Molegro Virtual Docker Research Articles

8308 Up-regulation of Diacylglycerol kinase gamma (DGKG) in aggressive recurrent pituitary tumors could be targeted by Dasatinib reducing cell proliferation and induced apoptosis

Abstract Disclosure: K. Taniguchi-Ponciano: None. I. Remba: None. M. Loza-Mejia: None. J. Salazar: None. A. Mendez-Perez: None. C. Aguilar-Flores: None. A. Chavez-Gonzalez: None. E. Ortiz-Reyes: None. L. Bonifaz: None. D. Marrero-Rodríguez: None. M. Mercado: None. Pituitary tumors (PT) represent 15% of all intracranial tumors. Some PTs exhibit an aggressive behavior, growing rapidly and invading surrounding tissues, and are frequently resistant to multimodal treatment showing multiple recurrences. Pituitary tumors often recur after initial surgery, particularly when invasive, precluding complete resection of the lesion, which can only be achieved in ∼40-50% of all patients.We have previously characterized transcriptome and exome from 22 tumor lesions from 11 patients by RNA- and DNAseq and methylome profile by microarrays of aggressive, both primary and recurrent PT from the same patient to identify molecular pharmacological targets.Among the differentially expressed genes in most recurrent tumors we found those related to fatty acid biosynthesis and metabolism, phosphatidylinositol, glycerophospholipid and phospholipase D signaling. Importantly, one gene found in most of the lipid-related pathways was diacylglycerol kinase gamma (DGKG). DGKG gene expression was confirmed by immunofluorescence and did not seem to be regulated by DNA methylation. And DGKG showed allelic c.G947A:p.R316K variant in all primary and recurrent tumor tissues analyzed, more research is needed to understand genetic variant impact on protein function. We then performed DGKG molecular docking for FDA-approved drug repurposing. Human DGKG tridimensional model was downloaded from AlphaFold and Autodock Vina, Molegro Virtual Docker, PyMol v2.5.2 program and the Protein-Ligand Interaction Profiler web tool were used. The in silico ADMET profiles were generated in ADMETLab 2.0 using only FDA approved drugs. We identified Dasatinib as a strong candidate for DGKG targeting. We then exposed GH3 cell line to increasing concentrations of Dasatinib (1, 2.5 y 5 μM) using DMSO as vehicle. After cell viability was assessed, approximatively 31% of all live GH3 cells were at proliferative state without any treatment, that was taken as our basal quantity to compare the GH3 cells treated with the TKI’s. Dasatinib reduced approximatively 28% the cell proliferation at 1 μM (p=0.0048), at 2.5 μM reduced nearly 50% of cell proliferation (p=0.003) and at 5 μM inhibited nearly 98% of cell proliferation (p=0.0395) by means of Click-iT EdU Cell proliferation Kit. We then, evaluated Dasatinib apoptosis induction capacity. Interestingly, the 1 μM Dasatinib concentration induced apoptosis (p=0.0001) as concentrations increased, cell death also increased considerably (p=0.0001) measured by Anexin V-FITC and DAPI assay. The RNAseq data from GH3 cells exposed to Dasatinib show diminished gene expression of cell cycle related genes and glycolysis.In conclusion, we observed DGKG upregulated in recurrent aggressive pituitary tumors participating in lipid metabolism pathways and could be targeted by Dasatinib at very low doses. Presentation: 6/3/2024

Drug repositioning identifies potential autophagy inhibitors for the LIR motif p62/SQSTM1 protein

Autophagy is a critical cellular process for degrading damaged organelles and proteins under stressful conditions and has casually been shown to contribute to tumor survival and drug resistance. Sequestosome-1 (SQSTM1/p62) is an autophagy receptor that interacts with its binding partners via the LC3-interacting region (LIR). The p62 protein has been a highly researched target for its critical role in selective autophagy. In this study, we aimed to identify FDA-approved drugs that bind to the LIR motif of p62 and inhibit its LIR function, which could be useful targets for modulating autophagy. To this, the homology model of the p62 protein was predicted using biological data, and docking analysis was performed using Molegro Virtual Docker and PyRx softwares. We further assessed the toxicity profile of the drugs using the ProTox-II server and performed dynamics simulations on the effective candidate drugs identified. The results revealed that the kanamycin, velpatasvir, verteporfin, and temoporfin significantly decreased the binding of LIR to the p62 protein. Finally, we experimentally confirmed that Kanamycin can inhibit autophagy-associated acidic vesicular formation in breast cancer MCF-7 and MDA-MB 231 cells. These repositioned drugs may represent novel autophagy modulators in clinical management, warranting further investigation.

In-silico Investigation of Ginseng Phytoconstituents as Novel Therapeutics Against MAO-A.

Ginseng (Panax ginseng) is a herb of medicinal and nutritional importance. Ginseng has been used since ancient times for the treatment of numerous ailments as it has many therapeutic properties. Several phytoconstituents are present in Panax ginseng that possess a variety of beneficial pharmacological properties. To explore the potential of phytoconstituents of Panax ginseng in the treatment of depression, a molecular modeling technique was utilized targeting monoamine oxidase-A (MAO-A). A total of sixty-one phytoconstituents of ginseng were drawn with the help of ChemBioDraw Ultra 12.0 software and PDBs for MAO-A enzyme were retrieved from the RCSB PDB database. The prepared ligands were screened for MAO-A properties using the software Molegro Virtual Docker (MVD 2010.4.1.0). All the prepared ligands were evaluated for drug-likeliness properties using Swiss ADME. Among the docking studies of 60 Ginseng phytochemicals including one standard, 15 phytoconstituents with the highest dock score and better binding interactions were selected further for absorption, distribution, metabolism and excretion (ADME) studies. Stachyose (-227.287, 17 interactions), Raffinose (-222.157, 14 interactions), and Ginsenoside Rg1 (-216.593, 10 interactions) were found to possess better interactions as compared to Clorgyline taken as a standard drug. Stachyose was found to be the most potent inhibitor of MAO-A enzyme under investigation and can be a potential lead molecule for the development of newer phytochemical-based treatment of depression.

Molecular structure similarity analysis using Tanimoto coefficient and its correlation analysis with Maltase-glucoamylase inhibitory activity of Nigella sativa’s compounds

Nigella sativa is one of the medicinal plants that are efficacious for treating diabetes mellitus. Diabetes mellitus is a chronic metabolic disorder characterized by hyperglycemia due to damage of insulin action, insulin production, and/or both. In this study, the molecular structure similarity analysis of the compounds in Nigella sativa to acarbose and the correlation analysis of the similarity with its activity as antidiabetic with the mechanism of maltase glucoamylase (MGAM) inhibition was carried out. Similarity analysis has been done used Tanimoto coefficient. The prediction of MGAM inhibitory activity has been done using molecular docking with molegro virtual docker. The Kaempferol 3-glucosyl-(1-2)-galactosyl-(1-2)-glucoside; (S)-2,3-Epoxysqualene; Quercetin 3-glucosyl-(1-2)-galactosyl-(1-2)-glucoside; Oleic Acid has activity as an inhibitor of MGAM with rerank score -107.8770, -102.1760, -95.7338, -92.4246 respectively and these has Tanimoto score 0.426, 0.319, 0.413, 0.357 respectively. The correlation analysis obtained that there is a significant relationship between the Tanimoto Coefficient and Rerank Score with the opposite relationship because the correlation value is negative. Greater the degree of molecular structure similarity of Nigella sativa’s compounds to acarbose more likely has the similar biological activity as MGAM inhibitory

In Silico Molecular Docking Analysis Of Anti-Alzheimer’s Compounds From Methanolic Extraction Of Indigofera Prostrta And Lantana Camara Against Alzheimer’s As A Potential Natural Lead Molecule For New Drug Design.

Alzheimer’s malady (Advertisement) is neurodegenerative disarranges that have developed as among the genuine wellbeing issues of the 21st century. The drugs as of now accessible to treat Advertisement have restricted adequacy and are related with side impacts. Characteristic items are one of the foremost imperative and traditionalist sources of solutions for treating neurological issues. To assess the neuroprotective impact of MELC, MEIP in silico ponders beginning with atomic docking against Throb (PDB ID: 3LII) targets for Advertisement was conducted utilizing Auto Dock 4.1 and Molegro Virtual Docker computer program. The docking scores (kcal/mol) appeared comparatively higher strength against Advertisement related targets than right now utilized standard drugs. By and large, the potential official partiality from atomic docking, inactive thermodynamics include from MD-simulation and other multiparametric drug-ability profiles propose that MELC and MEIP may well be considered as a reasonable helpful lead for Advertisement treatment. Besides, the show comes about were unequivocally connected with the prior think about on MELC and MEIP an Alzheimer’s creature show. Be that as it may, fundamental in vivo thinks about, clinical trials, bioavailability, porousness and secure dosage organization, etc. must be required to utilize MELC and MEIP as a potential sedate against Advertisement treatment, where the in silico comes about are more supportive to quicken the sedate improvement.

Kajian Farmakoinformatika Senyawa Caulerchlorin dan Racemosin sebagai kandidat Antimalaria

Caulerchlorin and racemosin were bioactive compounds containing in Caulerpa racemosa macroalgae. Previous study, those compounds promoted therapeutical target on metabolic syndrome. However, the therapeutical activity on Malaria not yet defined. Therefore, this study investigated potential activity of caulerchlorin and racemosin from Caulerpa racemosa as antimalarial activity through pharmacoinformatic study. Caulerchlorin and racemosin structures were retrieved from PubChem NCBI and the Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) structure was taken out from Protein database with ID 5GJG. Orotic acid was used as native ligand or control. Ligands were predicted their antiplasmodial activity and toxicity. Ligands and protein were interacted by redocking using Molegro Virtual Docker version 6.0 and analyzed by using PyMol 2.3 and Discovery Studio version 21.1.1. Two bioactive compounds also showed antiplasmodial activity and were not mutagenicity and hepatotoxicity affections. Molecular docking performed that caulerchlorin and racemosin exhibited same active residues as well as orotic acid as native substrate. Binding energy revealed two compounds, caulerchlorin and racemosin showed lower binding energy than orotic acid. In summary caulerchlorin and racemosin were potentially inhibited PfDHODH activity by binding substrate sites of PfDHODH protein.

Physicochemical, ADMET Properties, and Molecular Docking Studies of N-benzoyl-N’-naphtylthiourea Derivatives for Anti-Breast Cancer Activity

Background: N-benzoyl-N'-naphthylthiourea (BNTU) is a thiourea-derived compound that is predicted to have anti-breast cancer activity. However, their physicochemical properties, ADMET, and receptor-specific targets for their anti-breast cancer activity have not been reported. Objective: This study aimed to predict the physicochemical properties, ADMET, and anti-breast cancer activity of BNTU and its derivatives by in silico approach. Methods: The physicochemical and ADMET properties were predicted using the pkCSM online program and ProTox-II online tool. While the anti-breast cancer activity was predicted using the molecular docking method through the Molegro Virtual Docker (MVD) program on the HER-2 receptor. The parameter observed in the molecular docking method was the bond energy value or rerank score (RS). Compounds with small RS values were predicted to have a great activity. Results: Most BNTU derivatives had lower RS values than BNTU, especially 4TBBNTU, and 4CFBNTU, although their RS values were still higher than lapatinib and TAK-285. As for the reference ligand hydroxyurea, the RS value of BNTU and its derivatives was much lower. The physicochemical and pharmacokinetic properties (ADMET) of lapatinib and TAK-285 were not better than that of BNTU and its derivatives. Conclusion: Five compounds that deserve to be synthesized and tested for anti-breast cancer activity in vitro and in vivo are 4TBBNTU, 3CFBNTU, 4CFBNTU, 4OCBNTU, and the lead compound BNTU.

Insilico assessment of hesperidin on SARS-CoV-2 main protease and RNA polymerase: Molecular docking and dynamics simulation approach

The present study uses molecular docking and dynamic simulations to evaluate the inhibitory effect of flavonoid glycosides-based compounds on coronavirus Main protease (Mpro) and RNA polymerase. The Molegro Virtual Docker (MVD) software is utilized to simulate and calculate the binding parameters of compounds with coronavirus. The docking results show that the selected herbal compounds are more effective than those of chemical compounds. It is also revealed that five herbal ligands and two chemical ligands have the best docking scores. Furthermore, a Molecular Dynamics (MD) simulation was conducted for Hesperidin, confirming docking results. Analysis based on different parameters such as Root-mean-square deviation (RMSD), Root mean square fluctuation (RMSF), Radius of gyration (Rg), Solvent accessibility surface area (SASA), and the total number of hydrogen bonds suggests that Hesperidin formed a stable complex with Mpro. Absorption, Distribution, Metabolism, Excretion, And Toxicity (ADMET) analysis was performed to compare Hesperidin and Grazoprevir as potential antiviral medicines, evaluating both herbal and chemical ligand results. According to the study, herbal compounds could be effective on coronavirus and are admissible candidates for developing potential operative anti-viral medicines. Hesperidin was found to be the most acceptable interaction. Grazoprevir is an encouraging candidate for drug development and clinical trials, with the potential to become a highly effective Mpro inhibitor. Compared to RNA polymerase, Mpro showed a greater affinity for bonding with Hesperidin. van der Waals and electrostatic energies dominated, creating a stable Hesperidin-Mpro and Hesperidin-RNA polymerase complex.

Machine Learning Meets Physics-based Modeling: A Mass-spring System to Predict Protein-ligand Binding Affinity.

Computational assessment of the energetics of protein-ligand complexes is a challenge in the early stages of drug discovery. Previous comparative studies on computational methods to calculate the binding affinity showed that targeted scoring functions outperform universal models. The goal here is to review the application of a simple physics-based model to estimate the binding. The focus is on a mass-spring system developed to predict binding affinity against cyclin-dependent kinase. Publications in PubMed were searched to find mass-spring models to predict binding affinity. Crystal structures of cyclin-dependent kinases found in the protein data bank and two web servers to calculate affinity based on the atomic coordinates were employed. One recent study showed how a simple physics-based scoring function (named Taba) could contribute to the analysis of protein-ligand interactions. Taba methodology outperforms robust physics-based models implemented in docking programs such as AutoDock4 and Molegro Virtual Docker. Predictive metrics of 27 scoring functions and energy terms highlight the superior performance of the Taba scoring function for cyclin- dependent kinase. The recent progress of machine learning methods and the availability of these techniques through free libraries boosted the development of more accurate models to address protein-ligand interactions. Combining a naïve mass-spring system with machine-learning techniques generated a targeted scoring function with superior predictive performance to estimate pKi.

QSAR of acyl alizarin red biocompound derivatives of <i>Rubia tinctorum</i> roots and its ADMET properties as anti-breast cancer candidates against MMP-9 protein receptor: <i>In Silico</i> study

Alizarin is a polycyclic compound isolated from roots of Rubia tinctorum that has potential as a breast anticancer candidate. Increasing anticancer activity can be done through structural modification to produce derivatives in the form of group substitution in the meta position using acyl. The purpose of this work is to forecast the anticancer activity of alizarin and its derivatives on the MMP-9 receptor using. Important biological activity factors will be identified by Quantitative Structure Activity molecular docking Relationship (QSAR) and projected absorption, distribution, metabolism, elimination, and toxicity (ADMET). Using Molegro Virtual Docker (MVD), molecular docking was carried out on the MMP 9 receptor (4WZV.pdb). LogP, Etot, and MR are the physicochemical parameters that are examined in order to produce QSAR. Statistical Package for the Social Science (SPSS) was used for the QSAR analysis. The pkCSM was utilized to determine ADMET prediction. The acyl alizarin derivatives have a lower rerank score than alizarin, according to the docking results so that they are predicted to have more potent anticancer activity. The QSAR analysis's findings indicated that logP and Etot had the greatest effects on the alizarin compound's and its derivatives' activity. The results of the ADMET prediction indicate that acyl alizarin is less harmful and superior to alizarin. Research findings show that it is possible to synthesize acyl alizarin derivatives, especially alizarin octanoate, which will then be tested in vitro or in vivo to determine its anti-breast cancer activity and toxicity.

Antioxidant activity of Bougainvillea spectabilis ethanol extracts as an aryl hydrocarbon inhibitor

Background: Antioxidants overcome ageing processes and skin tissue damage caused by free radicals. The flavonoid contents of Bougainvillea spectabilis Willd contain hydroxyl groups attached to the carbon of the aromatic rings which makes them capable of catching free radicals and absorbing UV-A and UV-B. Objective: This study aimed to investigate the in silico antioxidant activities of various compounds contained in B. spectabilis Willd ethanol extracts compared to control. Method: The identification was carried out using GCMS methods and Molegro Virtual Docker. The molecular mechanics of scoring functions used in this study were the Rerank score, Root Mean Standard Deviation, and H Bond Result: p-Trimethylsylyoxylphenyl-(trimethylsilyoxy)trimethylsilyacrilate had a better bond than vitamin C used as the control and is smaller than BHF_401 (A) standard ligand, indicated by rerank scores of -92.6478, -76.0593, and -104.771. Conclusion: p-Trimethylsilyloxyphenyl-(trimethylsilyloxy)trimethylsilylacrylate had a better and more stable bond (rerank score: -92.6478) than the positive vitamin C control (76.0593).

In Silico Study of Acetogenin Compounds from Soursop (Annona muricata) Leaves as Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitors

Acetogenin derived from soursop (Annona muricata) leaves are known to have antidiabetic and anticancer activities. Nevertheless, there has been no study related to the compounds found in A. muricata leaves, such as acetogenin, as SGLT2 inhibitors. This research aims to investigate the activity of acetogenin compounds as SGLT2 inhibitors while maintaining low selectivity against SGLT1 using molecular docking methods using Molegro Virtual Docker (MVD). Based on the Rerank score, five acetogenin compounds, namely muricin H, annonacin A, annopentocin B, murihexocin C, and corossolone, are predicted to be SGLT2 inhibitors with better selectivity compared to empagliflozin. Among these five compounds, muricin H and corossolone exhibit the most similarity in interaction with amino acid residues in the SGLT2 A-chain compared to empagliflozin. In silico ADMET analysis results indicate that both compounds have absorption, distribution, and metabolism capabilities, similar to empagliflozin. However, it should be noted that both compounds are more toxic, with muricin H predicted to have hepatotoxic properties.

Antidiabetic Advancements In Silico: Pioneering Novel Heterocyclic Derivatives through Computational Design

Background:: Deficiency of insulin signaling in type 2 diabetes results from insulin resistance or defective insulin secretion and induced hyperglycemia. By reducing glycated hemoglobin, SGLT2 inhibitors improve hyperuricemia, blood lipids, and weight loss without increasing the risk of hypoglycemia. By targeting this pathway, SGLT2 inhibitors can become a prominent target in the management of type 2 diabetes. Objective:: This study aimed to carry out the molecular docking and ADMET prediction of novel imidazo(2,1-b)-1,3,4 thiadiazole derivatives as SGLT2 inhibitors. Methods:: The chemical structures of 108 molecules were drawn by using ChemDraw Professional 15.0. Further, their energy minimization was also carried out by using Chem Bio Draw three-dimensional (3D) Ultra 12.0. Molecular docking was also carried out using a Molegro Virtual Docker to identify the best-fitting molecules and to identify the potential leads on the basis of dock score. The predicted parameters of drug-likeness according to Lipinski’s rule of five, such as molecular weight, log P, hydrogen bond acceptor, hydrogen bond donors, and number of rotatable bonds of the selected compounds, were predicted using pKCSM software. Results:: About 108 molecules were designed by employing different substitutions on imidazothiadiazole nucleus as SGLT2 inhibitors. Out of these, 10 compounds were found to have better interactions with the active site of SGLT2 protein and the highest dock scores compared to canagliflozin. Compounds 39a and 39b demonstrated good interactions and the highest docking scores of -155.428 and -142.786, respectively. The in silico physicochemical properties of the best compounds were also determined. Additionally, these compounds suggested a good pharmacokinetic profile as per Lipinski's rule of five (orally active drugs). Conclusion:: Novel imidazo (2,1-b)-1,3,4 thiadiazole derivatives were strategically designed, and their binding affinity was meticulously evaluated against the SGLT2 protein. This endeavor yielded pioneering lead compounds characterized by ultimate binding affinity, coupled with optimal ADMET properties in adherence to Lipinski's rule of five and favourable noncarcinogenic profile.

Prediction of the Potential of Benzoxazinone, 2-phenyl-4H-benzo[1,3]oxazin-4-one, and 2-[2-(4-methoxyphenyl)vinyl]-3,1-benzoxazin-4-one as New Anti-Tuberculosis

Even though it had been almost 5 decades, the decline in the prevalence of tuberculosis was still low due to the rise of drug resistance. Recently, benzoxazinone compounds began to gain potential as anti-tuberculosis agents because of their interesting structure and similarity to isoniazid, the most widely used TB drug, which had reportedly experienced many cases of resistance. This research tested the ability of the core compound benzoxazinone and its 2 derivatives to bind to the enoyl ACP-CoA receptor, which was responsible for the formation of mycobacterial walls. In silico tests were carried out using pkcsm to determine the pharmacokinetic profile, and molecular docking tests using Molegro Virtual Docker were conducted to determine the pharmacodynamic profile through binding to the enoyl ACP-CoA receptor. The selected receptors were downloaded from the protein data bank with the code 2IDZ. The research results showed that the three test compounds had good intestinal and skin absorption profiles, indicating that they could be administered orally or transdermally. The docking results, expressed by moldock score and rerank score, showed that the three test compounds had better potential compared to isoniazid. Thus, the test compounds could be developed as new anti-tuberculosis agents

In Silico Study of the Potential of Brazilein Sappan Wood as a Beta-Lactamase Inhibitor against Extended-Spectrum Beta-Lactamase-Encoding Genes.

Infectious illnesses are a serious health concern in Indonesia. Widespread use of self-medication by the community increases the risk of developing multi-drug resistant (MDR) bacteria. This study assessed the potential of sappan wood as an inhibitor of extended-spectrum beta-lactamase (ESBL) encoded by blaSHV, blaTEM and blaCTX-M genes. In silico testing was conducted to develop an effective and economical starting strategy. Thereby, this study significantly advances the development of novel treatments to combat antibiotic resistance. Using clavulanic acid as the benchmark medicine, the potency of the beta-lactamase inhibitor brazilein was predicted. Using the Molegro Virtual Docker computer tool, docking was performed to estimate the chemical and physical properties of the compounds, as well as the biological activity of brazilein toward the required receptor. The receptors used were SHV-1 beta-lactamase, PDB code: 2H0T; TEM-1 beta-lactamase, PDB code: 4OQG and CTX-M-14 beta-lactamase, PDB code: 6VHS. Data analysis was performed by comparing the binding energies of the docking results between the ligands and the target receptor. The more stable the bond that formed between the ligand and the target receptor, the lower the bond energy. The in silico test results on the blaSHV gene were as follows: binding energy of ligand MA4_400[A] = -100.699, brazilein = -82.206, clavulanic acid = -79.3704; in the blaTEM gene: ligand bond energy 2UL_301[B] = -107.681, brazilein = -82.0296, clavulanic acid = -103.3; in the blaCTX-M gene: X57_301[A] ligand bond energy = -86.6197, and brazilein = -88.1586, clavulanic acid = -101.933. The findings of this study demonstrate the significant potential of brazilein sappan wood to block the beta-lactamase activity of blaCTX-M.

Activation Effect of 2-β-hydroxy Manoyl Oxide Isolated from Sideritis perfoliata on Carbonic Anhydrase Isoenzymes I and II

Background: Sideritis species were used for the treatment of mental disorders such as Alzheimer’s and dementia traditionally in Turkey. Several in vivo studies report that the mid-polar extract of Sideritis species can develop the brain functions of mice. 2-β-hydroxy manoyl oxide, isolated from ethyl acetate extract of Sideritis perfoliata, was assayed in vitro and in silico on human erythrocytes CA I and CA II. The compound was found to be an activator on two isoenzymes. It has been reported that activators of carbonic anhydrases may be used as a novel approach to treating disorders such as Alzheimer’s and age-related diseases. This study aimed to investigate the activity effect of 2-β-hydroxy manoyl oxide in vitro and in silico on human erythrocytes CA I and CA II (hCA I and hCA II) and to elucidate its pharmacokinetic and physicochemical characteristics. Methods: The test compound was isolated from ethyl acetate extract of Sideritis perfoliata using chromatographic techniques and identified with spectroscopic evidence. Carbonic anhydrase activities were assayed using CO2 substrates. Docking studies were carried out with Molegro Virtual Docker. The compound underwent ADME-Tox prediction by using AdmetSAR and SwissADME software. Results: 2-β-hydroxy manoyl oxide was found to increase the hCA-l and hCAII activity with AC50 values 9 and 19 μM, respectively. These results were further confirmed in silico molecular modeling. It showed favorable pharmacokinetic and physicochemical characteristics as a new drug candidate. Conclusion: These findings demonstrated that 2-β-hydroxy manoyl oxide activated the hCA-l and hCA II. These results provide a novel and alternative activator for the carbonic anhydrase and confirm the traditional usage of the Sideritis perfoliata.

Design, Docking, Characterisation, and Synthesis of Pyrimidine Derivatives for Antidepressant Activity.

According to the report, in 2022, the prevalence rate of depression in India was 4.50%, and the cases stood at 56,675,969. The development of antidepressant agents has reduced the number of depressant and suicidal cases. Many researchers have found that pyrimidine possesses antidepressant activity. With this background, we thought of synthesizing pyrimidine derivatives. The objective of this study is to carry out molecular docking, synthesis, characterization, and evaluation of 2-((4,6-diphenylpyrimidin-2-yl)oxy)-N-phenylacetamide derivatives (17-26) as in vivo antidepressant agent. The designed compounds were checked for their activity using Molegro virtual docker (MVD) and were further synthesized. Benzaldehyde reacted with acetophenone to give compound (3), which gave compound (4) upon reaction with urea. In another reaction, substituted anilines (5) were reacted with chloroacetyl chloride (6) to yield compounds (7-16), which upon further reaction with compound (4) yielded the final derivatives (17-26). The synthesized compounds were characterized by spectral analysis and checked for their antidepressant activity. The MolDock scores of the derivatives ranged from -147.097 to -182.095, whereas of active ligand IXX_801 was -115.566. All the synthesized pyrimidine derivatives showed better affinity towards the Cryo-EM structure of the wild-type human serotonin transporter complexed with vilazodone, imipramine, and 15B8 Fab protein (PDB ID: 7LWD) as compared to standard drug clomipramine (-101.064). All the synthesized derivatives were screened for antidepressant activity at a 100mg/kg dose level compared to the standard clomipramine HCl at a dose level of 20mg/kg. Among all the synthesized derivatives, compound 24 showed the most potent antidepressant activity, and Compound 20 showed moderate antidepressant activity, which reduced the duration of immobility times to 35.42% and 31.97% at 100mg/kg dose level when compared to the control, respectively. Compound 24 showed the highest MolDock score as well as found to be the most potent antidepressant agent.

Computational investigation of 2, 4-Di Tert Butyl Phenol as alpha amylase inhibitor isolated from Coccinia grandis (L.) Voigt using molecular docking, and ADMET parameters

IntroductionDiabetes Mellitus is the metabolic disorder most prevalent globally, accounting for a substantial morbidity rate. The conventional drugs available for the management of diabetes are either expensive or lack the required efficacy. The purpose of this research is to isolate and characterize an active phytoconstituent from Coccinia grandis and assess its anti-diabetic properties. Methods and materialsStems of Coccinia grandis are subjected to successive extraction and isolation. The isolated compound by column chromatography was characterized by FTIR (fourier-transform infrared), 1 H NMR (proton nuclear magnetic resonance), and Mass spectroscopy. The antidiabetic potential of the isolated compound was evaluated by in-vitro alpha-amylase inhibitory activity. Further, the compound was subjected to molecular docking studies to study its interaction with the human pancreatic alpha-amylase (Molegro Virtual Docker) as well to determine the pharmacokinetic and toxicity profile using computational techniques (OSIRIS property explorer, Swiss ADME, pkCSM, and PreADMET). ResultsThe characterization of the compound suggests the structure to be 2,4-ditertiary butyl phenol. The in-vitro alpha-amylase inhibitory study indicated a concentration-dependent inhibition and the IC50 (median lethal dose) value of the isolated compound was found to be 64.36 μg/ml. The docking study with the A chain of receptor 5EMY yielded a favorable docking score of −81.48 Kcal mol−1, suggesting that the compound binds to the receptor with high affinity through electrostatic, hydrophobic, and hydrogen bonds. Furthermore, the silico ADME analysis of the compound revealed improved metabolism, a skin permeability of −3.87 cm/s, gastrointestinal absorption of 95.48 %, and a total clearance of 0.984 log ml min−1 kg−1. In silico toxicity analysis also predicted cutaneous irritations but no carcinogenicity, mutagenicity, or hepatotoxicity. ConclusionThe data suggested that the isolated compound (2, 4-tertiary butyl phenol) has the potential to inhibit the alpha-amylase activity and possess optimal ADME properties as well as tolerable side effects.

Design, Facile synthesis, and Characterization of sulfonamide derivatives combined with amino acids and other drugs targeting HER2

Researchers have discovered that tyrosine kinase plays a significant role in cancer development. As a result, certain studies focused on synthesizing sulfonamide compounds due to their potent tyrosine kinase inhibitory (TKI). The designed compounds were docked against (HER2) human epidermal growth factor receptor 2 (PDB ID: 3pp0) to identify potential prospects for new cancer drugs. Docking studies using Molegro virtual docker (MVD) revealed the most favorable binding energy among our compounds. In total, all synthesized compounds had binding energies ranging from (-112.893 to -154.396kcal/mol) corresponding to (3a and 1a) respectively. It was found that compound 1a possessed the best binding energy value of synthesized compounds (-154.396 kcal/mol) compared to the recommended drug; trastuzumab (-133,419kcal/mol). Several of the newly designed sulfonamide derivatives were synthesized. An alkaline phase was used in our synthesis to combine some amino acids, sulfamethoxazole, and sulfadiazine with benzenesulfonyl chloride derivatives. The synthesis method was simple and cheap with yields ranging between (60.4% - 80%). Nuclear magnetic resonance spectroscopy, mass spectrometry, and infrared spectroscopy were used to characterize our compounds.

The potential active compounds of Jatropha multifida Linn. as an anti-COVID-19 mouthwash: In silico study

Background: Povidone-iodine 1% mouthwash is one of the products recommended for preventing and controlling COVID-19 infection in dental procedures. Jatropha multifida Linn. has the same antiseptic effect as povidone-iodine. Purpose: The objective is to determine the effectiveness and interaction effect of secondary metabolites from the latex of Jatropha multifida Linn. and povidone-iodine against the main protease (MPro) SARS-CoV-2 and the SARS-CoV-2 spike protein - ACE2 receptors. Methods: The in silico test was used in this study and carried out using the Molegro Virtual Docker software for molecular docking and BIOVIA Discovery Studio and PyMOL for visualization. Results: The results show that secondary metabolite compounds contained in the latex of Jatropha multifida Linn. have a better effectiveness potential in relation to MPro SARS-CoV-2 and SARS-CoV-2 spike protein - ACE2 receptors than povidone-iodine. Conclusion: The latex of Jatropha multifida Linn. shows potential as a preventive and curative therapy for COVID-19 in the in silico study.