Gln, Cys (CE). The catalytic mechanism of CPs is the essential cysteine residue present in the active site. These mechanisms are often studied through computational methods that provide new information about the catalytic mechanism and identify inhibitors. The role of computational methods during drug design and development stages is increasing. Methods in Computer-Aided Drug Design (CADD) accelerate the discovery process, increase the chances of selecting more promising molecules for experimental studies, and can identify critical mechanisms involved in the pathophysiology and molecular pathways of action. Molecular dynamics (MD) simulations are essential in any drug discovery program due to their high capacity for simulating a physiological environment capable of unveiling significant inhibition mechanisms of new compounds against target proteins, especially CPs. Here, a brief approach will be shown on MD simulations and how the studies were applied to identify inhibitors or critical information against cysteine protease from several microorganisms, such as Trypanosoma cruzi (cruzain), Trypanosoma brucei (rhodesain), Plasmodium spp. (falcipain), and SARS-CoV-2 (Mpro). We hope the readers will gain new insights and use our study as a guide for potential compound identifications using MD simulations.

Discovery of Novel Spike Inhibitors against SARS-CoV-2 Infection.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is responsible for the current coronavirus disease pandemic. With the rapid evolution of variant strains, finding effective spike protein inhibitors is a logical and critical priority. Angiotensin-converting enzyme 2 (ACE2) has been identified as the functional receptor for SARS-CoV-2 viral entry, and thus related therapeutic approaches associated with the spike protein-ACE2 interaction show a high degree of feasibility for inhibiting viral infection. Our computer-aided drug design (CADD) method meticulously analyzed more than 260,000 compound records from the United States National Cancer Institute (NCI) database, to identify potential spike inhibitors. The spike protein receptor-binding domain (RBD) was chosen as the target protein for our virtual screening process. In cell-based validation, SARS-CoV-2 pseudovirus carrying a reporter gene was utilized to screen for effective compounds. Ultimately, compounds C2, C8, and C10 demonstrated significant antiviral activity against SARS-CoV-2, with estimated EC50 values of 8.8 μM, 6.7 μM, and 7.6 μM, respectively. Using the above compounds as templates, ten derivatives were generated and robust bioassay results revealed that C8.2 (EC50 = 5.9 μM) exhibited the strongest antiviral efficacy. Compounds C8.2 also displayed inhibitory activity against the Omicron variant, with an EC50 of 9.3 μM. Thus, the CADD method successfully discovered lead compounds binding to the spike protein RBD that are capable of inhibiting viral infection.

Unlocking Brilliance: A Smart Approach to Icon Colour Design Inspired by Universal Design Principles

Icons are integral to the signature systems within architectural spaces, serving pivotal roles through human–environment interactions. However, previous icon designs often exhibited a considerable randomness and neglected the needs of visually impaired individuals. To address these issues and to overcome the limitations of the computer-aided design methods, such as most of them focusing only on text design which are not compatible with icons, this study presents an intelligent assistance method named “Universal Colour” for icon colour design based on universal design principles. Such a system enables the rapid generation of icon colour schemes and supports visual and quantitative filtering and comparison during the decision-making process for colour scheme optimization. To assess its usability, fifty-two participants conducted icon colour design experiments using this system, resulting in 87% of the design schemes meeting the universality requirements. The results have demonstrated that Universal Colour has the potential to significantly enhance efficiency and cognitive aspects within the decision-making process for users, regardless of their proficiency in icon design, thereby facilitating the generation of universal icon colour schemes in architectural design.

АРХІТЕКТУРНО-КОНСТРУКТИВНІ ЕЛЕМЕНТИ БУДІВЕЛЬ ПРИ 3D-ДРУЦІ: ПРОЕКТУВАННЯ, МАТЕРІАЛИ, ЕФЕКТИВНІСТЬ (ЧАСТИНА ПЕРША - ОГЛЯД)

The article provides an analysis of current approaches to 3D printing of buildings. It focuses on three key areas: 1) computer-aided design methods for 3D printing of buildings; 2) manufacturing methods and materials used; 3) methods for evaluating their effectiveness. The section "Design/Development" covers tools and techniques used from the design stage to the production of building elements. The Technology and Materials section looks at opportunities for engineering applications, categorized by material type. The Performance Evaluation section highlights current strategies for analyzing 3DP buildings. In the first part of this analysis (i.e., this article), the author discusses in detail the general concept of the study, focusing on its key aspects.

492 Novel BH3 Mimetic Bcl-2 Inhibitor Promotes Autophagic Cell Death and Reduces in Vivo Glioblastoma Tumor Growth

INTRODUCTION: Anti-apoptotic members of the Bcl-2 family proteins play central roles in the regulation of cell death in glioblastoma, the most malignant type of brain tumor. Despite the advances in GBM treatment, there is still an urgent need for new therapeutic approaches. METHODS: In silico studies resulted in 500,000 molecules being screened with computer-aided drug design methods and the molecule with the highest binding affinity was selected and named BAU-243. Cell viability, IC50 value, tumor formation potential, tumor spheroid formation potential, tumor invasion studies were investigated following BAU-243 application. The molecular changes caused by Bcl-2 inhibition were demonstrated by quantitative PCR, western blot and immunofluorescence methods. In in vivo studies, glioma tumors were transplanted intracranially into Nod Scid Gamma(NSG) mice using the mouse xenograft model. RESULTS: Here, we report a novel 4-thiazolidinone derivative BH3 mimetic, BAU-243 that binds to Bcl-2 with a high affinity. BAU-243 effectively reduced overall glioblastoma cell proliferation including a subpopulation of cancer-initiating cells in contrast to the selective Bcl-2 inhibitor ABT-199. While ABT-199 successfully induces apoptosis in high BCL2-expressing neuroblastoma SHSY-5Y cells, BAU-243 triggered autophagic cell death rather than apoptosis in A172 cells, indicated by the upregulation of BECN1, ATG5, and MAP1LC3B expression. Lc3b-II, a potent autophagy marker, was significantly upregulated following BAU-243 treatment. Moreover, BAU-243 significantly reduced tumor growth in vivo in orthotopic brain tumor models when compared to the vehicle group, and ABT-199 treated animals. To elucidate the molecular mechanisms of action of BAU-243, we performed computational modeling simulations that were consistent with in vitro results. CONCLUSIONS: Results indicated that BAU-243 activates autophagic cell death by disrupting Beclin 1:Bcl-2 complex, and may serve as a potential small molecule for the treatment of glioblastoma.

HighFold: accurately predicting structures of cyclic peptides and complexes with head-to-tail and disulfide bridge constraints.

In recent years, cyclic peptides have emerged as a promising therapeutic modality due to their diverse biological activities. Understanding the structures of these cyclic peptides and their complexes is crucial for unlocking invaluable insights about protein target-cyclic peptide interaction, which can facilitate the development of novel-related drugs. However, conducting experimental observations is time-consuming and expensive. Computer-aided drug design methods are not practical enough in real-world applications. To tackles this challenge, we introduce HighFold, an AlphaFold-derived model in this study. By integrating specific details about the head-to-tail circle and disulfide bridge structures, the HighFold model can accurately predict the structures of cyclic peptides and their complexes. Our model demonstrates superior predictive performance compared to other existing approaches, representing a significant advancement in structure-activity research. The HighFold model is openly accessible at https://github.com/hongliangduan/HighFold.

Biogas upgrading—Computer-aided ionic liquid absorbent design and process evaluation

Biogas is a renewable energy source and needs to be upgraded to biomethane for injection into the natural gas grid or use as fuel. To design ionic liquid (IL) solvents for biogas upgrading, a computer-aided ionic liquid design (CAILD) method and the corresponding process simulation are presented. The UNIFAC-IL model is employed to calculate the solubility of gases in ILs, while group contribution (GC) based models are used to predict the physicochemical properties of ILs. By using the performance index (PI) as the objective function and the structural feasibility and physicochemical properties as constraints, a mixed-integer nonlinear programming (MINLP) problem is formulated and solved by the generate-and-test method. Two IL solvents, [MMPY][Tf2N] (1,3-dimethylpyridinium bis(trifluoromethylsulfonyl)imide) and [MMPY][eFAP] (1,3-dimethylpyridinium tris(pentafluoroethyl) trifluorophosphate), are found to be the optimal IL solvents from 880 IL candidates. To perform the process simulation by using the designed ILs, the parameters for the equations of calculation of required properties are regressed. A sensitivity analysis is performed to find the optimal conditions for the process. Finally, the developed process is compared with the water-scrubbing process for biogas upgrading.

Insights into the selective mechanism of PDE2/9a inhibitors from silico aspects

The selective design of competitive enzyme inhibitors is an extremely difficult task but necessary work for certain types of systems, such as the phosphodiesterase (PDE) system addressed in this article. In the PDE family, PDE2A and PDE9 respectively target the central nervous system and heart failure, and share many conserved amino acids at their binding sites. Therefore, gaining a deep understanding of the selective mechanisms of PDE2A/9A is crucial for designing highly selective drugs. In this study, various computer-aided drug design (CADD) methods, including molecular docking, molecular dynamics simulations (MD), and binding free energy calculations, are employed to explore the selective mechanisms of PDE2A/9A. Overall, our research results indicate a selective design strategy for PDE2A, which involves incorporating hydrophobic or aromatic moieties into the molecular structure to better accommodate the hydrophobic pocket of PDE2A. Additionally, it is recommended to introduce functional groups capable of forming connections with selective residues, such as Phe830 and Gln812 for PDE2A, or Ala452 and Tyr424 for PDE9A, to enhance the selectivity of inhibitors targeting PDE2A/9A. This achievement is anticipated to pave the way for the development of innovative and selective small molecules targeting PDE2A/9A. Communicated by Ramaswamy H. Sarma

Optimized braces for the treatment of adolescent idiopathic scoliosis: A study protocol of a prospective randomised controlled trial.

Adolescent Idiopathic Scoliosis (AIS) is a 3D deformity of the spine that affects 3% of the adolescent population. Conservative treatments like bracing aim to halt the progression of the curve to the surgical threshold. Computer-aided design and manufacturing (CAD/CAM) methods for brace design and manufacturing are becoming increasingly used. Linked to CAD/CAM and 3D radiographic reconstruction techniques, we developed a finite element model (FEM) enabling to simulate the brace effectiveness before its fabrication, as well as a semi-automatic design processes. The objective of this randomized controlled trial is to compare and validate such FEM semi-automatic algorithm used to design nighttime Providence-type braces. Fifty-eight patients with AIS aged between 10 to 16-years and skeletally immature will be recruited. At the delivery stage, all patients will receive both a Providence-type brace optimized by the semi-automatic algorithm leveraging a patient-specific FEM (Test) and a conventional Providence-type brace (Control), both designed using CAD/CAM methods. Biplanar radiographs will be taken for each patient with both braces in a randomized crossover approach to evaluate immediate correction. Patients will then be randomized to keep either the Test or Control brace as prescribed with a renewal if necessary, and will be followed over two years. The primary outcome will be the change in Cobb angle of the main curve after two years. Secondary outcomes will be brace failure rate, quality of life (QoL) and immediate in-brace correction. This is a single-centre study, double-blinded (participant and outcome assessor) randomized controlled trial (RCT). ClinicalTrials.gov: NCT05001568.

Vibrational Analysis of a Splash Cymbal by Experimental Measurements and Parametric CAD-FEM Simulations

The present study encompasses a thorough analysis of the vibrations in a splash musical cymbal. The analysis is performed using a hybrid methodology that combines experimental measurements with parametric computer-aided design and finite element method simulations. Experimental measurements, including electronic speckle pattern interferometry, and impulse response measurements are conducted. The interferometric measurements are used as a reference for the evaluation of finite element method modal analysis results. The modal damping ratio is calculated via the impulse response measurements and is adopted by the corresponding simulations. Two different approximations are employed for the computer-aided design and finite element method models: one using three-point arcs and the other using lines to describe the non-smooth curvature introduced during manufacturing finishing procedures. The numerical models employing the latter approximation exhibit better agreement with experimental results. The numerical results demonstrate that the cymbal geometrical characteristics, such as the non-smooth curvature and thickness, greatly affect the vibrational behavior of the percussion instrument. These results are of valuable importance for the development of vibroacoustic numerical models that will accurately simulate the sound synthesis of cymbals.

Application status and challenges of molecular docking in development of traditional Chinese medicine

Traditional Chinese medicine is precious treasure of ancient Chinese science and a key to unlocking the treasure trove of Chinese civilization. To elucidate the efficacy and mechanism of traditional Chinese medicines, scientists have been engaged in the research on the molecular basis and regulatory targets. Molecular docking is a computer-aided drug design method capable of visualizing the interaction between components and target proteins. With the progress in the modernization of traditional Chinese medicine and the advancement of algorithms and computing power, molecular docking has become an essential approach in the development of new traditional Chinese medicines. This article summarizes the recent research progress in molecular docking in the development of traditional Chinese medicine, aiming to provide valuable references for further screening of active components and offering insights for improving the development of new traditional Chinese medicines.

Improved algorithm of finding the next volume in direct CAD method for fusion neutronics analysis

The magnetic confinement fusion device, Tokamak, has a complex 3D geometry structure. As a result, the fusion neutronics geometry modeling process will be time-consuming and labor-intensive. Some researchers have improved modeling methods by using CAD (Computer Aided Design) models, but there is still a need to convert CAD models to CSG (Constructive Solid Geometry) or pre-process CAD models. Based on the existing direct CAD Monte Carlo approach, this paper creates a new algorithm for finding the next volume, which greatly simplifies or even omits the preprocessing process. By forming a grouping bounding box acceleration algorithm, the improved finding next volume performance is adequate to ensure precision and computation speed for complex 3D models. The results are verified by comparing them with a commercial Monte Carlo code, cosRMC, and an example of neutron fluence per particle on real CAD models of the HL-3 first wall and divertor shows a better applicability of this new algorithm.

Rational design of novel phenol ether derivatives as non-covalent proteasome inhibitors through 3D-QSAR, molecular docking and ADMET prediction

Aim: The purpose of this paper is to use different structures and ligand-based drug design methods properly to provide theoretical guidance for the design of novel non-covalent proteasome inhibitors, and conduct theoretical analysis of the binding interaction mode between receptors and ligands. At the same time, the pharmacokinetic (PK) prediction, drug-likeness, and synthesis prediction were made for the screened novel drugs. Therefore, potentially attractive non-covalent proteasome inhibitors with low toxicity could be found as anticancer drugs. Methods: In this work, computer-aided drug design methods, including quantitative structure-activity relationship (QSAR), molecular docking, absorption, distribution, metabolism, excretion, and toxicology (ADMET) prediction, and drug-likeness prediction methods were performed. Results: In this study, the structure-activity relationship (SAR) of a series of non-covalent proteasome inhibitors were studied and the optimal comparative molecular field analysis (CoMFA; Q2 = 0.574, r2 = 0.999, r2pred = 0.755) and comparative molecular similarity indices analysis (CoMSIA)-SEHA (Q2 = 0.584, r2 = 0.989, r2pred = 0.921) models were obtained. According to the results of the QSAR model, some vital clues were found that would effectively enhance the biological activity of the compound. Based on these clues, 24 novel non-covalent proteasome inhibitors (D01–D24) were finally designed and screened. While the binding models between proteasome [protein data bank (PDB) code: 3MG6] and three representative compounds (15, 20, and D24) were also analyzed by using the molecular docking method. The results suggested that hydrogen bond and hydrophobic interaction played a key role in binding interaction between the receptor and ligand. In addition, the results of ADMET prediction indicated that the new designed compounds had reasonable PK parameters and drug-like properties. Conclusions: These statistical results can provide theoretical guidance for structural optimization, design, and synthesis of more effective non-covalent proteasome inhibitors in the future.

Влияние формы тороидальной задней поверхности на углы режущего клина и механические напряжения вдоль режущей кромки сверла

Introduction. Drilling holes with standard tolerance varying from IT8 to IT12 is widely used in industrial production. However, at present time, there are neither comprehensive studies, nor scientifically justified recommendations for the rational choice of the geometry of the cutting part of drills with a toroidal flank surface. Therefore, the computer-aided design (CAD) of new drill designs with a toroidal flank surface and finite element modeling (FEM) of the stressed state of its cutting part are important tasks. The purpose of the work is reducing both the range of change in the rake angle and the wedge angle of the cutting wedge along the cutting edge from the periphery to the center and the equivalent stresses in the cutting wedge. In this paper we investigate changes in the rake and wedge angles of the cutting wedge depending on the radius of the generatrix line of the toroidal flank surface as well as changes in equivalent stresses in the cutting wedge, which depend on changes in the radius of the generatrix line of the toroidal flank surface. The research methods include the fundamentals of the theory of cutting, CAD methods, and the FEM, which was applied in this work to new drill designs. Results and discussion. It is found that the range of changes in the rake angle and the wedge angle of the cutting wedge of the drill decreases compared to the standard design with decreasing radius of the generatrix line of the flank surface. A CAD system for drills with a toroidal flank surface is developed. As a result, the range of changes in the rake angle along the cutting edge decreased by 86 % for a drill with a minimum radius of the generatrix line of the toroidal surface compared to that with the conical flank surface, the range of the wedge angle of the cutting wedge decreased by 56 %, and the maximum equivalent stresses decreased by 2.13 times. It is also important to note that in this case, the wedge angle is close to constant for half of the drill tooth. These indicators exceed those for existing designs of the twist drills that indicate the key achievement of this paper.

Efficient design of synthetic gene circuits under cell-to-cell variability

BackgroundSynthetic biologists use and combine diverse biological parts to build systems such as genetic circuits that perform desirable functions in, for example, biomedical or industrial applications. Computer-aided design methods have been developed to help choose appropriate network structures and biological parts for a given design objective. However, they almost always model the behavior of the network in an average cell, despite pervasive cell-to-cell variability.ResultsHere, we present a computational framework and an efficient algorithm to guide the design of synthetic biological circuits while accounting for cell-to-cell variability explicitly. Our design method integrates a Non-linear Mixed-Effects (NLME) framework into a Markov Chain Monte-Carlo (MCMC) algorithm for design based on ordinary differential equation (ODE) models. The analysis of a recently developed transcriptional controller demonstrates first insights into design guidelines when trying to achieve reliable performance under cell-to-cell variability.ConclusionWe anticipate that our method not only facilitates the rational design of synthetic networks under cell-to-cell variability, but also enables novel applications by supporting design objectives that specify the desired behavior of cell populations.

Development and selection of working fluid pairs for cascade high-temperature heat pump based on computer-aided molecular design and group contribution method

Development and selection of working fluid pairs for cascade high-temperature heat pump based on computer-aided molecular design and group contribution method

Full Modification Control over Retrosynthetic Routes for Guided Optimization of Lead Structures.

Synthesizability is essential for compounds designed in silico. Regardless, synthetic accessibility is often considered only as an afterthought in the design and optimization process. In addition, the trend with modern computer-aided drug design methods is going toward full automation and away from the possibility of incorporating user knowledge. With this work, we present the second major release of our software tool, Synthesia, for synthesis-aware lead structure modification, where the user's expertise is now fully utilized. A provided retrosynthetic route is used as a pathway to guide structural modifications that introduce desired structural changes in the target compound. Moreover, the approach allows the user to define the exact position or component in the retrosynthetic route, which should be modified, further integrating the user's expert knowledge. This paper describes the functionality of Synthesia, its basic concepts, and several application scenarios ranging from simple examples to a comparison of the effects of the different exchange functions to an analysis of a set of bioisosteric linker structures, highlighting potential synthetically feasible replacements.

Fabrication of Ni-Cr-FeOx ceramic supercapacitor electrodes and devices by one-step electric discharge ablation

This investigation addresses the need in the development of a facile, low-cost and computer-aided design method to fabricate ceramic supercapacitors, based on patterned metal oxide films. It is motivated by the promising advantages of planar electrode arrangement for the fabrication of ceramic supercapacitors operating at extremely high charge-discharge rates. Herein, one-step electric discharge ablation (EDA) technique is developed for fabricating Ni-Cr-FeOx electrodes using commercial 304 stainless steel current collectors for the first time. The binder-free, noble materials-free, toxic chemical-free and conductive additives-free Ni-Cr-FeOx based in-plane microsupercapacitors (IMSC) are fabricated by the EDA technique. The obtained IMSC delivers a high areal capacitance of 38.3 mF cm−2 at 1 mV s−1 and shows superior capacitive behavior at an ultrahigh scan rate of 152,000 mV s−1, which is >760 times higher than the reported values for ceramic metal oxide based electrodes in the literature. This one-step, low-cost, environmental friendly, and automatic fabrication method is promising for the scale-up synthesis of various ceramic metal oxides and fabrication of supercapacitor devices.

Quinolines: A Promising Heterocyclic Scaffold for Cancer Therapeutics.

The quinoline scaffold is a widely recognized heterocycle with applications across various disease categories, ranging from malaria and viral infections to bacterial infections, high cholesterol, and even tumors. Consequently, quinoline plays a crucial role in the development of new drugs, and the field greatly benefits from advancements in computer-aided drug design. This review aims to provide insights into the evolution of quinoline and its derivatives, offering a comprehensive exploration of both marketed and developing drugs. Furthermore, the function and mechanism of quinoline compounds are introduced. Many studies rely on cell experiments to demonstrate drug cytotoxicity. In the concluding section of this review, the interaction between quinoline compounds and targets is simulated using computer-aided drug design methods. A thorough analysis is conducted on the potential influencing factors affecting the binding state between quinoline compounds and targets. Notably, the Pi-Alkyl interaction emerges as a significant contributor, while hydrogen bonding is identified as a pivotal bond in these interactions. This review serves as a valuable overview of the potential contributions of quinoline compounds to cancer treatment. It seamlessly combines the essential functions of marketed quinoline drugs with the promise held by emerging quinoline-based compounds. Additionally, the simulation of interactions between quinoline compounds and proteins through computer-aided design enhances our understanding of these compounds' efficacy.