Current computer-aided drug design最新文献

Background: Research has elucidated that the pathophysiological underpinnings of non-alcoholic fatty liver disease and type 2 diabetes mellitus are intrinsically linked to insulin resistance (IR). However, there are currently no pharmacotherapies specifically approved for combating IR. Although Alpinia officinarum Hance (A. officinarum) can ameliorate diabetes, the detailed molecular mechanism through which it influences IR has not been fully clarified.

Aims: To predict the active components of A. officinarum and determine the mechanism by which A. officinarum affects IR.

Methods: The active compounds and molecular mechanism underlying the improvement of IR by A. officinarum were predicted via network pharmacology and molecular docking. To further substantiate these predictions, an in vitro model of IR was induced in HepG2 cells using high glucose concentrations. Cytotoxicity and oxidative stress levels were evaluated using Cell Counting Kit-8, reactive oxygen species (ROS), malondialdehyde (MDA), and superoxide dismutase (SOD) assay kits. The putative molecular mechanisms were corroborated through Western blot and RT-PCR analyses.

Results: Fourteen principal active components in A. officinarum, 133 potential anti-IR gene targets, and the top five targets with degree values were ALB, AKT1, TNF, IL6, and VEGFA. A. officinarum was posited to exert its pharmacological effects on IR through mechanisms involving lipid and atherosclerosis, the AGE-RAGE signaling pathway in diabetic complications, the PI3K-AKT signaling pathway, fluid shear stress, and atherosclerosis. Intriguingly, network pharmacology analysis highlighted (4E)-7-(4-hydroxy-3-methoxyphenyl)-1-phenylhept-4-en-3- one (A14) as the most active compound. Molecular docking studies further confirmed that A14 has a strong binding affinity for the main targets of PI3K, AKT, and Nrf2. The experiments demonstrated that A14 significantly diminished the ROS and MDA levels while augmenting the SOD activity. Moreover, A14 was found to elevate the protein expression of PI3K, AKT, Nrf2, and HO-1, and increase the mRNA levels of these targets as well as NQO1.

Conclusion: A. officinarum could play a therapeutic role in IR through multiple components, targets, and pathways. The most active component of A. officinarum responsible for combating IR is A14, which has the ability to regulate oxidative stress in IR-HepG2 cells by activating the PI3K/AKT/Nrf2 pathway. These findings suggest a potential pharmacological intervention strategy for the treatment of IR.

Introduction: With a projected mortality toll of 1.4 million in 2019, tuberculosis (TB) continues to be a significant public health concern around the world. Studies of novel treatments are required due to decreased bioavailability, increased toxicity, increased side effects, and resistance of several first- and second-line TB therapies, including isoniazid and ethionamide.

Methods: This study reports the synthesis of oxindole-based hybrids as potent InhA inhibitors targeting Mycobacterium tuberculosis. The synthesized compounds (5a-5e and 8a-8c) were evaluated for their anti-mycobacterial activity against Mycobacterium tuberculosis and nontuberculous mycobacteria (NTMs), viz. M. abscessus (ATCC 19977), M. fortuitum (ATCC 6841), and M. chelonae (ATCC 35752) using the Microplate Alamar Blue Assay (MABA). Molecular docking studies were performed using AutoDock Vina to explore the binding interactions of these compounds with the InhA enzyme (PDB: 2NSD). Additionally, biochemical and histopathological studies were conducted to assess the hepatotoxicity of the lead compounds. Insilico molecular properties and ADMET properties of the synthesized compounds were predicted using SwissADME and Deep-PK online tools to assess their drug-likeness.

Results: Among the tested compounds, 8b exhibited significant anti-mycobacterial activity with a minimum inhibitory concentration (MIC = 1 μg/mL) comparable to the reference drug ethambutol. Further, the compound demonstrated a binding affinity and orientation similar to the reference inhibitor 4PI, indicating its potential as a potent InhA inhibitor, and was found to be stabilized within the binding pocket of InhA through H-bonding, hydrophobic and van der Waal's interactions. Besides, the compounds hepatotoxicity assessment studies depicted that 8b showed no significant liver dysfunction or damage to liver tissues. Additionally, 8b adhered to Lipinski's rule of five and Veber's rule, displaying favourable pharmacokinetic and drug-like properties, including high human intestinal absorption, distribution, and acceptable metabolic stability and excretion.

Conclusion: Compound 8b emerged as a promising candidate for further optimization and development as a therapeutic agent for tuberculosis, offering a new avenue for tackling tuberculosis.

Introduction: DENV NS2B-NS3 protease inhibitors were designed based upon the reference molecule, 4-(1,3-dioxoisoindolin-2-yl)-N-(4-ethylphenyl) benzenesulfonamide, reported by our team with the aim to optimize lead compound via rational approach. Top five best scoring molecules with zinc ids ZINC23504872, ZINC48412318, ZINC00413269, ZINC13998032 and ZINC75249613 bearing 'pyrimidin-4(3H)-one' basic scaffold have been identified as a promising candidate against DENV protease enzyme.

Methods: The shape and electrostatic complementary between identified HITs and reference molecules were found to be Tanimotoshape 0.453, 0.690, 0.680, 0.685 & 0.672 respectively and Tanimotoelectrostatic 0.211, 0.211, 0.441, 0.442, 0.442 and 0.442 respectively. The molecular docking studies suggested that the identified HITs displayed the good interactions with active site residues and lower binding energies. The stability of docked complexes was assessed by MD simulations studies. The RMSD values of protein backbone (1.6779, 3.1563, 3.3634, 3.3893 & 3.0960 Å) and protein backbone RMSF values (1.0126, 1.0834, 1.0890, 0.9974 & 1.0080 Å respectively) for all top five HITs were stable and molecules did not fluctuate from the active pocket during entire 100ns MD run.

Results: The druggability Dscore below 1 indicate the tightly binding of ligand at the active site. Dscore for ZINC23504872 was found to be 1.084 while for the second class of compounds ZINC48412318, ZINC00413269, ZINC13998032 and ZINC75249613, 0.503, 0.484, 0.487 and 0.501 Dscores were observed. In-silico ADMET calculations suggested that all five HITs were possessed the drug likeliness properties and did not violate the Lipinski's rule of five.

Conclusion: Summing up, these in-silico generated data suggested that the identified molecules bearing pyrimidin-4(3H)-one would be promising scaffold for DENV protease inhibitors. However, experimental results are needed to prove the obtained results.

Objective: Kushen (Sophora flavescens Ait.) has a long history of medicinal use in China due to its medicinal values, such as antibacterial, antiviral, and anti-inflammatory. Rapid discovery of the components and the medicinal effects exerted by Kushen will help elucidate the science of Kushen in curing diseases. GSK3β (glycogen synthase kinase-3 beta) is a protein kinase with a wide range of physiological functions, such as antibacterial, antiviral, and anti-inflammatory. The discovery of inhibitors targeting GSK3β from Kushen was not only helpful for the rapid discovery of the components responsible for the efficacy of Kushen but also important for the development of novel drugs.

Methods: In this study, the chemical composition of Kushen was extracted from the TMSCP database. Molecular docking, GSK3β enzyme assay, and molecular dynamics simulations were used to discover the GSK3β inhibitors from the chemical composition of Kushen.

Results: A total of 113 chemical compositions of Kushen were extracted from the TMSCP database. Molecular docking indicated that 15 chemical compositions of Kushen scored better than -8 kcal/mol against GSK3β. GSK3β enzyme assay demonstrated several inhibitory activities of kushenol I and kushenol F with IC50 values of 7.53 ± 2.55 μM and 4.96 ± 1.29 μM, respectively. Molecular dynamics simulations were used to reveal the interactions of kushenol I and kushenol F with GSK3β from structural and energetic perspectives.

Conclusion: Kushenol I and kushenol F could be the material basis for the antibacterial, antiviral, and anti-inflammatory properties of Kushen.

Background: Berberine (BBR), also known as berberine hydrochloride, was isolated from the rhizomes of the Coptis chinensis. Studies have reported that BBR plays an important role in glycolipid metabolism, including insulin (IR). The targets, and molecular mechanisms of BBR against hyperlipid-induced IR is worthy to be further studied.

Material and methods: The related targets of BBR were identified via Pharmmapper database and relevant targets of diabetes were obtained through GeneCards and Online Mendelian Inheritance in Man (OMIM) database. The common targets were employed with the STRING database and visualized with the protein-protein interactions (PPI) network. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was performed to explore the biological progress and pathways. In vitro, human hepatocellular carcinomas (HepG2) cell was used as experimental cell line, and an insulin resistant HepG2 cell model (IR-HepG2) was constructed using free fatty acid induction. After intervention with BBR, glucose consumption and uptake in HepG2 cells were observed. Molecular docking was used to test the interaction between BBR and key targets, and real-time fluorescence quantitative PCR was used to detect the regulatory effect of BBR on related targets.

Results: 262 overlapped targets were extracted from BBR and diabetes. In the KEGG enrichment analysis, the peroxisome proliferator activated receptor (PPAR) signaling pathway was included. In vitro experiments, BBR can significantly increase sugar consumption and uptake in IR HepG2 cells, while PPAR inhibitors can weaken the effect of BBR on IR-HepG2.

Conclusion: The PPAR signaling pathway is one of the important pathways for BBR to improve high-fat-induced insulin resistance in HepG2 cells.

Background: Plants represent a rich reservoir of bioactive compounds with established therapeutic value in diverse diseases. Notably, the Toll-like receptor-4 (TLR-4) signaling pathway plays a pivotal role in inflammation. Upon engagement with pro-inflammatory ligands like lipopolysaccharide, TLR-4 triggers downstream cascades involving nuclear factor ĸappa B and mitogen- activated protein kinases. This signaling cascade ultimately dictates the onset and progression of inflammatory diseases. Therefore, targeting TLR-4 signaling offers a promising therapeutic approach for managing inflammatory disorders.

Methods: This study investigated the potential of Costus speciosus rhizome phytocompounds, a traditional medicinal plant, as novel as modulators of TLR-4 signaling, highlighting their mechanisms of action and potential clinical applications. In the present study, 18 phytocompounds isolated from the rhizome of Costus speciosus, were studied against TLR-4/AP-1 signaling, which is implicated in the inflammatory process using a computational approach.

Results: The compounds exhibited binding affinities ranging from -4.087 to -8.93 kcal/mol with the TLR-4 protein due to the formation of multiple intermolecular interactions. Benzenepropanoic acid, 3,5-bis(1,1-dimethylethyl)-4-hydroxy-, methyl ester (compound 7) exhibited exceptional binding energy (-8.93 kcal/mol), indicating strong affinity for the TLR-4 protein. Additionally, compound 7 displayed favorable ADMET properties, suggesting promising drug development potential. Molecular dynamics simulations confirmed the stability of the compound 7-TLR4 complex, further supporting its ability to modulate TLR-4 signaling.

Conclusion: These findings highlight the therapeutic potential of Costus speciosus phytocompounds, particularly compound 7, as potent anti-inflammatory modulators. Further research is warranted to validate their anti-inflammatory and neuroprotective effects in pre-clinical models, paving the way for their development as novel therapeutic agents for inflammatory diseases.

Aim: To Discover novel PTP1B inhibitors by high-throughput virtual screening Background: Type 2 Diabetes is a significant global health concern. According to projections, the estimated number of individuals affected by the condition will reach 578 million by the year 2030 and is expected to further increase to 700 million deaths by 2045. Protein Tyrosine Phosphatase 1B is an enzymatic protein that has a negative regulatory effect on the pathways involved in insulin signaling. This regulatory action ultimately results in the development of insulin resistance and the subsequent elevation of glucose levels in the bloodstream. The proper functioning of insulin signaling is essential for maintaining glucose homeostasis, whereas the disruption of insulin signaling can result in the development of type 2 diabetes. Consequently, we sought to utilize PTP1B as a drug target in this investigation.

Objective: The purpose of our study was to identify novel PTP1B inhibitors as a potential treatment for managing type 2 diabetes.

Methods: To discover potent PTP1B inhibitors, we have screened the Maybridge HitDiscover database by SBVS. Top hits have been passed based on various drug-likeness rules, toxicity predictions, ADME assessment, Consensus Molecular docking, DFT, and 300 ns MD Simulations.

Results: Two compounds have been identified with strong binding affinity at the active site of PTP1B along with drug-like properties, efficient ADME, low toxicity, and high stability.

Conclusion: The identified molecules could potentially manage T2DM effectively by inhibiting PTP1B, providing a promising avenue for therapeutic strategies.

Background: Centipeda minima (CM) is a traditional Chinese herbal medicine used for the treatment of sinusitis and rhinitis, and it possesses anti-cancer properties. However, the mechanism of CM in the treatment of nasopharyngeal carcinoma (NPC) remains unclear.

Objective: This study aimed to explore the mechanism of CM in the treatment of NPC using a network pharmacology approach.

Methods: The active components and targets of CM and NPC were screened using TCMSP, SwissTarget, and GeneCards database. The association between CM components and NPC targets or pathways was analyzed using String, Cytoscape 3.9.1, David 6.7, and AutoDock Vina. The Sangerbox platform was used to conduct differential expression and Kaplan-Meier survival analysis of core genes.

Results: We identified 17 active compounds of CM and 146 corresponding targeted proteins in NPC. These targets may modulate pathways in cancer, PI3K-Akt, apoptosis, prolactin, relaxin, and TNF signaling. The top 5 core genes of the PPI network were found to be AKT1, STAT3, CASP3, EGFR, and SRC, which may be the main targets of CM in treating NPC. Molecular docking confirmed the binding energies of quercetin with CASP3, 8-Hydroxy-9,10-diisobutyryloxythymol with AKT1, and plenolin with AKT1, which were particularly low, suggesting robust and stable interactions. The expression levels of AKT1, CASP3, EGFR, SRC, MMP9, CCND1, and PTGS2 were significantly higher in head and neck squamous cell carcinoma (HNSC) samples compared to normal samples. In addition, the hub genes could predict the prognosis of HNSC as the Kaplan-Meier survival curve showed that patients with lower expressions of AKT1, STAT3, CASP3, EGFR, MMP9, ESR1, PTGS2, and PPARG had better overall survival.

Conclusion: By conducting a network pharmacology approach, we revealed the main ingredients, key targets, and regulatory pathways of Centipeda minima in the treatment of NPC.

Background: As a traditional Chinese medicine, Danshen shows potential efficacy for treating ulcerative colitis (UC). However, the bioactive components and mode of action were unclear.

Aim of this study: This paper uses a combination of network pharmacology, serum medicinal chemistry, and gene expression profiling to clarify its possible molecular mechanism of action and material basis.

Methods: Ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS) was utilized to analyze the herbal components and metabolites from the serum of Danshen-treated mice. Gene expression profiles were applied to construct a database of Danshen action targets. Then, active ingredient-target-biological functional module networks were constructed to analyze the mechanism of action. Molecular docking has further confirmed the possibility of its components to the targets.

Results: As a result, 193 common targets between 1684 Danshen-related DEGs and 1492 UC targets were determined as the potential targets for Danshen in treatment with UC. Serum pharmacochemistry and target prediction showed that 22 components in serum acted on 777 targets. Intersection with common targets yielded 46 core targets, and an active ingredienttarget- biological functional module network was constructed for analysis. Network prediction and molecular docking results showed that the main action modules were inflammatory response and cell apoptosis, which mainly acted on targets SRC, RELA, HSP90AA1, CTNNB1, STAT3, and CASP3. The main components of Danshen intervention in UC were predicted to include Catechol, 3,9-Dimethoxypterocarpan, 8-Prenylnaringenin, Isoferulic acid, Salvianolic acid C, and Danshensu.

Conclusion: The present study provides a scientific foundation for further explicating the mechanisms of Danshen against UC.

Background: The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing globally, impacting individuals in Western nations and rapid growing in Asian countries due to sedentary lifestyles; thus, NAFLD has emerged as a significant worldwide health concern. Presently, lifestyle changes represent the primary approach to managing NAFLD.

Methods: This research aimed to identify the potential drug targets for treating NAFLD through comprehensive in silico computational analysis. These include the prediction of the three-dimensional structure of the protein, the prediction of inhibitors by PubChem and ZINC, molecular docking by Autodcok, pharmacophore modeling, molecular dynamics simulation by the OPLS_2005 force field, and the orthorhombic box solvent model Intermolecular Interaction Potential 3 Points Transferable to the selected compound. The toxicity of the lead compounds was analyzed through AdmetSAR software.

Results: The protein associated with the PNPLA3 gene, whose overall three-dimensional structure was 95% accurate, were retrieved following inhibitor selection via PubChem and ZINC. Among the selected inhibitors and docked compounds with ID 10033935 (ellagitannin) showed a minimum E-Score of -17.266. In docking and pharmacophore modeling the compound ellagitannin shows promise as a potential drug candidate. Moreover, the molecular dynamics and structural stability of the protein-ligand complex were evaluated with several metrics such as as root mean square fluctuation and root mean square deviation and resulted in the stability not only of PNPLA3-10033935 (ellagitannin) but also of compound PNPLA3-71448940 and PNPLA3-5748394 complexed proteins at 400 ns with very slight variation.

Conclusion: Overall, ellagitannin was identified as the best druggable target with the best therapeutics profile. The findings of our study can pave the way for the development of a new drug against NALFD.