Highest Docking Score Research Articles

An Immunoinformatics Approach to Design Novel and Potent Multi-Epitope-Based Vaccine to Target Lumpy Skin Disease

The lumpy skin disease (LSD) virus of the Poxviridae family is a serious threat that mostly affects cattle and causes significant economic loss. LSD has the potential to spread widely and its rapidly across borders. Despite the availability of information, there is still no competitive vaccine available for LSD. Therefore, the current study was conducted to develop an epitope-based LSD vaccine that is efficient, secure, and biocompatible and stimulates both innate and adaptive immune responses using immunoinformatics techniques. Initially, putative virion core proteins were manipulated; B-cell and T-cell epitopes have been predicted and connected with the help of adjuvants and linkers. Numerous bioinformatics methods, including antigenicity testing, transmembrane topology screening, allergenicity assessment, conservancy analysis, and toxicity evaluation, were employed to find superior epitopes. Based on promising vaccine candidates and immunogenic potential, the vaccine design was selected. Strong interactions between TLR4 and TLR9 and the anticipated vaccine design were revealed by molecular docking. Finally, based on the high docking score, computer simulations were performed in order to assess the stability, efficacy, and compactness of the constructed vaccine. The simulation outcomes showed that the polypeptide vaccine design was remarkably stable, with high expression, stability, immunogenic qualities, and considerable solubility. Additionally, computer-based research shows that the constructed vaccine provides adequate population coverage, making it a promising candidate for use in the design of vaccines against other viruses within the Poxviridae family and potentially other virus families as well. These outcomes suggest that the epitope-based vaccine developed in this study will be a significant candidate against LSD to control and prevent LSDV-related disorders if further investigated experimentally.

Phytochemical analysis and nephroprotective potential of Ajwa date in doxorubicin-induced nephrotoxicity rats: Biochemical and molecular docking approaches.

The purpose of this study is to evaluate the likely defensive impact of Ajwa date aqueous extract (AJDAE) in alleviating the nephrotoxicity generated by doxorubicin (DOX) injection in rats. Sixty male Wister albino rats were randomly and equally separated into six groups (n= 10), and they were treated as follows: untreated control group, extract groups administered with 0.75 and 1.5mg kg bw of AJDAE, toxicant control group administered with DOX, and prophylactic groups were treated with 0.75 and 1.5 mg/kg of AJDAE and 15 mg/kg DOX. Biochemical parameters, antioxidant enzymes, renal functions, DNA integrity, and histopathology were studied to evaluate the nephroprotective activity of AJDAE. Furthermore, bioactive compounds were utilized for in silico molecular docking. AJDAE treatment resulted in significant improvements in the amended renal biomarkers (urea, creatinine, calcium, phosphorous, and uric acid), antioxidative markers, and MDA. Noticeable histopathological improvements supported this result. Results of in silico studies revealed that d-Mannitol, 6TMS derivative, palmitic acid, and TMS derivative had a higher docking score with human soluble epoxide hydrolase (-10.9kcal/mol) and NF-κB-DNA (-7kcal/mol). The present findings indicated that AJDAE could decrease ROS generation and lipid peroxidation (LPO) and repair the DOX injection-related DNA damage.

Synthesis, spectroscopic, in vitro, in vivo biological evaluation, and in silico docking analysis of new meloxicam metal complexes

In the present study, two new meloxicam complexes with Mg(II) and Sr(II) were synthesized and characterized by spectroscopic and analytical methods, that is, UV–vis, IR, 1H NMR, 13C NMR, powder XRD, SEM–EDX, and TG analysis. The biological evaluation was done by in vitro antioxidant, BSA‐binding, DNA cleavage activities, and in vivo anti‐inflammatory, analgesic, and anxiolytic methods. Furthermore, in silico docking was done with Keap1 receptor to visualize the anti‐inflammatory effect of complexes. The spectral characterization suggested that meloxicam coordinated with the metal ions by oxygen and nitrogen of amide group and thiazolyl ring (Oamide and Nthiazolyl), respectively. The SEM pictures depicted dissimilar morphologies, and the powder XRD patterns showed different crystallinities of complexes than meloxicam. TG analysis exhibited high thermal stabilities of complexes and Coats–Redfern method was employed to calculate the important thermodynamic parameters. The complexes showed effective biological activities and enhanced safety index (LD50 = 1000 mg kg−1). The Mg(II) complex revealed greatest inhibitory effects in carrageenan‐induced paw inflammation (92.85%) and in acetic acid‐induced writhing (71.05%). Furthermore, the complexes showed higher potential to bind with BSA and cleave the DNA as compared with the meloxicam. Moreover, molecular docking against Keap1 showed that Mg(II) complex inhibited Keap1 with highest docking score (6166 kcal mol−1), docking area (804.40) and ACE (−417.49 kJ mol−1) which explained its higher anti‐inflammatory effect. Mg(II) complex of meloxicam might be considered as a candidate anti‐inflammatory drug; however, more research is required to investigate their other biological potential.

Molecular Generative Model via Retrosynthetically Prepared Chemical Building Block Assembly.

Deep generative models are attracting attention as a smart molecular design strategy. However, previous models often render molecules with low synthesizability, hindering their real-world applications. Here, a novel graph-based conditional generative model which makes molecules by tailoring retrosynthetically prepared chemical building blocks until achieving target properties in an auto-regressive fashion is proposed. This strategy improves the synthesizability and property control of the resulting molecules and also helps learn how to select appropriate building blocks and bind them together to achieve target properties. By applying a negative sampling method to the selection process of building blocks, this model overcame a critical limitation of previous fragment-based models, which can only use molecules from the training set during generation. As a result, the model works equally well with unseen building blocks without sacrificing computational efficiency. It is demonstrated that the model can generate potential inhibitors with high docking scores against the 3CL protease ofSARS-COV-2.

Hydrazide-hydrazones as Small Molecule Tropomyosin Receptor Kina se A (TRKA) Inhibitors: Synthesis, Anticancer Activities, In silico ADME and Molecular Docking Studies.

The aim of the study was to search for new anticancer agents as TRKA inhibitors. A series of new salicylic acid hydrazide hydrazones were synthesized and evaluated for their in vitro anticancer activities against lung (A549), ovarian (SK-OV-3), skin (SK-MEL-2), and colon (HCT15) cancer cell lines, and tropomyosin receptor kinase A (TRKA) inhibitory activities. In this study, we focused on the synthesis and anticancer properties evaluation of salicylic acid hydrazide hydrazones as TRKA inhibitors. The in vitro anticancer activities of hydrazone analogs were measured against four cancer cell lines, and the TRKA inhibitory properties were investigated using an enzyme assay to determine their modes of action. In silico molecular docking was conducted using the crystal structure of the TRKA receptor to study the interactions and modes of binding at its active site, and ligand-based target predictions were used to identify putative secondary enzymatic targets of the synthesized compounds. Additionally, pharmacokinetic properties, toxicity effects, and drug scores of the studied molecules were also assessed. A series of hydrazide hydrazones were prepared by means of a facile and straight-forward two-step reaction under soft reflux conditions from a methyl ester of substituted aromatic acids and hydrazine hydrate followed by the condensation with substituted aldehydes. In vitro cytotoxic properties of the synthesized compounds were screened against four human cancer cells using the SRB (sulforhodamine-B) colorimetric method. The TRKA inhibitory activity was measured by enzymatic assay. In silico ADME, drug score properties, docking studies, and ligand-based target prediction analyses were performed using Osiris Cheminformatics and AutoDock Vina, and SwissTargetPrediction bioinformatics software. In vitro bioassays revealed that compound 6 exhibited the most potent broad-spectrum anticancer activities with IC50 values of 0.144, <0.001, 0.019, and 0.022 μM against A549, SK-OV-3, SK-MEL-2, and HCT15 cancer cells, respectively, followed by compounds 11, 3a, and 9. In TRKA inhibitory assays, compounds 3e and 11 demonstrated the highest potency with IC50 values of 111 and 614 nM, respectively. The results of docking studies on 3e and 11 with the active site of the TRKA receptor revealed that both compounds interacted as previously reported TRKA inhibitors with high docking scores. New salicylic acid hydrazide hydrazones were synthesized, and the most active compounds exhibited significant anticancer properties against A549, SK-OV-3, SK-MEL-2, and HCT15 cancer cells, suggesting to be good candidates for in vivo studies. The results obtained in the present study would help in the design and preparation of new hydrazidehydrazone analogs as potential TRKA inhibitors for cancer treatment.

Molecular modeling of the interactions of Curcuma longa compounds with VEGFR towards colorectal cancer drug development

Curcuma longa, a member of Curcuma Zingiberaceae family is said to possess anti-carcinogenic, anti-oxidant, and anti-inflammatory properties. Mechanistic studies on its effectiveness against carcinogenesis are still under investigation. This study assessed the molecular interactions of C. longa compounds with VEGFR. Computational methods such as molecular docking, calculation of binding free energy, induced fit docking, Molecular dynamic simulation,PPI targets and KEGGS enrichment pathways were employed to discover approximately 117 bioactive compounds against VEGFR in designing novel anticancer drugs. The five top-scoring C. longa compounds out of the 117 bioactive compounds are 2-Hydroxymethyl anthraquinone (HMA), Riboflavin, Quercetin, Vitamin E, and Dicinnamoylmethane (−8.515 kcal/mol to −7.293 kcal/mol) with higher docking scores. These compounds had stable conformation within the flexible protein's active site. The molecular interactions of these compounds with surrounding amino acids in the ATP binding gouge of VEGFR2 and their drug-like qualities with excellent safety profile make them potential inhibitors of VEGFR2 and future drug development against colorectal cancer.

In silico Studies, Synthesis and Antibacterial Activity of Heterocyclic Compounds with Mannich Bases

Aim The present study aimed to identify the potent 123-triazole derivatives for synthesis and also assess their anti-bacterial activity.Methodology In silico design of novel analogues was carried out for ten derivatives using Auto Dock Vina and compared with standard drug Ciprofloxacin. Swiss ADME software was used to analyze lsquoLipinski Rule of Fiversquo and drug likeness properties. Three derivatives which obeyed rule of five having desired physicochemical properties and highest docking score were synthesized PDB code 2K35. The synthesis was carried out in two step process to determine their antibacterial activity. The synthesized compounds were structurally elucidated using Fourier-transform infrared spectroscopy FTIR Nuclear Magnetic Resonance 1H NMR and Mass spectroscopy .Results Antibacterial activity of different compounds was observed by disc diffusion method against two organisms E. coli and Streptococcus. Among the tested compounds 4A showed significant antibacterial activity. Compounds 6A and 8A also exhibited appreciable antibacterial activity against E. coli while compound 6A showed appreciable antibacterial activity against Streptococcus.Conclusion According to data obtained from the present study piperazine incorporated triazole derivatives were found to possess effective antibacterial activity. Further modifications of triazole based compounds at different positions to generate new molecules with potent anti-tumor activities will be described in future.

Ancoragem molecular, ADMET e simulação de dinâmica molecular revelaram o metralindol como inibidor multialvo para divisão quinases

Lung cancer is the most common type of cancer in the world, and alone, in 2020, almost 2.21 million new cases were diagnosed, with 1.80 million deaths, and are increasing daily. Non-small cell lung (NSCLC) is the primary type of lung cancer, predominantly forms around 80% of cases compared to small cell carcinoma, and about 75% of patients are already in an advanced state when diagnosed. Despite notable advances in early diagnosis and treatment, the five-year survival rate for NSCLC is not encouraging. Therefore, it is crucial to investigate the molecular causes of non-small cell lung cancer to create more efficient therapeutic approaches. Lung cancer showed a more significant and persistent binding affinity and energy landscape with the target CDK2 staurosporine and FGF receptor-1. In this study, we have picked two essential target proteins, human cyclin-dependent kinase-2 and Human Protein Kinase CK2 Holoenzyme and screened the entire prepared DrugBank prepared library of 1,55,888 compounds and identified 2-(2-methyl-5-nitroimidazole-1-yl) ethanol (Metralindole) as a major inhibitor. Metralindole has displayed high docking scores of -5.159 Kcal/mol and -5.99 Kcal/mol with good hydrogen bonding and other bonding topologies such as van der Waals force, and ADMET results shown excellent bioavailability, outstanding solubility, no side effects, and toxicity. The molecular dynamics simulation for 100ns in a water medium confirmed the compound's stability and interaction pattern with the lowest deviation and fluctuations. Our in-silico study suggests Metralindole, an experimental compound, can effectively cure lung cancer. Further, the experimental validation of the compound is a must before any prescription.

Molecular docking analysis of mefluhybenamine with lung cancer targets.

Lung cancer is the most prevalent type of cancer worldwide, with 2.21 million cases and 1.80 million fatalities in 2020. The main factor influencing lung cancer is smoking, and the most common form of lung cancer, non-small cell lung cancer (NSCLC), accounts for around 80% of instances compared to small cell carcinoma, and about 75% of patients are already in an advanced stage when they are detected. Despite significant early detection and therapy improvements, the five-year survival rate for NSCLC is not encouraging. Therefore, it is essential to look into the molecular origins of non-small cell lung cancer to develop more effective therapeutic strategies-the binding affinities and energy landscape with the proteins. Cyclin Dependent kinase 2 (CDK2) and Insulin-like Growth Factor 1 Receptor (IGF1) were more substantial and sustained in lung cancer that was chosen as the two primary target proteins in this. We screened the entire Drug Bank-prepared library of 1,55,888 compounds and found (2R,3R)-7-(Methylsulfonyl)-3-(2,4,5-trifluorophenyl) -1,2,3,4-tetrahydropyrido[1,2-a] benzimidazol-2-aminium (Mefluhybenamine) to be a significant inhibitor. Mefluhybenamine showed strong hydrogen bonding and other bonding topologies, such as van der Waals force, in its high docking scores of -6.168 Kcal/mol and -5.26 Kcal/mol, and ADMET results showed excellent bioavailability, remarkable solubility, no side effects, and toxicity. The molecular dynamicsimulation confirmed the compound's stability and interaction pattern for 100 ns in an SPC water medium with the slightest deviation and fluctuation. Data shows that Mefluhybenamine is a potential candidate. However, validation of the compound is essential.

Synthesis, Anticancer Activity, Pharmacokinetics, and Docking Study of Some New Heterocycles Linked Indole Moiety

A novel series of five or six new nitrogenated heterocyclic compounds were obtained by reacting a chalcone derivative of 3-acetylindole with various reagents such as malononitrile under different conditions, some hydrazine derivatives, some cyclic and heterocyclic amines, ethyl cyanoacetate, and urea. Elements analysis and spectral data were used to validate the newly synthesized compounds. Also, they were tested for their anticancer activity against three cancer cell lines including MCF7, HCT116, and HeLa cell lines, cells were subjected to treatment with one concentration (10uM) of compounds over 48 h incubation. Furthermore, a docking study was carried out to investigate the interaction of the newly prepared derivatives with vascular endothelial growth factor-2 tyrosine kinase (VEGFR-2) for their cancer-fighting potential. The docking study results showed that six indolyl derivatives (7 b, 9, 10, 11, 12, and 17) had high docking scores and a strong fitting interaction in the active site of vascular endothelial growth factor-2 tyrosine kinase (VEGFR-2). Furthermore, the pharmacokinetics and physicochemical properties, as well as drug-likeness and bioactivity, were investigated and analyzed.

3D-QSAR, E-pharmacophore and molecular docking to explore substituted sulfonamides as carbonic anhydrase inhibitors in epilepsy

Background- A series of aromatic sulfonamides incorporating coumarin as a lead were designed a for epilepsy target. Carbonic anhydrase is an influential target for the expansion of lead to treat epilepsy. Experimentally known carbonic anhydrase determents were identified to develop ligand based pharmacophore for anticonvulsant model. The X-ray crystallographic make-up of carbonic anhydrases with several inhibitors were utilized to develop ten energy optimized structure based (E- pharmacophore model). Pharmacophore matched candidates were utilized for docking to reclaim hits with scaffolds. The molecules having diverse structures, high docking score and low binding energy for various crystal structures of carbonic anhydrase were selected as final hits (leads). DFT is utilized to get electronic features of hits. The docking study of ligands by discovery studio had helped to establish binding interactions. The known carbonic anhydrase was reused for the development of pharmacophore hypothesis DHHRR. Based on Insilco process we came across structurally diverse hits as noncompetitive carbonic anhydrase inhibitors with better ADME. The best three hits 4, 6 and 17 were nontoxic and were selective carbonic anhydrase inhibitors with the IC50 values respectively (IC50 2.01, 2.59, 2.469). The study describes that the combined pharmacophore appeal to identify various hits which have good binding affinity for the active site of enzyme in all feasible bioactive conformations.

Screening and Molecular Mechanisms of Novel ACE-Inhibitory Peptides from Gracilariopsis lemaneiformis

Candidate peptides with novel angiotensin-I-converting enzyme (ACE) inhibitor activity were obtained from hydrolysates of Gracilariopsis lemaneiformis by virtual screening method. Our results showed that G. lemaneiformis peptides (GLP) could significantly lower blood pressure in spontaneously hypertensive rats (SHR). At least 101 peptide sequences of GLP were identified by LC-MS/MS analysis and subjected to virtual screening. A total of 20 peptides with the highest docking score were selected and chemically synthesized in order to verify their ACE-inhibitory activities. Among them, SFYYGK, RLVPVPY, and YIGNNPAKG showed good effects with IC50 values of 6.45 ± 0.22, 9.18 ± 0.42, and 11.23 ± 0.23 µmoL/L, respectively. Molecular docking studies revealed that three peptides interacted with the active center of ACE by hydrogen bonding, hydrophobic interactions, and electrostatic forces. These peptides could form stable complexes with ACE. Furthermore, SFYYGK, RLVPVPY, and YIGNNPAKG significantly reduced systolic blood pressure (SBP) in SHR. YIGNNPAKG exhibited the highest antihypertensive effect, with the largest decrease in SBP (approximately 23 mmHg). In conclusion, SFYYGK, RLVPVPY, and YIGNNPAKG can function as potent therapeutic candidates for hypertension treatment.

Phenolic, nutritional and molecular interaction study among different millet varieties

Millet varieties were analyzed for nutritional, antinutritional, mineral and phenolic profiles. Inhibition potential of phenolic acids for enzyme inhibition ,activity was estimated, alongside starch digestibility of millet grains was evaluated. Finger millet was found to have high contents of Ca, Mn and Cu minerals. Proso and pearl millet had high protein content, whereas kodo and foxtail millet contained high content of dietary fiber. Phytic acid was comparatively higher in kodo millet, whereas oxalic acid and total tannin content was abundant in finger millet. Total phenolic content and total flavonoid content in bound phenolic fractions were comparatively higher than the free phenolic fractions and total anthocyanin content was found highest in finger millet followed by kodo and pearl millet. The millet varieties showed optimum antioxidant potential studied through different assay methods. Ferulic acid was predominantly found among all the millets in bound fraction of phenolic extract. Furthermore, phenolic acids were used to investigate different docking techniques with α-amylase, α-glucosidase, and leptin receptor enzymes. Docking studies revealed, chlorogenic acid had a high docking score and a high binding affinity against α-amylase, α-glucosidase, and leptin receptor enzymes.

Molecular modelling of SdiA protein by selected flavonoid and terpenes compounds to attenuate virulence in Klebsiella pneumoniae

Klebsiella pneumoniae is one of the perturbing multidrug resistant (MDR) and ESKAPE pathogens contributing to the mounting morbidity, mortality and extended rate of hospitalization. Its virulence, often regulated by quorum sensing (QS) reinforces the need to explore alternative and prospective antivirulence agents, relatively from plants secondary metabolites. Computer aided drug discovery using molecular modelling techniques offers advantage to investigate prospective drugs to combat MDR pathogens. Thus, this study employed virtual screening of selected terpenes and flavonoids from medicinal plants to interrupt the QS associated SdiA protein in K. pneumoniae to attenuate its virulence. 4LFU was used as a template to model the structure of SdiA. ProCheck, Verify3D, Ramachandran plot scores, and ProSA-Web all attested to the model’s good quality. Since SdiA protein in K. pneumoniae leads to the expression of virulence, 31 prospective bioactive compounds were docked for antagonistic potential. The stability of the protein-ligand complex, atomic motions and inter-atomic interactions were further investigated through molecular dynamics simulations (MDS) at 100 ns production runs. The binding free energy was estimated using the molecular mechanics/poisson-boltzmann surface area (MM/PB-SA). Furthermore, the drug-likeness properties of the studied compounds were validated. Docking studies showed phytol possesses the highest binding affinity (−9.205 kcal/mol) while glycitein had −9.752 kcal/mol highest docking score. The MDS of the protein in complex with the best-docked compounds revealed phytol with the highest binding energy of −44.2625 kcal/mol, a low root-mean-square deviation (RMSD) value of 1.54 Å and root-mean-square fluctuation (RMSF) score of 1.78 Å. Analysis of the drug-likeness properties prediction and bioavailability of these compounds revealed their conformed activity to lipinski’s rules with bioavailability scores of 0.55 F. The studied terpenes and flavonoids compounds effectively thwart SdiA protein, therefore regulate inter- or intra cellular communication and associated in virulence Enterobacteriaceae, serving as prospective antivirulence drugs. Communicated by Ramaswamy H. Sarma

Combination of Donepezil and Memantine Attenuated Cognitive Impairment Induced by Mixed Endocrine-Disrupting Chemicals: an In Silico Study.

Little is known about the effects of endocrine-disrupting chemicals (EDCs) and the combination of memantine and donepezil on the pathogenesis of cognitive impairment. Here, we aimed to identify in silico the molecular mechanisms of the combination of memantine and donepezil that combat cognitive impairment induced by nine common EDCs using GeneMania, AutoDock Vina, Metascape, SwissADME, MIENTURNET, and miRNAsong. We observed that the mixture of memantine and donepezil had therapeutic effects on mixed EDC-induced cognitive impairment via five genes (TNF, ACHE, BAX, IL1B, and CASP3). With ACHE and TNF, donepezil and memantine both had a high docking score, respectively. The predominant connections among five mutual genes were physical interactions (77.6%). The major pathways associated with memantine and donepezil countering cognitive impairment generated by mixed EDCs were discovered to be "AGE-RAGE signaling pathway in diabetic complications," "pro-survival signaling of neuroprotectin D1," and "non-alcoholic fatty liver disease." The miRNAs and transcription factors implicated in memantine and donepezil protecting against mixed EDCs were hsa-miR-128-3p and hsa-miR-34a-5p, NFKB1, NFKB2, IRF8, and E2F4. The sponges' tertiary structure predictions for two major miRNAs were provided. The physicochemical and pharmacokinetic properties of memantine and donepezil highlighted the need for a therapeutic combination of these medications to treat cognitive impairment.

New Route to the Synthesis of Novel Pyrazolo[1,5-a]pyrimidines and Evaluation of their Antimicrobial Activity as RNA Polymerase Inhibitors.

The current study aimed to synthesize novel pyrazolo[1,5-a]pyrimidines based on 5- aminopyrazoles 3, evaluate their antimicrobial activity, and study the minimum inhibitory concentration (MIC) for the most active compounds. In addition, molecular docking studies and RNA polymerase inhibitory activity were determined. Starting with our previously reported 5-aminopyrazoles 3, a number of novel pyrazolo[1,5- a]pyrimidines were synthesized. Due to the similarity of pyrazolopyrimidine derivatives with the purine systems, pyrazolopyrimidines are important in many different biological applications, most notably as anti-tumor, antibacterial, and hepatitis C virus inhibitors. The pharmaceutical applications of the pyrazolopyrimidine derivatives were explained in several approved drugs like Indiplon, Zaloplan, and Ocinaplon. To prepare a novel antimicrobial agent, namely pyrazolo[1,5-a]pyrimidine, reveal their structures using different spectral data, the minimum inhibitory concentration (MIC) for the most active compounds was evaluated, and both the molecular docking and the RNA polymerase inhibitory activity were determined. A number of different pyrazolopyrimidines namely 2-(phenylamino)-6,11-dihydrobenzo[g]pyrazolo [1,5-a]quinazoline-3-carboxamides (5a-c), (E)-5,7-dimethyl-2-(phenylamino)-6-(phenyldiazenyl)pyrazolo-[1,5- a]pyrimidine-3-carboxamides (7a-c), 7-amino-2-(phenylamino) pyrazolo[1,5-a]pyrimidine-3-carboxamides (11af), 7-amino-2-(phenylamino)-5-(2-thienyl)pyrazolo[1,5-a]pyrimidine-3-carboxamides (14-f) and ethyl 7-amino-3- carbamoyl-2-(phenylamino)-5-(4-pyridyl)pyrazolo[1,5-a]pyrimidine-6-carboxylate derivatives (14g-i) were synthesized through the reaction of 5-aminopyrazoles 3 with a variety of chemical reagents. On the other hand, the evaluation of the antimicrobial activity for all the prepared compounds was screened through different strains as Gram-positive bacteria, such as staphylococcus aureus and Streptococcus mutans, and Gram-negative bacteria, such as Escherichia coli, Pseudomonas aeruginosa, and klebsiella. The antifungal activity was determined by Candids Albicans fungal strain, and the MIC of the most active compounds was measured. The molecular docking was recorded, and the RNA polymerase inhibitory activity was estimated for the high docking score compounds. Compounds 5a, 5b, 5c, 7a, 7b, 7c, 11d, 14b, and 14h were the most active compounds against some of the bacterial and fungal tested strains. MIC was determined for the most active tested compounds. As an antimicrobial agent, compound 7b was the most potent, with a high docking score and RNA polymerase inhibitory activity (IC50= 0.213 μg/ml) compared to Rifampicin (IC50= 0.244 μg/ml). The reactivity of the latter compound was attributed to the presence of 4-Br-C6H4 moiety. The results demonstrated that docking studies on the most active compounds in the RNA polymerase active site were consistent with in vitro assays. The resultant novel bioactive pyrazolo[1,5-a]pyrimidine derivatives were synthesized based on 5- aminopyrazole derivatives 3. The current study evaluated the antimicrobial activity for all the prepared compounds, followed by the determination of the MIC for the most potent active compounds. The molecular docking study was performed, and it was appropriate with the in vitro activity. The RNA polymerase inhibitory activity was assessed for the most active antimicrobial compounds with a high docking score (7b, 7c, 14a, 14b, 14e, 14i). Compound 7b was the most potent compound inhibiting RNA polymerase enzyme compared to the reference drug Rifampicin. Other: The novel prepared heterocyclic systems are extremely important in a variety of domains, especially biological and pharmacological ones.

RF15 | PMON293 Metabolic activation of tachysterol to biologically active hydroxyderivatives that act on VDR, AhR, LXRs and PPARγ receptors

Abstract Absorption of ultraviolet B (UVB) radiation by the B ring of 7-dehydrocholesterol (7-DHC) leads to the transformation of 7-DHC to previtamin D3, which after absorption of additional UVB isomerizes to tachysterol3 (T3) and lumisterol3 (L3). Previously we demonstrated that CYP11A1 can hydroxylate the side chain of vitamin D3 (D3), 7-DHC and L3. Similarly CYP27A1 can hydroxylate the side chain of L3 to biologically active hydroxyderivatives. In a continuation of these studies, we report that CYP11A1 and CYP27A1 hydroxylate T3 to 20S(OH)T3 and 25(OH)T3, respectively, plus minor unidentified hydroxyderivatives. Both 20S(OH)T3 and 25(OH)T3were detected in the human epidermis and serum. T3 was also detected in human serum and was present at a concentration of 7.3±2.5 ng/ml. 20S(OH)T3 and 25(OH)T3 inhibited the proliferation of epidermal keratinocytes and dermal fibroblasts and stimulated the expression of differentiation and anti-oxidative genes in keratinocytes in a similar manner to 1,25-dihydroxyvitamin D3 . They acted on the vitamin D receptor (VDR) as demonstrated by image flow cytometry and the translocation of VDR-coupled GFP (VDR-GFP) from the cytoplasm to the nucleus of melanoma cells, as well as by the stimulation of CYP24A1 expression. Functional studies using a human aryl hydrocarbon receptor (AhR) reporter assay revealed marked activation of AhR by 20S(OH)T3, a smaller effect by 25(OH)T3 and only minimal activation by T3. The T3 hydroxyderivatives showed high affinity binding to the ligand binding domain (LBD) of the liver X receptor (LXR) α and β, and to the peroxisome proliferator-activated receptor γ (PPARg) in LanthaScreen TR-FRET coactivator assays. Molecular docking using crystal structures of the LBDs of VDR, AhR, LXRs and PPARγ revealed high docking scores for 20S(OH)T3 and 25(OH)T3, comparable to their previously characterized ligands. The scores for binding to the non-genomic site of the VDR were very low indicating a lack of interaction with hydroxy-T3 ligands. In conclusion, we have identified 20S(OH)T3 and 25(OH)T3 in the human epidermis and serum, identified CYP enzymes responsible for their production, demonstrated phenotypic effects on skin cells, and identified VDR, AhR, LXRs and PPARγ, and possibly RORs, as their genomic receptor targets. Thus CYP11A1, aside from its role in steroidogenesis, not only metabolizes vitamin D3, 7-DHC and L3 to biologically active metabolites, but also activates T3 to biologically active 20S(OH)T3. Similarly, CYP27A1, previously reported to act on L3, D3 and 7DHC, also activates T3 via hydroxylation at C25. We believe that these novel findings open new areas for future studies on the role of active forms of T3, not only in the skin, but also in systemic physiology and pathology. Presentation: Sunday, June 12, 2022 12:54 p.m. - 12:59 p.m., Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Identification of phytochemical as a dual inhibitor of PI3K and mTOR: a structure-based computational approach.

Breast cancer is a common form of cancer that affects both men and women. One of the most common types of genomic flaws in cancer is the aberrations in the PI3K/AKT/mTOR pathway. The benefit of dual targeting PI3K as well as mTOR is that the kinase-positive feedback loops are more effectively inhibited. Therefore, in the current study, structure-based models like molecular docking, MM-GBSA, Qikprop, induced fit docking, simulated molecular dynamics (MD), and thermal MM-GBSA were used to identify the phytochemicals from the zinc 15 database, which may inhibit PI3K and mTOR. After docking the phytochemicals with PI3K (PDB 4FA6), ten ligands based on the docking score were selected, among which salvianolic acid C had the highest docking score. Hence, salvianolic acid A was also docked. All the ligands taken showed a binding energy of greater than -30kcal/mol. The predicted ADME showed that the ligands have druggable properties. By performing MD of the top five ligands and salvianolic acid A, it was found that ZINC000059728582, ZINC000257545754, ZINC000253532301, and salvianolic acid A form a stable complex with PI3K protein, among which ZINC000014690026 showed interaction with Val 882 for more than 89% of the time. Salvianolic acid A is already proven to suppress tumor growth in acute myeloid leukemia by inhibiting PI3K/AKT pathway, but the exact protein target is unknown. Therefore, the present study identifies new molecules and provides evidence for salvianolic acid A for dual inhibition. Further experiments must be performed both in vitro and in vivo to support the predictions of these computational tools.

In-silico investigations on the anticancer activity of selected 2-aryloxazoline derivatives against breast cancer

As the in-silico study has become an important tool to search for new drugs in the concurrent era with towering acceptance and accuracy, it has been employed in our research to unearth effective cancer drugs. Breast cancer has accounted for the most serious diseases for both men and women. Although few research outputs have been obtained on breast cancer, these are not an adequate amount to ascertain new drugs. Due to this gap, virtual screening, in-silico study, and computational techniques have been used to provide the ability to design and select anticancer compounds with desirable drug-like properties of breast cancer protein, which is commonly known as fatty acid synthase. A total of nine derivatives of 2-aryloxazoline compounds were chosen, and In-silico was studied to evaluate as a potential anticancer agent with the comparison of seven Food and Drug Administration(FDA) approved breast cancer drugs. These compounds were subjected to computational studies for quantum calculations, ADME and Lipinski analysis, as well as molecular docking and MD simulations against a variety of therapeutic targets involved in cell proliferation of fatty acid synthase (PDB ID:3TJM, 3ERT, 4OAR, 2J6M). An in-silico docking study reveals that ligands Hit-4, Hit-6, and Hit-8 had the highest docking scores at −10.3 kcal/mol, −10.3 kcal/mol, and −10.2 kcal/mol towards the protein of fatty acid synthase. The ligands had docking scores better than the standard anti-breast cancer drug gefitinib (−5.3 kcal/mole). Our findings demonstrate how crucial it is for pharmaceutical researchers to develop novel drugs for the treatment of breast cancer. Communicated by Ramaswamy H. Sarma

Effects of Sedi Herba (Sedum sarmentosum) on attenuating cholestasis by the activation of the farnesoid x receptor (FXR)-mediated signaling

Sedum sarmentosum (Sedi Herba) has traditionally been used to treat jaundice and various types of liver disease. This study aimed to clarify the anti-cholestatic efficacy and the mechanism of S. sarmentosum ethyl acetate extract (SDEAE), as well as to screen the potential compounds with FXR activation. SDEAE effectively ameliorated ANIT-induced cholestasis in rats, as evidenced by the ameliorative histopathology of the liver and the significant decrease in biochemical markers (ALT, AST, ALP, GGT, TBIL, DBIL and TBA). The analysis of bile acid profile by LC–MS indicated that SDEAE decreased the toxic bile acid levels (TCA, TMCA and CA). Western blotting indicated that SDEAE activated FXR-associated pathway, thereby upregulating FXR, SHP, BSEP and UGT2B4 expression, and downregulating CYP7A1 and NTCP expression. Twenty-three compounds (7 nor-sesquiterpenoids, 13 flavonoids, 1 lignin, 1 sterol and 1 anthraquinone) were isolated and identified from SDEAE by comparing NMR data with the literature. The HPLC profiles of SDEAE and isolated compounds were also compared. High-content analysis showed that eight compounds (6, 7, 8, 11, 12, 13, 14 and 23) could activate FXR and compound 8 exhibited the most potent activity (p < 0.01). Molecular docking suggested that the main binding modes between these active compounds and FXR were hydrogen bonding and van der Waals forces, and compound 8 had the highest docking score 6.34. The activation of compound 8 on FXR-mediated signaling was validated in L02 cells. After siRNA down-regulation of FXR, compound 8 significantly elevated FXR, SHP, BSEP and UGT2B4 expression, and reduced CYP7A1 and NTCP expression.