PyRx Software Research Articles

In silico identification and virtual screening to discover potent therapeutic phytochemicals against CMT2A

Charcot-Marie-Tooth (CMT2A) neuropathies are a set of monogenic diseases that affect the peripheral nervous system. The pathogenesis of CMT2A, a disease caused by genetic mutations, is linked to impaired mitochondrial dynamics and axonal biology. Therapeutic options are still limited, with only a few drugs and other authorized or underdeveloped approaches. A ligand-based virtual screening methodology was used to identify the potential MFN promoters. The natural compound subset of the ZINC database (n = 559600) was obtained and filtered using a ligand-based virtual screening technique. The top 200 compounds were identified to have more than four features that matched the target compound. Pyrx software was used to analyze the molecular docking. Based on the number and type of important binding interactions and docking results, we selected top-20 compounds with the best binding affinities for the targeted protein. 3D-QSAR analyses were performed on potential ligands identified through molecular docking analyses to predict biological activity. The pEC50 and docking scores were used to identify the potential drugs. The ADMET analysis was used to assess the kinetic characteristics of the top two drugs. According to molecular dynamics simulation, the top compound ZINC000005313168 showed high conformational stability. Based on docking results and MD findings, the best in silico hits among the compounds investigated was ZINC000005313168. These findings suggest that the compound ZINC000005313168 could be used to treat CMT2A disease. Further in vivo and in vitro studies are required to consider the present analyses.

Ligand-based pharmacophore modeling, virtual screening, and molecular dynamics simulations of Pfhsp90 fingerprints in Plasmodium malaria treatment

The World Health Organization (WHO) documents malaria as one of the leading causes of high morbidity and mortality worldwide. The disease affects millions and kills thousands of people annually. Efforts to reduce the global burden of malaria have prompted the WHO to recommend prevention strategies such as using antimalarial drugs. However, these strategies have been ineffective because of antimalarial drug resistance. The only efficacious malaria treatment is Artemisinin-based Combination Therapy (ACT). However, the extended ACT clearance times, linked to the emergence of artemisinin monotherapy resistance recorded most recently in Africa and the Great Mekong region, pose a danger to its efficacy. Therefore, better efficacious antimalarial drugs are required. Since P. falciparum heat shock protein 90 (PfHsp90) is a well-characterized malaria drug target, this study uses it to discover more efficacious antimalarial drugs. An in silico approach was used to discover PfHsp90 inhibitors with pharmacological properties against Plasmodium malaria using a molecular dynamics simulation (MDS) and hierarchical virtual screening. Geldanamycin (GDM), a well-known anti-PfHsp90 compound, was used to identify PfHsp90 inhibitors with pharmacological properties against Plasmodium malaria by screening it against the ZINC20 database via the ZINCPHARMER web server. This virtual screening process resulted in 17 hits. These ZINCPHARMER hits were subjected to drug-likeness and pharmacokinetics properties analysis in the SwissADME web server, and nine of them satisfied the requirements. The nine ZINC20 compounds were docked with PfHsp90 using the PyRx software version 0.8 to understand their interactions. From the molecular docking results, ZINC09060002 (−8.2 kcal/mol), ZINC72133064 (−7.8 kcal/mol), ZINC72163401 (−7.7 kcal/mol), ZINC72358537 (−8.1 kcal/mol), and ZINC72358557 (−7.6 kcal/mol) had better binding affinities to PfHsp90 than GDM (−7.5 kcal/mol). The stability of these molecularly docked protein–inhibitor complexes was assessed through MDS using GROMACS 2022. ZINC72163401, ZINC72358537, and ZINC72358557 formed stable complexes with PfHsp90. The lead compounds were subjected to in vitro validation for their inhibitory capability. They showed promising inhibition of parasite growth with IC50 values ranging between 200 and 400 ng/mL. In this regard, the three PfHsp90 inhibitors can be further developed as potential antimalarial drugs. However, further structural optimization studies and clinical (in vivo) tests are necessary to ascertain the antimalarial activity of these compounds in humans.

Implications of trinodal inhibitions and drug repurposing in MAPK pathway: A putative remedy for breast cancer

Breast cancer has been one of the supreme causes of cancer-related deaths among women worldwide. To make the case even more compounded, due to innate or acquired causes, cancer cells often develop resistance against the available chemotherapy or monotargeted treatments. This resistance is concomitant with increased activation of the MAPK (mitogen-activated protein kinase) signaling pathway. This study simultaneously targets three imperative intermediates in this pathway using molecular docking and real-time simulation. Docking was performed via the integrated AutoDock Vina 1.1.2 & 1.2.5 of the PyRx software, while the Discovery Studio (BIOVIA) v24.1.0.23298 was utilized to conduct the simulation. The aim is to investigate the therapeutic prospects of known potential inhibitors of the targeted intermediates and repurposable drugs to comprehend the effectiveness of targeting these trinodes simultaneously. The target points were deemed to be PDPK1 (3-phosphoinositide-dependent protein kinase 1), ERK1/2 (extracellular signal-related protein kinases 1/2), and mTOR (mammalian target of Rapamycin). Our study reveals that out of the candidate inhibitors chosen for each node, MP7 exhibited the most superior binding affinities for all three: −10.918 kcal/mol for PDPK1, −10.224 kcal/mol for ERK1, −10.134 kcal/mol for ERK2, and −9.2 kcal/mol for mTOR (via AutoDock Vina 1, .2.5). Some scores with MP7 were often higher than the available single-targeted drugs for different nodes in the MAPK pathway. Additionally, a total of 1867 repurposed analgesic, antibiotic, and antiparasitic drugs, including Zavegepant (−13.399 kcal/mol for PDPK1), Adozelesin (−11.74 kcal/mol for mTOR) and Modoflaner (−11.29 kcal/mol for PDPK1), showed promising binding energetics while targeting our triad points than other compounds used. This approach prompts for mitigating not only breast cancer but other elusive diseases as well, with state-of-the-art multitargeted therapies coupled with bioinformatic strategies.

Phytochemical profiling, molecular docking, and ADMET evaluation of essential oils from Anaphalis busua and Anaphalis margaritacea in Uttarakhand's Himalayan Terrain

BackgroundThe study focuses on a comparative analysis of essential oils derived from two species of the Anaphalis genus, namely Anaphalis busua and Anaphalis margaritacea, collected at varying elevations in the hilly terrain of Uttarakhand. The investigation aims to explore the phytochemical composition, conduct in silico molecular docking studies, and evaluate ADMET properties of the essential oils to understand their potential bioactivity. MethodsEssential oils were extracted from the whole plants using the hydrodistillation method, and GC–MS was employed for compound identification. A total of 31 compounds were identified in A. busua and 32 in A. margaritacea, constituting 87.86 % and 87.83 % of the total composition, respectively. Major compounds included isocaryophyllene, caryophyllene oxide, geranyl-α-terpinene, α-pinene, γ-muurolene, δ-cadinene, humulene, and copaene. ResultsMolecular docking studies were conducted using PyRx software on ten notable compounds as ligands, targeting cyclooxygenase-2 (COX-2) and human peroxiredoxin 5 to assess antioxidant and anti-inflammatory activities. Isocaryophyllene, with concentrations of 14.07 % (A. busua) and 17.82 % (A. margaritacea), exhibited significant binding affinities of -5.7 and -7.2 kcal/mol against 1HD2 and 4COX, respectively. ConclusionThe research provides valuable insights into the chemical composition of essential oils from Anaphalis plants and validates their bioactive potential through in silico analysis. Isocaryophyllene emerges as a key compound with noteworthy binding affinities, emphasizing its importance in the medicinal and pharmacological applications of essential oils derived from A. busua and A. margaritacea. The results enhance our understanding of the therapeutic potential of Anaphalis essential oils, opening avenues for future research in natural products and drug discovery.

Chemical Profiling, In Silico Pharmacokinetics Analysis and Molecular Docking Study of Phytocompounds of Homeopathy Medicine Echinacea angustifolia Q against Suppurative Bacterial Proteins

Background Computer-aided drug design is the emerging field for identification of drug action on its target organs. The pharmacokinetic study helps find out drug ADMET (absorption, distribution, metabolism, excretion, and toxicity) and drug likeness properties. PyRx software helps with molecular docking of the bioactive compounds on their target organ within a short period of time. In homeopathy, Echinacea angustifolia is one of the most commonly used drugs for microbial infective skin lesions used in internal administration as well as an external application. Objective This study was aimed at identifying the compounds present in Echinacea angustifolia Q through liquid chromatography mass spectrometry (LC-MS), ADMET, and drug likeness properties, followed by molecular docking by PyRx software to recognize the interaction between drug compounds against 12 target microbial proteins of commonly infective suppurative bacteria. Materials and Methods An analysis of the phytoconstituents of Echinacea angustifolia Q was performed using the Agilent 1290 Infinity LC system coupled to the Agilent 6545 Accurate Mass Quadrupole Time-of-Flight (QTOF) with Agilent Jet Stream Thermal Gradient Technology. In silico ADMET and drug likeness properties were assessed by free online tools, followed by a detailed docking study by PyRx software. The drug compounds with the lower glide docking score are considered to have the best binding affinity. Result The five compounds of Echinacea angustifolia Q satisfy all properties of ADMET and drug likeness. The three compounds of Echinacea angustifolia Q have low glide score of >-7.0 kcal/mol against the three microbial target proteins of Salmonella enterica, Proteus mirabilis, and Staphylococcus aureus. Conclusion Echinacea angustifolia Q has fulfilled the ADMET and drug-likeness properties for internal administration as well as external application for various suppurative bacterial infective disorders, which were confirmed through molecular docking. Therefore, Echinacea angustifolia Q may function as a potential therapeutic agent for the treatment of illnesses associated with antimicrobial resistance.

Comprehensive investigation of two substituted benzimidazoles: Design, synthesis, biological assessment, and characterization

Benzimidazole is a bicyclic molecule that is mostly used in medicinal chemistry. The 2-substituted benzimidazoles that are now on the market include omeprazole, flubendazole, mebendazole, and albendazole. Antioxidants are compounds that impede the oxidation process, which is the chemical process that produces free radicals. A computational technique called "in-silico screening" is used in drug discovery to effectively estimate a molecule's likelihood of interacting with a target of interest. Antihelminthics are a class of antiparasitic drugs that either kill or paralyze internal parasites like parasitic worms, all without endangering the host. A standard procedure was used to create the 2-substituted benzimidazole. PyRx software was used to do the in-silico screening for anthelmintic drugs. The DPPH and ABTS methods were used to measure the antioxidant activity. Melting point, TLC, and IR spectra were used to confirm the structures of the produced compounds. The binding affinity for sulphosalicylic acid in the anthelmentic in silico screening was -7.7. Salicylic acid demonstrated excellent antioxidant activity, as seen by its IC50 values of less than 5 mg/ml for the ABTS method and 37 mg/ml for the DPPH method. Overall, the combination of theoretical and practical yield data, along with melting points, ATR Spectra and Rf values, offers valuable insights into the synthesis and characterization of chemical compounds. The salicylic acid derivative exhibits good antioxidant activity by both the methods. The Sulphosalicylic acid derivative shows prominent In-silico anthelmintic activity result hence the synthesized compounds can be tested for anthelmintic activity in future.

An in silico Drug Repurposing Study to Inhibit the Spike Protein of SARS-CoV2

SARS-CoV2 has caused the recent mortal pandemic known as COVID-19. The drug repurposing approach can be employed to find the potential drugs capable of binding SARS-CoV2 structural and nonstructural proteins. The present study aimed to repurpose some common FAD-approved antiviral and non-antiviral drugs computationally for SARS-CoV2 treatment. In the in silico study, 89 FDA-approved drugs and Remdesivir, as the control, were analyzed by molecular docking to inhibit the SARS-CoV2 spike (S) protein as the key player in virus-cell binding. First, the Uniport website was used to find receptor and ganglioside binding domains (RBD and GBD, respectively) of the S protein as the target. The structure of the target was downloaded from RCSB, and 'the ligands' structures were downloaded from PubChem. All structures were refined using SPDV and PyRx software. AutoDock Vina was employed for the docking process. The result showed that 8 drugs, including Ledipasvir, Montelukast, Domperidone, Aprepitant, Folic acid, Losartan, Ticagrelor, and Rivaroxaban, can bind S protein and then inhibit the protein function. In addition, Ledipasvir, Montelukast, and Domperidone can bind GBD of the S protein with higher binding energy (-8.2, -8, -7.9 kcal/mol, respectively). On the other hand, higher RBD binding energy was calculated for Ticagrelor (-6.9 kcal/mol), Folic acid, Montelukast, and Domperidone (-6.5 kcal/mol). Generally, the ligands could inhibit GBD more than RBD. According to the binding energy to S protein and low side effects of the studied medications, Ledipasvir and Losartan can be introduced as the most effective candidates for repurposed drugs. Also, Gly496 and Asn137 are the most engaged amino acids in the ligand-receptor interaction from RBD and GBD, respectively.

Integrated network pharmacology and molecular docking to investigate the potential mechanism of Tufuling on Alzheimer's disease

ObjectiveThis study aimed to investigate the mechanism of Tu Fu Ling in treating Alzheimer's disease (AD) using network pharmacology and molecular docking. MethodsThe TCMSP and Swiss target prediction databases were utilized to confirm the active components of Tu Fu Ling and their corresponding targets, with target gene names converted using the UniProt database. Genes related to AD were collected from DisGeNET, GeneCards, and the Open Target Platform databases. Common target genes between the disease and the drug were obtained using Venny 2.1 tools and visualized using Cytoscape software. Protein-protein interaction (PPI) data were further analyzed to determine correlations between common target genes, and GO and KEGG pathway enrichment analyses were performed for intersecting genes. Finally, PYmol, AutoDock Tool, Discovery Studio 2020, and PyRx software were used for preliminary computer virtual verification and visualization of active drug ingredients and target proteins. ResultsNine active ingredients meeting the screening criteria yielded a total of 168 genes after removing duplicates. A total of 3833 target genes were collected, with 129 overlapping target genes identified. GO enrichment analysis identified 643 biological processes, 82 cellular components, and 147 molecular functions. KEGG pathway enrichment analysis also revealed a pathway closely related to AD (hsa05010: Alzheimer's disease). In molecular docking analysis, the binding affinity between the 9 active ingredients and 10 core targets ranged from −3.5 to −12.3 kcal/mol, indicating strong binding. ConclusionThis study preliminarily verified the combination of Tu Fu Ling's screened active ingredient and the calculated core target, suggesting a potential mechanism of action to improve the symptoms of AD patients through multi-target and multi-pathway approaches. This provides a valuable reference for further exploration of the pharmacological mechanism of AD and the formulation of drug therapy.

Identification of novel NLRP3 inhibitors as therapeutic options for epilepsy by machine learning-based virtual screening, molecular docking and biomolecular simulation studies

The NOD-Like Receptor Protein-3 (NLRP3) inflammasome is a key therapeutic target for the treatment of epilepsy and has been reported to regulate inflammation in several neurological diseases. In this study, a machine learning-based virtual screening strategy has investigated candidate active compounds that inhibit the NLRP3 inflammasome. As machine learning-based virtual screening has the potential to accurately predict protein-ligand binding and reduce false positives outcomes compared to traditional virtual screening. Briefly, classification models were created using Support Vector Machine (SVM), Random Forest (RF), and K-Nearest Neighbor (KNN) machine learning methods. To determine the most crucial features of a molecule's activity, feature selection was carried out. By utilizing 10-fold cross-validation, the created models were analyzed. Among the generated models, the RF model obtained the best results as compared to others. Therefore, the RF model was used as a screening tool against the large chemical databases. Molecular operating environment (MOE) and PyRx software's were applied for molecular docking. Also, using the Amber Tools program, molecular dynamics (MD) simulation of potent inhibitors was carried out. The results showed that the KNN, SVM, and RF accuracy was 0.911 %, 0.906 %, and 0.946 %, respectively. Moreover, the model has shown sensitivity of 0.82 %, 0.78 %, and 0.86 % and specificity of 0.95 %, 0.96 %, and 0.98 % respectively. By applying the model to the ZINC and South African databases, we identified 98 and 39 compounds, respectively, potentially possessing anti-NLRP3 activity. Also, a molecular docking analysis produced ten ZINC and seven South African compounds that has comparable binding affinities to the reference drug. Moreover, MD analysis of the two complexes revealed that the two compounds (ZINC000009601348 and SANC00225) form stable complexes with varying amounts of binding energy. The in-silico studies indicate that both compounds most likely display their inhibitory effect by inhibiting the NLRP3 protein.

Molecular Docking-Based Screening of Five Heterocyclic Quinone Compounds for Antifungal Activity on Yeast Sec14p and Validation by Redocking

Discover new antifungal drugs by evaluating the efficacy of heterocyclic compounds. Investigate the potential of yeast Sec14p protein as a target for antifungal drugs. Compare the effectiveness of Auto Dock and PyRX software for docking simulations of heterocyclic compounds against Sec14p. Docking simulations were performed using Auto Dock and PyRX software to assess the binding affinity of five specific heterocyclic compounds to the yeast Sec14p protein. The reference compound for comparison was a known antifungal agent with a Picolamide scaffold (PDB ID: 6FOE). Atovaquone exhibited the strongest binding affinity (-9.4 kcal/mol) using PyRX. A known antifungal agent showed a significant discrepancy in binding energy between Auto Dock (-6.2 kcal/mol) and PyRX (-3.64 kcal/mol). This study explores a novel class of compounds (Quinones) for antifungal drug discovery. It highlights the potential of yeast Sec14p protein as a target for antifungal drugs. The findings suggest that PyRX might be more suitable for docking simulations of certain compound classes than Auto Dock. This emphasizes the importance of software selection based on the specific molecules under investigation. Keywords: Molecular docking, Quinones, Antifungal, PyRX, Auto dock

Computational Discovery of AngiomiRs and Evaluating the Synergistic Effects of Target miRNA with Tranexamic Acid in Colorectal Cancer.

microRNA (miRNA) levels are dysregulated in many cancers, suggesting that miRNA-based therapy may be effective. The molecular pathways of colorectal cancer (CRC) development are unknown. Understanding miRNAs implicated in CRC formation may reveal new diagnostic and therapeutic targets. Angiogenesis is a key mechanism in tumor growth. CRC treatment may involve inhibiting angiogenesis, but existing drugs can cause negative effects. Tranexamic acid, an FDA-approved medication, may reduce the adverse effects of angiogenesis inhibitors. This work examined miRNAs implicated in CRC angiogenesis and how miR-16 and tranexamic acid may synergistically decrease CRC cell migration and angiogenesis. We identified miRNAs targeting CRC angiogenesis genes using bioinformatic databases. Proteins were docked with tranexamic acid utilizing the PyRx software. Quantitative Real-time PCR was used to analyze the effects of overexpressed miRNA and tranexamic acid on the expression of target genes. Scratch, transwell migration, and Chicken Chorioallantoic Membrane (CAM) assays were used to evaluate the effect of selected miRNA and tranexamic acid on the invasion and angiogenesis of CRC cells. in silico studies identified hsa-miR-16-5p, -101-3p, and 34a-5p as possible CRC angiogenesis modulators. The study found that miR-16 and tranexamic acid influence the expression of VEGFA, ANGPT2, MMP9, and HIF1A. miR-16 and tranexamic acid influenced CRC cell movement in scratch tests and transwell migration assays. Furthermore, the CAM assay results demonstrated that miR-16 and tranexamic acid can alter angiogenesis in CRC. These findings highlight the potential of miR-16 and tranexamic acid as combination therapeutic agents for CRC, with the ability to simultaneously target tumorigenesis and angiogenesis.

A computational approach to identify phytochemicals as potential inhibitor of acetylcholinesterase: Molecular docking, ADME profiling and molecular dynamics simulations.

Inhibition of acetylcholinesterase (AChE) is a crucial target in the treatment of Alzheimer's disease (AD). Common anti-acetylcholinesterase drugs such as Galantamine, Rivastigmine, Donepezil, and Tacrine have significant inhibition potential. Due to side effects and safety concerns, we aimed to investigate a wide range of phytochemicals and structural analogues of these compounds. Compounds similar to the established drugs, and phytochemicals were investigated as potential inhibitors for AChE in treating AD. A total of 2,270 compound libraries were generated for further analysis. Initial virtual screening was performed using Pyrx software, resulting in 638 molecules showing higher binding affinities compared to positive controls Tacrine (-9.0 kcal/mol), Donepezil (-7.3 kcal/mol), Galantamine (-8.3 kcal/mol), and Rivastigmine (-6.4 kcal/mol). Subsequently, ADME properties were assessed, including blood-brain barrier permeability and Lipinski's rule of five violations, leading to 88 compounds passing the ADME analysis. Among the rivastigmine analogous, [3-(1-methylpiperidin-2-yl)phenyl] N,N-diethylcarbamate showed interaction with Tyr123, Tyr336, Tyr340, Phe337, Trp285 residues of AChE. Tacrine similar compounds, such as 4-amino-2-styrylquinoline, exhibited bindings with Tyr123, Phe337, Tyr336, Trp285, Trp85, Gly119, and Gly120 residues. A phytocompound (bisdemethoxycurcumin) showed interaction with Trp285, Tyr340, Trp85, Tyr71, and His446 residues of AChE with favourable binding. These findings underscore the potential of these compounds as novel inhibitors of AChE, offering insights into alternative therapeutic avenues for AD. A 100ns simulation analysis confirmed the stability of protein-ligand complex based on the RMSD, RMSF, ligand properties, PCA, DCCM and MMGBS parameters. The investigation suggested 3 ligands as a potent inhibitor of AChE which are [3-(1-methylpiperidin-2-yl)phenyl] N,N-diethylcarbamate, 4-Amino-2-styrylquinoline and bisdemethoxycurcumin. Furthermore, investigation, including in-vitro and in-vivo studies, is needed to validate the efficacy, safety profiles, and therapeutic potential of these compounds for AD treatment.

Investigation into in silico and in vitro approaches for inhibitors targeting MCM10 in Leishmania donovani: a comprehensive study.

Visceral Leishmaniasis (VL), the second neglected tropical disease caused by various Leishmania species, presents a significant public health challenge due to limited treatment options and the absence of vaccines. The agent responsible for visceral leishmaniasis, also referred to as "black fever" in India, is Leishmania donovani. This study focuses on L. donovani Minichromosome maintenance 10 (LdMcm10), a crucial protein in the DNA replication machinery, as a potential therapeutic target in Leishmania therapy using in silico and in vitro approaches. We employed bioinformatics tools, molecular docking, and molecular dynamics simulations to predict potential inhibitors against the target protein. The research revealed that the target protein lacks homologues in the host, emphasizing its potential as a drug target. Ligands from the DrugBank database were screened against LdMcm10 using PyRx software. The top three compounds, namely suramin, vapreotide, and pasireotide, exhibiting the best docking scores, underwent further investigation through molecular dynamic simulation and in vitro analysis. The observed structural dynamics suggested that LdMcm10-ligand complexes maintained consistent binding throughout the 300ns simulation period, with minimal variations in their backbone. These findings suggest that these three compounds hold promise as potential lead compounds for developing new drugs against leishmaniasis. In vitro experiments also demonstrated a dose-dependent reduction in L. donovani viability for suramin, vapreotide, and pasireotide, with computed IC50 values providing quantitative metrics of their anti-leishmanial efficacy. The research offers a comprehensive understanding of LdMcm10 as a drug target and provides a foundation for further investigations and clinical exploration, ultimately advancing drug discovery strategies for leishmaniasis treatment.

Potential Effect of Chloroquine in Modulating Hyperglycemia and PTEN Receptor Linked Dyslipidemia on Alloxan-induced Diabetic Mice

Background: Diabetes mellitus is a life-threatening disease associated with worsening of glycemic control, progressive metabolic dysfunctions and disruption of the Phosphatase and Tensin Homolog (PTEN) receptor. Purpose: To evaluate the effect of chloroquine on blood glucose level and lipid profile of alloxan-induced diabetic mice and to observe its interaction with PTEN, a negative regulator of insulin signaling pathway. Methodology: Thirty mice were used for the experiment. A group (n = 5) was kept as healthy control while the others were pre-treated with 140 mg/kg of alloxan monohydrate in distilled water. The alloxan-induced diabetic mice were randomly divided into four groups: diabetic model control group, 60 mg/kg chloroquine, 120 mg/kg chloroquine, and 10 mg/kg glibenclamide treatment groups respectively. Treatment was done once daily for seven days and the blood glucose level was investigated acutely and then daily throughout the experimental period. A molecular docking study was also conducted to evaluate the interaction of chloroquine with PTEN using PYRX software, while an automated COBAS C 311 machine was used to analyze the lipid profile after the treatment period. Results: Oral administration of chloroquine gradually and significantly lowered the raised blood glucose level in a time- and dose-dependent manner. A repeated study with 120 mg/kg of chloroquine revealed a decline in blood sugar from 221.5 ± 3.6 on day 1 to 85.5 ± 2.4 on day 7 in comparison to glibenclamide, whose sugar level was reduced to 75.5 ± 3.7 at the end of day 7. The docking study revealed a non-competitive inhibition with an inhibition score of -6.1 in comparison to metformin, which had a score of -4.4, and glibenclamide, which had a score of -9.0. This interaction resulted in a conformational change of the receptor, hence, enhancing glucose uptake and reducing the raised hyperglycemia. Treatment with chloroquine was also observed to reduce the total cholesterol and triglyceride levels from 162 in the model group to 144 and 141 to 116 mmol/L, respectively. The levels of low-density lipoprotein cholesterol (LDL-C) and very low-density lipoprotein (VLDL) following treatment with chloroquine were not statistically different from the non-diabetic healthy mice. These values were very similar to those obtained with glibenclamide-treated diabetic mice. Conclusion: From the results, chloroquine possesses potent antidiabetic properties and can improve dyslipidemia imposed by hyperglycemia probably owing to its inhibition of PTEN, a negative regulator of insulin resistance.

In Silico Identification of Novel HDAC2 Inhibitors for Reinstating Synaptic wiring in Autism Spectrum Disorder

Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder with an increasing incidence rate. For the treatment of ASD, several pharmaceutical approaches, dietary supplements, and behavioral therapy have been proposed, but a definitive cure remains elusive. Histone deacetylases (HDACs) are critical epigenetic regulators whose molecular and pharmacological roles are being studied extensively in medically significant ailments such as neuropsychiatric disorders, neurodegenerative diseases, and cancer on a global scale. HDAC2's specific expression pattern in CNS makes it an appealing therapeutic target for neurological illnesses such as ASD.Methods: The study used PyRx software (version 0.8) to screen a library of 401 alkaloid compounds against HDAC2. In addition, the DS software was used to predict the physicochemical and DMET properties of the compound library.Results: Valaciclovir hydrochloride, Dihydrocapsaicin, Guanosine, Santacruzamate A, and 2'-Deoxyguanosine monohydrate compounds exhibited strong interactions with HDAC2. These compounds had a higher binding energy than the control compound, and they have promising drug-like properties and ADMET characteristics.Conclusion: These identified compounds could be used as HDAC2 inhibitors for the management of ASD, however, experimental research is needed to optimize them as HDAC2 inhibitors.Keywords: Autism spectrum disorder; Histone deacetylases; Alkaloid compounds; Drug-likeness

EFFECT OF CLITORIA TERNATEA ON FOLLICLE STIMULATING HORMONE RECEPTOR: MOLECULAR DOCKING STUDY

Polycystic Ovary Syndrome (PCOS) is a common endocrine disorder in women that is characterized by hormonal imbalances, anovulation, and ovarian cysts. Folliculogenesis, which is the process of follicle development, is perturbed in PCOS, leading to irregular menstrual cycles and fertility issues. Clitoria ternatea, a medicinal plant with potential hormonal regulatory properties, is of interest for exploring its effects on folliculogenesis and PCOS management. In this in silico study, we employed molecular docking techniques to investigate the interaction between bioactive compounds from Clitoria ternatea and Follicle Stimulating Hormone Receptor (FSHR), a key regulator of folliculogenesis. AutoDock Vina and PyRx software were used to predict the binding affinities and interactions between the ligands and FSHR. The results of our in silico study indicate that bioactive compounds from Clitoria ternatea exhibit a strong binding affinity for FSHR. These compounds form stable interactions with the receptor, suggesting a potential regulatory effect on FSHR activity during folliculogenesis. The findings from this in silico study suggest that Clitoria ternatea may play a role in modulating folliculogenesis by interacting with FSHR. Further experimental studies, including in vitro and in vivo studies, are warranted to validate these computational predictions and explore the potential therapeutic implications of Clitoria ternatea in managing PCOS related folliculogenesis disorders.

Exploring the potential of phytoconstituents from Phaseolus vulgaris L against C-X-C motif chemokine receptor 4 (CXCR4): a bioinformatic and molecular dynamic simulations approach

IntroductionThe CXCR4 chemokine receptor is a G protein-coupled receptor that plays a role in many physiological processes and diseases, such as cancer metastasis, HIV infection, and immune response. Because of this, it may be possible to target it therapeutically. In addition, the active ingredient of Phaseolus vulgaris L (PVL) has been reported to have anti-inflammatory, antioxidant, and anticancer properties. Novel CXCR4 antagonists from natural resources can be a promising drug development product using a computational approach. This study aims to explore the active compound in PVL that has the responsibility to inhibit CXCR4 using molecular docking and dynamics simulation.Materials and methodsPharmacokinetic analysis were performed using the pkCSM, OSIRIS for toxicity risk analysis, and the PerMM for membrane permeability assessment. Molecular docking was performed using PyRx software to determine the interaction between the CXCR4 target protein from the PDB database and the active component of PVL from the PubChem database. A molecular dynamics (MD) simulation was performed to determine the stability of the interaction using the WEBGRO Macromolecular Simulations online server. The analysis were performed by comparing the results with plerixafor as a control ligand.Results and discussionThe pharmacokinetic analysis of quercetin, kaempferol, myricetin, catechin, 3,4-dihydroxybenzoic acid, and daidzin in PVL showed that they met the drug-like criteria. These chemicals were expected to have medium-risk effects on mutagenesis and tumorigenesis, with the exception of catechin, which has no risk of toxicity, and daidzin, which has high-risk effects on mutagenesis and reproduction. Molecular docking identified that quercetin (− 6.6 kcal/mol), myricetin (− 6.6 kcal/mol), catechin (− 6.5 kcal/mol), and 3,4-dihydroxybenzoic acid (− 5.4 kcal/mol) bind to CXCR4 with the highest affinity compared to plerixafor (− 5.0 kcal/mol) and can bind to the same binding pocket with key residues Asp187, Asp97, and Glu288. The MD simulation analysis showed that quercetin has a similar stability interaction compared to the control.ConclusionsConsidering the pharmacokinetic analysis, molecular docking, and MD simulations, quercetin, myricetin, and 3,4-dihydroxybenzoic acid have the potential to become CXCR4 agonists with their good oral bioavailability and safety properties for the novel drug candidates. Future studies are needed to consider the molecular docking result.

Network ethnopharmacological and molecular docking based evaluation of the anti-breast cancer activity for ayurvedic botanicals acting on hypoxia-inducible factor-1

The recognized root causes of breast cancer aggressiveness, resistance to therapy, and poor prognosis encompass hypoxia-inducible factors (HIFs), the HIF-dependent cancer hallmarks angiogenesis and metabolic reconfiguration.There is enough evidence to suggest that HIF is involved in the progression of breast cancer.Information for the network was gathered from the following databases: Dr. Duke's, IMPPAT, PubChem, Binding DB, UniProt, and DisGeNET. The network was created using the Cytoscapeprogramme. Screened bioactives having similarity index more than 0.6 from polypharmacology approach were subjected to docking studies with HIF-1 (PDB ID: 1H2K) with PyRx software and the ligands with good docking score was further explored for molecular docking interaction analysis. The number of bioactives having interaction with HIF-1, equal to or greater than 0.6 from Ashwagandh, Shatavari, Neem, Alsi seeds, Methi, Haldi, Ghritkumari, Yashtimadhu, and KadiPatta was 12, 9, 2, 6, 12, 11, 5, 10, and 3, respectively. On performing the docking against the target HIF-1for top molecules with Araboglycyrrhizin (-10.1kcal/mol), Asparanin-A (-9.2 kcal/mol), Shatavarin-I (-9.2 kcal/mol), Shatavarin-X (-9.1 kcal/mol), Somniferanolide (-9.1 kcal/mol), Somniferawithanolide (-9.7 kcal/mol), Trigofoenoside-A (-9.2 kcal/mol), Trigofoenoside-F (-9.4 kcal/mol), Trillin (-9.9 kcal/mol), and Withanolide (-9.2 kcal/mol), the binding energies and molecular interactions of the ligands were fairly good as compared with standard synthetic ligand Acriflavine (-7.6 kcal/mol). The study elucidated an in silico molecular mechanism of HIF-1 inhibition by various bioactive phytoconstituents from selected plants. Comprehending the logic behind anti-breast cancer action was made easier with the help of experimental evidence of the network findings.

The potency of lempuyang wangi (Zingiber zerumbet) as aldose reductase inhibitor: an alternative of anti-diabetes drugs

Aldose reductase is an enzyme that plays a role in glucose metabolism. An increase in aldose reductase will trigger an increase in blood sugar concentration by converting glucose to sorbitol. Increased sorbitol conditions will result in diabetes complications such as diabetic cataracts. So we need an inhibitor that can inhibit the working system of the aldose reductase enzyme. One of the medicinal plants that has anti-diabetic properties is lempuyang wangi. Lempuyang wangi has a secondary metabolite compound which has the potential as an antidiabetic. The purpose of this study was to examine the anti-diabetic properties of lempuyang wangi using the in silico method. In this research, docking was carried out with Pymol and Pyrx software, and visualization using Biovia Discovery Studio to see the interaction between zerumbone compounds and aldose reductase and compared with zopolrestat compounds. The docking result of zopolrestat as a comparison compound is -9 kcal/mol, while xanthorrhizol has a binding affinity value of -8,7 kcal/mol and has the same amino acid bonds with zopolrestat, making it a potential candidate as an antidiabetic herbal drug in inhibiting the working system of the aldose reductase enzyme

The identification of c-Abl inhibitors as potential agents for Parkinson's disease: a preliminary in silico approach.

Parkinson's disease (PD) is the most common movement disorder worldwide. PD is primarily associated with the mutation, overexpression, and phosphorylation of α-synuclein. At the molecular level, the upstream protein c-Abl, a tyrosine kinase, has been shown to regulate α-synuclein activation and expression patterns. This study aimed to identify potential c-Abl inhibitors through in silico approaches. Molecular docking was performed using PyRx software, followed by Prime MM-GBSA studies. BBB permeability and toxicity were predicted using CBligand and ProTox-II, respectively. ADME was assessed using QikProp. Molecular dynamics were carried out using Desmond (Academic version). DFT calculations were performed using the Gaussian 16 suite program. The binding scores of the top hits, norimatinib, DB07326, and entinostat were - 11.8kcal/mol, - 11.8kcal/mol, and - 10.8kcal/mol, respectively. These hits displayed drug-likeness with acceptable ADME properties, except for the standard, nilotinib, which violated Lipinski's rule of five. Similarly, the molecular dynamics showed that the top hits remained stable during the 100ns simulation. DFT results indicate DB04739 as a potent reactive hit. While based on toxicity prediction, entinostat may be a potential candidate for preclinical and clinical testing in PD. Further studies are warranted to confirm the activity and efficacy of these ligands for PD.