Computer-aided Design Techniques Research Articles

In-silico Binding, Stability, Pharmacokinetics, and Toxicity Studies on Natural (-)-ambrox Metabolites as Binding Ligands to Luminal B and Triple-negative/basal-like Proteins for Breast Cancer Therapy

Background:: Breast cancer is the most prevalent malignant tumour in women of all races and is the second largest cause of cancer-related death in the majority of races. Based on the pattern of gene expression, five intrinsic or molecular classifications for breast tumours are frequently used. Our research, which is presently being utilized to treat breast cancer and has the potential to significantly change the course of the illness, is focused on two of them: luminal B breast cancer and triplenegative/ basal-like breast cancer. Methods:: Screening a database containing millions of drug molecules or phytochemicals has become rapid and simple due to computer-aided drug design (CADD) techniques. In the current work, nine natural compounds were screened for ambrox from a sperm whale using docking research. Results:: Following docking studies, nine substances were discovered to interact with basal-like and luminal B breast cancer proteins. All nine metabolites, however, adhered to Lipinski's rule of five and had sufficient oral bioavailability. The greatest binding affinities were demonstrated by 13,14,15,16-tetranorlabdane-3-oxo-8,12-diol, 6-β-hydroxy ambrox, 1-α-hydroxy-3-oxoambrox, and 2-α-3-β-dihydroxy ambrox. Conclusion:: Therefore, it can be concluded that research on molecular docking and pharmacological mimics may hasten the discovery of new medications. The use of ambrox metabolites in the treatment of breast cancer also requires future perspectives on their therapeutic use.

Analysis of Gingival Fibroblasts Behaviour in the Presence of 3D-Printed versus Milled Methacrylate-Based Dental Resins-Do We Have a Winner?

Computer-aided design and computer-aided manufacturing (CAD/CAM) techniques are based on either subtractive (milling prefabricated blocks) or additive (3D printing) methods, and both are used for obtaining dentistry materials. Our in vitro study aimed to investigate the behavior of human gingival fibroblasts exposed to methacrylate (MA)-based CAD/CAM milled samples in comparison with that of MA-based 3D-printed samples to better elucidate the mechanisms of cell adaptability and survival. The proliferation of human gingival fibroblasts was measured after 2 and 24 h of incubation in the presence of these samples using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and the membrane integrity was assessed through the lactate dehydrogenase release. The level of reactive oxygen species, expression of autophagy-related protein LC3B-I, and detection of GSH and caspase 3/7 were evaluated by fluorescence staining. The MMP-2 levels were measured using a Milliplex MAP kit. The incubation with MA-based 3D-printed samples significantly reduced the viability, by 16% and 28% from control after 2 and 24 h, respectively. There was a 25% and 55% decrease in the GSH level from control after 24 h of incubation with the CAD/CAM milled and 3D-printed samples, respectively. In addition, higher levels of LC3B-I and MMP-2 were obtained after 24 h of incubation with the MA-based 3D samples compared to the CAD/CAM milled ones. Therefore, our results outline that the MA-CAD/CAM milled samples displayed good biocompatibility during 24-h exposure, while MA-3D resins are proper for short-term utilization (less than 24 h).

Insights into the computer-aided drug design and discovery based on anthraquinone scaffold for cancer treatment: A systematic review.

In the search for better anticancer drugs, computer-aided drug design (CADD) techniques play an indispensable role in facilitating the lengthy and costly drug discovery process especially when natural products are involved. Anthraquinone is one of the most widely-recognized natural products with anticancer properties. This review aimed to systematically assess and synthesize evidence on the utilization of CADD techniques centered on the anthraquinone scaffold for cancer treatment. The conduct and reporting of this review were done in accordance to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) 2020 guideline. The protocol was registered in the "International prospective register of systematic reviews" database (PROSPERO: CRD42023432904) and also published recently. The search strategy was designed based on the combination of concept 1 "CADD or virtual screening", concept 2 "anthraquinone" and concept 3 "cancer". The search was executed in PubMed, Scopus, Web of Science and MedRxiv on 30 June 2023. Databases searching retrieved a total of 317 records. After deduplication and applying the eligibility criteria, the final review ended up with 32 articles in which 3 articles were found by citation searching. The CADD methods used in the studies were either structure-based alone (69%) or combined with ligand-based methods via parallel (9%) or sequential (22%) approaches. Molecular docking was performed in all studies, with Glide and AutoDock being the most popular commercial and public software used respectively. Protein data bank was used in most studies to retrieve the crystal structure of the targets of interest while the main ligand databases were PubChem and Zinc. The utilization of in-silico techniques has enabled a deeper dive into the structural, biological and pharmacological properties of anthraquinone derivatives, revealing their remarkable anticancer properties in an all-rounded fashion. By harnessing the power of computational tools and leveraging the natural diversity of anthraquinone compounds, researchers can expedite the development of better drugs to address the unmet medical needs in cancer treatment by improving the treatment outcome for cancer patients.

Three Decades of Targeting Falcipains to Develop Antiplasmodial Agents: What have we Learned and What can be Done Next?

Malaria is a devastating infectious disease that affects large swathes of human populations across the planet's tropical regions. It is caused by parasites of the genus Plasmodium, with Plasmodium falciparum being responsible for the most lethal form of the disease. During the intraerythrocytic stage in the human hosts, malaria parasites multiply and degrade hemoglobin (Hb) using a battery of proteases, which include two cysteine proteases, falcipains 2 and 3 (FP-2 and FP-3). Due to their role as major hemoglobinases, FP-2 and FP-3 have been targeted in studies aiming to discover new antimalarials and numerous inhibitors with activity against these enzymes, and parasites in culture have been identified. Nonetheless, cross-inhibition of human cysteine cathepsins remains a serious hurdle to overcome for these compounds to be used clinically. In this article, we have reviewed key functional and structural properties of FP-2/3 and described different compound series reported as inhibitors of these proteases during decades of active research in the field. Special attention is also paid to the wide range of computer-aided drug design (CADD) techniques successfully applied to discover new active compounds. Finally, we provide guidelines that, in our understanding, will help advance the rational discovery of new FP-2/3 inhibitors.

Investigating the bioactive compounds from Capsicum annum as a probable alternative therapy for prostate cancer treatment: a structure-based drug design approach

Abstract Prostate cancer remains a significant global health challenge, necessitating the exploration of novel therapeutic approaches. Androgen receptor (AR) signaling plays a critical role in prostate cancer progression and is a primary target for therapy. This study investigates the potential of phytochemicals from Capsicum annuum (Bell pepper) along with two common standand drugs (Apalutamide and Enzalutamide) as inhibitors of the human androgen receptor (AR) and prostate-specific membrane antigen (PSMA). Utilizing computer-aided drug design techniques, molecular docking studies were conducted to evaluate the binding affinities of selected ligands against AR (PDB ID: 1XOW) and PSMA (PDB ID: 2XEI), their ADMET properties, drug-likeness, oral bioavailability, and bioactivity profiles were also examined. Coumaroylquinic acid and 5-O-caffeoylquinic acid methyl-ester emerged as top-performing ligands, demonstrating strong binding affinities of −9.4 kcal/mol and −9.2 kcal/mol, respectively, against PSMA. Additionally, molecular dynamics simulations provided insights into the stability of protein-ligand complexes, with Coumaroylquinic acid exhibiting a stable binding conformation throughout the simulation. These findings suggest the potential of C. annuum phytochemicals, particularly Coumaroylquinic acid and 5-O-caffeoylquinic acid methyl-ester, as promising inhibitors of PSMA. Moreover, other ligands (Caffeoylglucoside and 1-O-galloyl-beta-d-glucose) identified in the study demonstrate interactions with AR, highlighting a multifaceted approach to prostate cancer treatment. Overall, this study underscores the potential of C. annuum phytochemicals as a source of novel therapeutic agents for prostate cancer, laying the groundwork for further lead optimization efforts.

Abstract 1815: Optimization of Lin28 inhibitors: A promising therapeutic approach for the suppression of cancer cell proliferation, stemness properties, and spheroid growth

Abstract Background: The pluripotency factor known as Lin28 plays a crucial role in the regulation of cancer cell stem-like characteristics, hence facilitating the formation of cancer and the evolution of therapy-resistant tumors. The protein exerts its function by utilizing its cold shock domain and zinc knuckle domain (ZKD) to engage with the Let-7 pre-microRNA and impede the process of Let-7 production. The implementation of chemical agents to hinder the interaction between Lin28 and Let-7 has been proven as a therapeutic approach for treating aggressive tumors. Methods: Computer-aided drug design techniques were employed in the development of a novel series of small molecule inhibitors, which are derivatives of our previously identified lead compounds Ln115, Ln15, and Ln7. Fluorescent Polarization Assay (FP), and Electrophoretic Mobility Shift Assay (EMSA) were used to screen the chemicals as Lin28-Let7 interaction disruptors using Lin28A/B ZKD domain. To further screen the chemicals, the Incucyte cell proliferation assay was performed using two Lin28A and Lin28B positive cells, IGROV-1, and DuNE cells, respectively. The inhibition of Lin28 activity was subsequently evaluated by measuring Let-7 micro-RNA and Lin28 protein levels using RT-PCR and Western Blot. Then, the metabolism profile was explored using Microsomal Stability Assay. Incucyte proliferation assay and MTS assay determined the IC50 of lead compound in Lin28 positive cells. The anti-stemness properties of the lead compound were subsequently evaluated through assays for stem gene expression levels and colony formation. To evaluate the potential of the lead compound to further move into animal studies, we tested it on a newly developed 3D Neuroendocrine Prostate Cancer (NEPC) model. Results: In this study, we provide a novel set of derivatives, within which, Ln268 was chosen as the lead compound. Ln268 shows higher metabolic stability with a half-life time of 462 min and clearance rate of 5 ul/min/mg, compared to its father compound at 347 min and 46 ul/min/mg, respectively. Ln268 treatment resulted in a time-dependent inhibition of cell growth with an IC50 of 2.5 uM at 72 hrs. Ln268 reduces mRNA levels of stemness and neurodifferentiation markers such as CHGA, CHG, SYP, SCGN, OCT3/4, NANOG, ID4, FOXC1, ALDH1A2, and FOXO3. In the 3D NEPC model, Ln268 suppresses spheroid growth in a dose- and time-dependent manner. Ln268 achieved 100% spheroid growth inhibition at the concentration of 100 uM, while the current commercially available C1632 only reached 50%. Conclusion: We discovered a novel Ln15 derivative named Ln268, which has a better metabolism profile and increased inhibitory activity to distrust Lin28-Let7 interaction and cancer cell proliferation. Ln268 has the potential to be improved and used as an anti-cancer treatment for a variety of malignancies, such as prostate cancer. Citation Format: Victor M. Matias-Barrios, Mariia Radaeva, Graciella Rosellinny, Artem Cherkasov, Xuesen Dong. Optimization of Lin28 inhibitors: A promising therapeutic approach for the suppression of cancer cell proliferation, stemness properties, and spheroid growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1815.

Computational Molecular Docking and In-Silico, ADMET Prediction Studies of Quinoline Derivatives as EPHB4 Inhibitor

Background:: The creation and development of novel chemical entities is made possible by numerous computer-aided drug design techniques. The ability to visualize the ligand-target interaction and forecast the important holding pocket locations and affinities of ligands to their intended macromolecules is made possible by pharmacophore-based drug design and understanding in-silico methodologies. Objective:: The aim of the current investigation was to find novel 2-chloroquinoline-3-carboxamide derivatives that target the Ephrin B4 (EPHB4) receptor to treat cancer. Materials and Methods:: Chem Axon Marvin Sketch 5.11.5 was used to create derivatives of 2-chloroquinoline-3-carboxamide. The physicochemical characteristics of compounds as well as their toxicity were predicted using SwissADME& the admet SAR online software’s. Molecular docking technology was used to examine the ligand-receptor interactions of 2-chloroquinoline-3-carboxamide derivatives with the target receptor (PDB- 6FNM) using a variety of software’s, including Autodock1.1.2,Procheck, ProtParam tool, Biovia Discovery Studio Visualizer v20.1.0.19295, MGL Tools 1.5.6, PyMOL, and were all included. Results:: All developed compounds were determined to be orally bioavailable, less toxic, and have acceptable pharmacokinetic properties according to in silico studies. In comparison to the traditional medication Erdafitnib, all new compounds displayed higher docking scores. Conclusion:: The increase in binding energy and the number of H-bonds created by novel derivatives with interactions at distances below 3.40A provide a helpful starting point for formulating and synthesizing compounds that are most suitable for additional research. The application of the 2- chloroquinoline-3-carboxamide moiety as a potential new cancer treatment candidate is supported by its pharmacokinetics &toxicological profile, which may aid medicinal chemists in conducting more in-depth in vitro, in vivo chemical and pharmacological studies.

A 3D-simulation study of the deformation, tension, and stress of 3D-printed and conventional denture base materials after immersion in artificial saliva.

The worldwide application of digital technology has presented dentistry with transformative opportunities. The concept of digital dentures, incorporating computer-aided design (CAD) and computer-aided manufacturing (CAM) techniques, holds the promise of improved precision, customization, and overall patient satisfaction. However, the shift from traditional dentures to their digital counterparts should not be taken lightly, as the intricate interplay between oral physiology, patient comfort, and long-term durability requires thorough examination.

Development of Anti-metastatic Drugs Based on Banned Imide-Polyamine Conjugates and Their Application in The Treatment of Liver Cancer

The purpose of this study was to develop an anti-metastasis drug based on a banned imide-polyamine conjugate and to explore its application in the treatment of liver cancer. First, we designed and synthesized a series of forbidden imide-polyamine conjugates and evaluated their inhibitory effects on the migration and invasion capacity of HCC cells by cell assay. The results showed that these compounds were able to significantly reduce the metastatic ability of HCC cells. Further mechanistic studies revealed that these compounds are able to inhibit the metastasis of HCC cells by interfering with intracellular signaling pathways and affecting cytoskeletal reorganization. These compounds also showed promising anti-HCC metastatic effects in animal models. To further optimize the structure and activity of these compounds, we optimized their structures using computer-aided design techniques. Through molecular docking and molecular dynamics simulations, we found a number of compounds with higher activity and selectivity. These optimized compounds further validate their anti-metastatic effect in cellular experiments and have less effect on normal cells, showing better biocompatibility. We also explored the mechanism of action of these compounds in HCC treatment. These compounds were found to be able to induce apoptosis in HCC cells and to inhibit their proliferation. At the same time, they can also promote the autophagy and cell cycle arrest of HCC cells, thus inhibiting the development of HCC in many ways. The forbidden imide-polyamine conjugates developed in this study have the potential to serve as novel anti-HCC metastasis agents. In the future, we will continue to optimize the structure and activity of these compounds and conduct clinical trials to validate their efficacy and safety. In addition, we will further explore the mechanisms of these compounds in order to provide new strategies for the prevention and treatment of HCC.

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.

G-code generation for deposition of continuous glass fibers on curved surfaces using material extrusion-based 3D printing

Improving the mechanical properties of 3D printed parts produced through a material extrusion-based 3D printer with continuous fibers (carbon, glass, and aramid) has been a focal point for numerous researchers. Given the layered nature of additive manufacturing (AM) processes, wherein parts are built up layer by layer, most studies involve the deposition of continuous fibers onto a 2D surface. Cases involving curved surfaces have employed robots with high degrees of freedom. This research introduces a method for depositing continuous glass fibers onto curved surfaces, implemented on a cost-effective material extrusion-based 3D printer. The presented approach involves G-code modification, the incorporation of a rotating axis for the nozzle, and the application of computer-aided design and manufacturing techniques. Experimental results affirm the efficacy of this method for depositing continuous fibers onto curved surfaces. The developed technique enables the production of free-form composite shells with a thermoplastic matrix and continuous fiber reinforcement. Lastly, through 3D scanning of the printed sample and subsequent comparison with the 3D model, the degree of surface form deviation and tolerance is determined. The maximum deviation identified in this study is 0.1 mm, a tolerable amount considering the inherent characteristics and behaviors of thermoplastic materials (shrinkage and warpage) during production processes.

Virtual Surgical Guidance Improves Quality of Life Following Scapular Free-Flap Reconstruction of Maxillary Defects

BackgroundThe best way for maxillary reconstruction remains the subject of debate, with negative impacts on the patient’s quality of life (QOL). PurposeThis study was designed to evaluate the QOL outcomes following maxillary reconstruction using a scapular-free flap, with and without the computer-aided design and computer-aided manufacturing (CAD/CAM) technique. Study design and patientsA prospective randomized controlled clinical trial was performed following the CONSORT checklist. To be included, patients suffering from maxillary defects without previous surgery or lymph node involvement were selected. Patients with poor oncological prognosis, deficient performance status, preoperative chemotherapy, or radiotherapy, besides vascular contraindications, were excluded. Predictor variableThe predictor variable was the reconstruction technique, grouped into two equal categories. Patients were randomly assigned to reconstruction with a scapular-free flap, with the control group not utilizing a guide and the study group utilizing a CAD/CAM-customized guide. Outcome variableThe primary outcome variable was the various domains of QOL, measured using the University of Washington-QOL (UW-QOL) score, 12 months after reconstruction. Covariatesage; sex; scapular flap side; and maxillary defect tumour type, histopathology, side, length, class, sagittal, and axial differential areas were considered. AnalysesShapiro-Wilk and Kolmogorov-Smirnov tests were performed for normality. For comparisons between the two groups, Student’s t-test and Mann-Whitney test were used. The category variables were compared using the chi-square test. p ≤ 0.05 was considered statistically significant. ResultsThe sample was composed of twenty-two eligible patients, eleven in each group. The mean age of the control group was (50.09±17.14) years, and 45.45% were male, while in the study group, the mean age was (48.36±14.14) years, with 36.36% male. All the patients were evaluated, showing statistically significant differences between control and study groups in terms of pain, appearance, chewing, swallowing, speech, and shoulder (p ≤ 0.05), indicating that the scapular-free flap with a CAD/CAM osteotomy guide had improved the patient's QOL. ConclusionsThe findings of this study indicate that VSP with a CAD/CAM customized osteotomy guide using a scapular-free flap can improve QOL in maxillary reconstruction in terms of pain, appearance, chewing and swallowing food, pronouncing words, and shoulder QOL outcomes.

New Drug Design to Suppress Nonalcoholic Steatohepatitis

A de novo designed biomolecule called INASHD was utilized through computer-aided drug design techniques to specifically target β2-spectrin, effectively suppressing and preventing NASH disease. Advanced computational software tools concerning the technologies of molecular docking and molecular dynamics (MD), were employed to showcase the drug's remarkable ability to efficiently suppress and control the α-helical topology of β2-spectrin. This protein is a vital component within the disease pathway. We successfully devised an effective design suppressing β2-spectrin, exhibiting an inhibition score surpassing any other molecule documented in scientific literature. With robust support from validated computational software, this bioorganic structure holds significant value and can be applied for a patent due to its innovative design. It shows promising potential for delivering positive outcomes in various stages, including in vitro, in vivo, ex vivo, and human phase studies.

Hemodynamic-based virtual surgery design of double-patch repair for pulmonary arterioplasty in tetralogy of Fallot

Background and objectiveSurgical correction of pulmonary artery stenosis (PAS) is essential to the prognosis of patients with tetralogy of Fallot (TOF). The double-patch method of pulmonary arterioplasty is usually applied in case of multiple stenosis in TOF patients’ pulmonary artery (PA) and when PAS cannot be relieved by the single-patch method. The surgical planning for the double-patch design remains challenging. The purpose of this study is to investigate the double-patch design with different angulations between the left pulmonary artery (LPA) and the right pulmonary artery (RPA), and to understand postoperative hemodynamic alterations by the application of computer-aided design (CAD) and computational fluid dynamics (CFD) techniques. MethodsThe three-dimensional model of the PA was reconstructed based on preoperative computed tomography imaging data obtained from the patient with TOF. Three postoperative models with different designs of double-patch were created by “virtual surgery” using the CAD technique. Double-Patch 120 Model was created with double patches implanted in the main pulmonary artery (MPA) and the PA bifurcation and without changing the spatial position of PA. The angulation between the LPA and the RPA was defined as θ, which equaled to 120° in Pre-Operative Model and Double-Patch 120 Model. Based on Double-Patch 120 Model, Double-Patch 110 Model and Double-Patch 130 Model were generated with θ equaled to 110° and 130°, respectively. Combined with CFD, the differences of velocity streamlines, wall shear stress (WSS), flow distribution ratio (FDR), and energy loss (EL) were compared to analyze postoperative pulmonary flow characteristics. ResultsThe values of velocity and WSS decreased significantly after virtual surgery. Obvious vortices and swirling flows were observed downstream of the stenosis of RPA and LPA in Pre-Operative Model, while fewer vortices developed along the anterior wall of the expanded lumens of RPA, especially in Double-Patch 110 Model. With the relief of PAS, two relatively higher WSS regions were observed at the posterior walls of RPA and LPA. The maximum WSS values in these regions of Double-Patch 110 Model were lower than those in Double-Patch 120 Model and Double-Patch 130 Model. Furthermore, the FDRs were elevated and the ELs were greatly reduced. It was found that Double-Patch 110 Model with the angulation between the LPA and the RPA equaled to 110° showed relatively better properties of hemodynamics than other models. ConclusionsThe angulation between the LPA and the RPA is an important factor that should be integrated in the double-patch design for TOF repair. Virtual surgery based on patient-specific vascular model and computational hemodynamics can be used to provide assistance for individualized surgical planning of double-patch arterioplasty.

Characterization of prevalent tyrosine kinase inhibitors and their challenges in glioblastoma treatment.

Glioblastoma multiforme (GBM) is a highly aggressive malignant primary tumor in the central nervous system. Despite extensive efforts in radiotherapy, chemotherapy, and neurosurgery, there remains an inadequate level of improvement in treatment outcomes. The development of large-scale genomic and proteomic analysis suggests that GBMs are characterized by transcriptional heterogeneity, which is responsible for therapy resistance. Hence, knowledge about the genetic and epigenetic heterogeneity of GBM is crucial for developing effective treatments for this aggressive form of brain cancer. Tyrosine kinases (TKs) can act as signal transducers, regulate important cellular processes like differentiation, proliferation, apoptosis and metabolism. Therefore, TK inhibitors (TKIs) have been developed to specifically target these kinases. TKIs are categorized into allosteric and non-allosteric inhibitors. Irreversible inhibitors form covalent bonds, which can lead to longer-lasting effects. However, this can also increase the risk of off-target effects and toxicity. The development of TKIs as therapeutics through computer-aided drug design (CADD) and bioinformatic techniques enhance the potential to improve patients' survival rates. Therefore, the continued exploration of TKIs as drug targets is expected to lead to even more effective and specific therapeutics in the future.

Deciphering Campylobacter jejuni DsbA1 protein dynamics in the presence of anti-virulent compounds: a multi-pronged computer-aided approach

The current study aims to evaluate Asinex library compounds against Campylobacter jejuni DsbA1 protein, a thiol disulfide oxidoreductase enzyme that plays a major role in the oxidative folding of bacterial virulence proteins, making it a promising anti-viral drug target. By employing several techniques of computer-aided drug design, BDC25697459, BDD33601083, and BDC30129064 were identified with binding energy scores of −8.8 kcal/mol, −8.8 kcal/mol, and −8.3 kcal/mol, respectively. However, the control molecule, tetraethylene glycol, exhibited a binding energy score of −7.0 kcal/mol. The control, BDD33601083, and BDC30129064 were unveiled to bind the same co-crystallized binding site (pocket 1), while BDC25697459 interacted with a new binding pocket (pocket 2) adjacent to the control binding region. The molecular dynamics simulation showed that complexes exhibit stable dynamics without significant global or residue-level fluctuations. The average RMSD values were in the range of 2.07 Å–2.45 Å. Similarly, mean RMSF was recorded between 1.30 and 1.42 Å. The C. jejuni DsbA1 was also observed as compact in the presence of the compounds, showing a mean RoG value in the range of 16.42 Å–16.55 Å. In terms of MM/PBSA binding energy, the BDC30129064 complex was ranked top with −44.88 ± 4.14 kcal/mol, whereas the positive control molecule exhibited −22.22 ± 3.33 kcal/mol. From a pharmacokinetic perspective, the compounds are suitable candidates for clinical trial investigation. Preliminary computational analysis of these virtual hits indicates that these compounds have a low potential for ADME and toxicity-associated liabilities. In summary, the compounds displayed a high affinity for the C. jejuni DsbA1 protein, indicating potential efficacy that requires further investigation. Communicated by Ramaswamy H. Sarma

Molecular dynamics exploration of Lupenone: therapeutic implications for glioblastoma multiforme and alzheimer's amyloid beta pathogenesis.

Neuro-oncological and neurodegenerative disorders, represented paradigmatically by glioblastoma and Alzheimer's disease, respectively, persist as formidable challenges in the biomedical realm. The interconnected molecular underpinnings of these conditions necessitate rigorous and novel therapeutic examinations. This comprehensive research was anchored on the premise of unveiling the therapeutic potential and specificity of Lupenone, a potent phytoconstituent, in targeting the molecular pathways underpinning both glioblastoma and Alzheimer's amyloid beta pathology. This was gauged through its interactions with key protein structures, 5H08 and 2ZHV. An integrative approach was adopted, marrying advanced proteomics and modern computer-aided drug design techniques. Molecular docking of Lupenone with 5H08 and 2ZHV was meticulously executed, with subsequent molecular dynamics simulations providing insights into the stability, viability, and intricacies of these interactions. Lupenone demonstrated profound binding affinities, evidenced by robust docking scores of -9.54kcal/mol for 5H08 and -10.59kcal/mol for 2ZHV. These interactions underscored Lupenone's eminent therapeutic potential in mitigating glioblastoma and modulating the amyloid beta pathology inherent to Alzheimer's. The introduction of Proteolysis Targeting Chimeras (PROTACs) further magnified the therapeutic prospects, accentuating Lupenone's efficacy. The findings of this study not only underscore the therapeutic acumen of Lupenone in addressing the challenges posed by glioblastoma and Alzheimer's but also lay a strong foundation for its consideration as a leading candidate in future neuro-oncological and neurodegenerative research endeavors. Given the compelling in-silico data, a clarion call is made for its empirical validation in holistic in-vivo settings, potentially pioneering a new therapeutic epoch in both glioblastoma and Alzheimer's interventions.

Natural product rhynchophylline prevents stress-induced hair graying by preserving melanocyte stem cells via the β2 adrenergic pathway suppression

Norepinephrine (NA), a stress hormone, can accelerate hair graying by binding to β2 adrenergic receptors (β2AR) on melanocyte stem cells (McSCs). From this, NA-β2AR axis could be a potential target for preventing the stress effect. However, identifying selective blockers for β2AR has been a key challenge. Therefore, in this study, advanced computer-aided drug design (CADD) techniques were harnessed to screen natural molecules, leading to the discovery of rhynchophylline as a promising compound. Rhynchophylline exhibited strong and stable binding within the active site of β2AR, as verified by molecular docking and dynamic simulation assays. When administered to cells, rhynchophylline effectively inhibited NA-β2AR signaling. This intervention resulted in a significant reduction of hair graying in a stress-induced mouse model, from 28.5% to 8.2%. To gain a deeper understanding of the underlying mechanisms, transcriptome sequencing was employed, which revealed that NA might disrupt melanogenesis by affecting intracellular calcium balance and promoting cell apoptosis. Importantly, rhynchophylline acted as a potent inhibitor of these downstream pathways. In conclusion, the study demonstrated that rhynchophylline has the potential to mitigate the negative impact of NA on melanogenesis by targeting β2AR, thus offering a promising solution for preventing stress-induced hair graying.Graphical

Logic-based modeling and drug repurposing for the prediction of novel therapeutic targets and combination regimens against E2F1-driven melanoma progression

Melanoma presents increasing prevalence and poor outcomes. Progression to aggressive stages is characterized by overexpression of the transcription factor E2F1 and activation of downstream prometastatic gene regulatory networks (GRNs). Appropriate therapeutic manipulation of the E2F1-governed GRNs holds the potential to prevent metastasis however, these networks entail complex feedback and feedforward regulatory motifs among various regulatory layers, which make it difficult to identify druggable components. To this end, computational approaches such as mathematical modeling and virtual screening are important tools to unveil the dynamics of these signaling networks and identify critical components that could be further explored as therapeutic targets. Herein, we integrated a well-established E2F1-mediated epithelial-mesenchymal transition (EMT) map with transcriptomics data from E2F1-expressing melanoma cells to reconstruct a core regulatory network underlying aggressive melanoma. Using logic-based in silico perturbation experiments of a core regulatory network, we identified that simultaneous perturbation of Protein kinase B (AKT1) and oncoprotein murine double minute 2 (MDM2) drastically reduces EMT in melanoma. Using the structures of the two protein signatures, virtual screening strategies were performed with the FDA-approved drug library. Furthermore, by combining drug repurposing and computer-aided drug design techniques, followed by molecular dynamics simulation analysis, we identified two potent drugs (Tadalafil and Finasteride) that can efficiently inhibit AKT1 and MDM2 proteins. We propose that these two drugs could be considered for the development of therapeutic strategies for the management of aggressive melanoma.Graphical abstract

Employing Atrous Pyramid Convolutional Deep Learning Approach for Detection to Diagnose Breast Cancer Tumors.

Breast cancer is among the most common diseases and one of the most common causes of death in the female population worldwide. Early identification of breast cancer improves survival. Therefore, radiologists will be able to make more accurate diagnoses if a computerized system is developed to detect breast cancer. Computer-aided design techniques have the potential to help medical professionals to determine the specific location of breast tumors and better manage this disease more rapidly and accurately. MIAS datasets were used in this study. The aim of this study is to evaluate a noise reduction for mammographic pictures and to identify salt and pepper, Gaussian, and Poisson so that precise mass detection operations can be estimated. As a result, it provides a method for noise reduction known as quantum wavelet transform (QWT) filtering and an image morphology operator for precise mass segmentation in mammographic images by utilizing an Atrous pyramid convolutional neural network as the deep learning model for classification of mammographic images. The hybrid methodology dubbed QWT-APCNN is compared to earlier methods in terms of peak signal-to-noise ratio (PSNR) and mean square error (MSE) in noise reduction and detection accuracy for mass area recognition. Compared to state-of-the-art approaches, the proposed method performed better at noise reduction and segmentation according to different evaluation criteria such as an accuracy rate of 98.57%, 92% sensitivity, 88% specificity, 90% DSS, and ROC and AUC rate of 88.77.