Glide Score Research Articles

In-silico molecular modelling, MM/GBSA binding free energy and molecular dynamics simulation study of novel pyrido fused imidazo[4,5-c]quinolines as potential anti-tumor agents.

With an alarming increase in the number of cancer patients and a variety of tumors, it is high time for intensive investigation on more efficient and potent anti-tumor agents. Though numerous agents have enriched the literature, still there exist challenges, with the availability of different targets and possible cross-reactivity. Herein we have chosen the phosphoinositide 3-kinase (PI3K) as the target of interest and investigated the potential of pyrido fused imidazo[4,5-c]quinoline derivatives to bind strongly to the active site, thereby inhibiting the progression of various types of tumors. The AutoDock, Glide and the Prime-MM/GBSA analysis are used to execute the molecular docking investigation and validation for the designed compounds. The anti-tumor property evaluations were carried out by using PASS algorithm. Based on the GLIDE score, the binding affinity of the designed molecules towards the target PI3K was evaluated. The energetics associated with static interactions revealed 1j as the most potential candidate and the dynamic investigations including RMSD, RMSF, Rg, SASA and hydrogen bonding also supported the same through relative stabilization induced through ligand interactions. Subsequently, the binding free energy of the Wortmannin and 1j complex calculated using MM-PBSA analysis. Further evaluations with PASS prediction algorithm also supported the above results. The studies reveal that there is evidence for considering appropriate pyrido fused imidazo[4,5-c]quinoline compounds as potential anti-tumor agents.

GC-MS Characterization, In Vitro Antioxidant, Antimicrobial, and In Silico NADPH Oxidase Inhibition Studies of Anvillea radiata Essential Oils

Anvillea radiata is a medicinal plant that has been used in traditional phytotherapy in North Africa as a treatment for various illnesses. In this study, we aim to explore the antioxidant, antifungal, and antibacterial effects of essential oils of Anvillea radiata (EOAR) collected in Morocco. EOAR was extracted by the hydrodistillation method, and the phytochemical identification was carried out by gas chromatography-Mass Spectrometry (GC/MS). The antioxidant capacity was evaluated by the 2.2-diphenyl-1-picrylhydrazyl (DPPH) method, ferricyanide method (FRAP) as well as total antioxidant capacity (TAC). Antifungal and antibacterial properties were determined by use of the disc diffusion and minimum inhibitory concentration assays. The microbial strains used in the antimicrobial evaluation were: Aspergillus niger (MTCC 282), Aspergillus flavus (MTCC 9606), Fusarium oxysporum (MTCC 9913), Candida albicans (ATCC 10231), Escherichia coli (ATB 97/BGM), Staphylococcus aureus (ATCC 6633), Bacillus subtills (DSM 6333), and Escherichia coli (ATB 57/B6N). Based on in silico simulations, the inhibitory power of EOAR against nicotinamide adenine dinucleotide phosphate oxidase (NADPH) was evaluated. The yield of the oil was 0.96% wherein 12 compounds were identified including α-cuprenene (33.48%) camphor (21.41%) and α-himachalene (15.88%) as major compounds. The antioxidant capacity showed an IC50 of 32.36 µg/mL (DPPH) and an EC-50 value of 64.60 ± 3.71 µg/mL in the FRAP assay. The total antioxidant capacity showed a concentration of 977.51 ± 22.38 µg AAE/mg (TAC). As for the antimicrobial effects, the inhibition diameter of the studied bacteria ranged from 23.50 ± 2.31 to mm 29.50 ± 2.21 mm, while for fungi, ranged from 25.12 ± 2.82 mm to 11.42 ± 1.90 mm. Minimum Inhibitory Concentration (MIC) ranged from 12.71 ± 1.59 µg/mL to 23.53 ± 0.78 µg/mL for bacterial strains and 10.31 ± 1.34 µg/mL to 22.75 ± 1.06 µg/mL for fungal strains. In silico, among all Anvillea radiata essential oils analyzed, the sesquiterpene γ-dehydro-ar-himachalene, monoterpenoid phenol carvacrol, as well as sesquiterpene α-cadinene were the most active compounds against NADPH oxidase with a glide score of −6.233, −6.082, and −5.057 Kcal/mol, respectively. Taken together, these data showed that EOAR exhibited enormous significance as an antioxidant, antifungal, and antibacterial agent.

GC-MS Profiling, In Vitro Antioxidant, Antimicrobial, and In Silico NADPH Oxidase Inhibition Studies of Essential Oil of Juniperus thurifera Bark.

Juniperus thurifera is a native species to the mountains of the western Mediterranean region. It is used in traditional medicine as a natural treatment against infections. The present study aimed to carry out the chemical analysis and evaluate the antioxidant, antimicrobial, as well as in silico inhibition studies of the essential oils from Juniperus thurifera bark (EOEJT). Chemical characterization of EOEJT was done by gas chromatography (GC-MS). We have performed three antioxidant assays (Reducing power (FRAP), 2, 2-diphenylpicrylhydrazyl (DPPH), and total antioxidant capacity (TAC)) of the EOEJT. We next evaluated the antimicrobial activity against in silico study, which was carried out to help evaluate the inhibitory effect of EOEJT against NADPH oxidase. Results of the GC/MS analysis revealed seven major compounds in EOEJT wherein muurolol (36%) and elemol (26%) were the major components. Moreover, EOEJT possessed interesting antioxidant potential with an IC50 respectively of 21.25 ± 1.02 μg/mL, 481.02 ± 5.25 μg/mL, and 271 μg EAA/mg in DPPH, FRAP, and total antioxidant capacity systems. Molecular docking of EOEJT in NADPH oxidase active site showed inhibitory activity of α-cadinol and muurolol with a glide score of −6.041 and −5.956 Kcal/mol, respectively. As regards the antibacterial and antifungal capacities, EOEJT was active against all tested bacteria and all fungi, notably, against Escherichia coli K12 with an inhibition diameter of 21 mm and a MIC value of 0.67 mg/mL, as well as against Proteus mirabilis ATCC 29906 with an inhibition diameter of 18.33 ± 1.15 mm and a MIC value of 1.34 mg/mL. A more pronounced effect was recorded for the fungal pathogens Fusarium oxysporum MTCC 9913 with inhibition of 37.44 ± 0.28% and MIC value of 6.45 mg/mL, as well as against Candida albicans ATCC 10231 with an inhibition diameter of 20.33 ± 1.15 mm and a MIC value of 0.67 ± 0.00 mg/mL. Altogether, these results highlight the importance of EOEJT as a source of natural antibacterial and antioxidant drugs to fight clinically important pathogenic strains.

Structure Based Drug Designing of Histone Deacetylase-2 inhibitors as an Anticancer Agents

Background and purpose- Histone deacetylase 2 (HDAC2) in tumour development and carcinogenesis as a promising therapeutic target for cancer treatment. HDAC-2 belongs to class I histone deacetylase and acts as a transcriptional repressor through the deacetylation of lysine residues present at the N-terminal tail of histone proteins (H2A, H2B, H3 and H4). They are overexpressed in various solid tumours like cutaneous t cell lymphoma, colorectal, prostate cancer, lung cancer, breast cancer, gastric cancer, liver cancer and medulloblastoma. Hence, targeting HDAC-2 could be rewarding strategy to combat cancer. The goal of the research is to design, develop and identification of molecules through docking, Ligplot, ADMET properties and dynamic studies. Objective- To update HDAC-2 databases as a resource for Structure based drug designing. Validation of model by understanding the interaction pattern with known inhibitors. To identify selective and trapping HDAC-2 inhibitors by targeting the catalytic domain through structure-based pharmacophore study. To design novel HDAC inhibitors (HDACi) analogues for further generation of new compounds through software. Molecular dynamics simulations for most active compound. Methods- In the present study HDAC-2 protein (PDB-4LY1) from RCSB PDB screened and retrieved. The different set of data for ligand preparation were downloaded from CHEMBL, NCI, Anticancer databases and FDA approved drugs of HDACi were downloaded from PubChem. The compounds were screened with two software Schrodinger and gold. The multiset framework combining ligand preparation, protein preparation, grid generation, ADMET prediction, molecular docking, Ligplot analysis and molecular dynamics (MD) simulation studies was performed to find the potential compound with HDAC-2 binding affinity. Result- The optimised compound shows high docking score from ChEMBL (-14.078) and NCI library it shows (-12.083) as compared to reference drug Panobinostat (-9.157). binding energy, hydrogen bonding and hydrophobic interaction against the reference compound. 20 compounds were selected as the best HDAC2 inhibitors based on the glide score, binding energy, hydrogen bonding, hydrophobic interaction. Top two compound show Ligplot analysis. Then the one highest docked compound shows dynamic study at 50ns shows binding stability with the inhibitor. Finally find its ADMET property. Conclusion- The virtual screening of drugs through software is ongoing process and 20 modified analogues those which satisfied all the screening results have been found to be better than the conventional drugs available. Further, synthesis, in vivo and cytotoxic studies of synthesised molecules are under process. KEYWORDS- Histone acetylase, histone deacetylase, histone deacetylase-2, molecular dynamics, 4LY1, ADME property, histone deacetylase inhibitor, Optimized Potential for Liquid Simulation 3e, high throughput virtual screening, standard precision, extra precision.

Pharmacokinetic profile of sarcin and thionin from Aspergillus giganteus and in vitro validation against human fungal pathogen.

Fungal infections are more predominant in agricultural and clinical fields. Aspergillosis caused by Aspergillus fumigatus leads to respiratory failure in patients along with various illnesses. Due to the limitation of antifungal therapy and antifungal drugs, there is an emergence to develop efficient antifungal compounds (AFCs) from natural sources to cure and prevent fungal infections. The present study deals with the investigation of the mechanism of the active compounds from Aspergillus giganteus against aspergillosis. Primarily, the bioavailability and toxicological properties of antifungal proteins such as, sarcin, thionin, chitinase and their derivatives have proved the efficiency of pharmacokinetic properties of selected compounds. Molecular interactions of selected compounds from A. giganteus with the virulence proteins of A. fumigatus (UDP-N-acetylglucosamine pyrophosphorylase, N-myristoyl transferase and Chitinase) have exhibited a good glide score and druggable nature of the AFCs. The antagonistic potential of AFCs on the pathogen was confirmed by SEM analysis where the shrunken and damaged spores of AFCs treated pathogen were observed. The integrity of A. fumigatus cell membrane and nuclear membrane treated with AFCs were analyzed by determining the release of cellular materials. The effective concentration of AFCs was found to be 250 µg/ml (P<0.0001). The GC-MS profiling has revealed the volatile bioactive metabolites present in A. giganteus. Further, interaction studies might provide more information on the synergism activity with the non-volatile metabolites which leads to the development of novel drugs for the treatment of aspergillosis.

Rutin induces endoplasmic reticulum stress-associated apoptosis in human triple-negative breast carcinoma MDA-MB-231 cells – In vitro and in silico docking studies

Rutin is a bioactive compound that possesses anti-tumor activities through triggering apoptosis. Triple-negative breast cancer (TNBC) is insensitive to targeted anti-tumoral drugs, and drug resistance in TNBC poses a challenge for a successful cure. The accumulation of misfolded proteins in the lumen of the endoplasmic reticulum (ER) results in cellular stress that initiates a specialized response designated as the unfolded protein response. This study aimed to find potential ER stress targets in triple-negative breast cancer. The viability of cells was evaluated using an MTT assay. Cell migration and proliferation were done by wound scratch and colony formation assay. Cell cycle detection, measurement of ER stress, mitochondrial membrane potential disruption, and cell death identification was performed using flow cytometry. The interaction of rutin with ER stress proteins is predicted using in silico docking. The pattern of gene expression was determined by qRT-PCR. The elevated rate of cell viability, cell cycle arrest, ER stress, MMP, and apoptotic induction was observed in combination treatment. Rutin exhibited the highest glide score with ASK1 and JNK. The results of qRT-PCR showed that rutin induced apoptosis through upregulation of ASK1 and JNK. The present study provides strong evidence supporting an important role of the ER stress response in mediating rutin-induced apoptosis in triple-negative breast cancer.

In vivo and In silico Anti Inflammatory Studies of Alstonia scholaris Bark Extract

The present research is focused on screening In vivo anti-inflammatory activity using carrageen and formalin induced paw edema model in rodents and In silico approaches like docking studies (mcule), Ramchandran plot (procheck) and PASS. The extract significantly inhibited inflammation caused by carrageenan and formalin at doses of 200 mg and 400 mg/kg body weight which is compared to the the effect of the standard drugs meloxicam and indomethacin. Docking studies for natural compounds were carried out against PDB ID: 2AZ5, PDB ID: 1IBC, PDB ID: 6COX, and PDB ID: 4NOS in order to assess the ligand-binding affinity of the active principles of the extract. The docking results showed that the phytoconstituents from the extract and standard drugs meloxicam and indomethacin had shown highest glide scores with all the selected proteins which indicate a greater affinity for binding between receptor and ligand. From the PASS results the possible interventions of selected active constituents of Alstonia scholaris were found to be anti- inflammatory intestinal, Prostaglandin-E2 9-reductase inhibitor, TNF expression inhibitor, Cyclooxygenase 1 and 2 inhibitors, NOS2 expression inhibitor, and Interleukin1 and 6 antagonists. From the prediction results of adverse effects the constituents like Stigmasterol, Diospyrolide, D-Friedoolean-14-en-3-one and Lupeol acetate were found to be free from any adverse effects. All the constituents of Alstonia scholaris were found to have interventions either as direct targets or possible targets with Histamine H2 receptor, Arachidonate 5-lipoxygenase, Interleukin-1 receptor-associated kinase 3 TNF-alpha, Cyclooxygenase 1, Prostanoid EP2 receptor, Prostaglandin E synthase, and Serotonin 1e (5-HT1e) receptor. From In vivo and In silico results it is evident that ethanolic bark extract of Alstonia scholaris possessed significant anti-inflammatory activity.

Binding and mechanistic studies of 5-HT7 specific benzothiazolone derivatives with bovine serum albumin: Spectroscopic and in silico studies

Serotonin, commonly known as 5-Hydroxytryptamine, or 5-HT, is a neurotransmitter having a single amine group and is distributed throughout the peripheral nervous system (PNS) and central nervous system (CNS).It is involved in a variety of physiological and behavioural disorders, including severe depression, pain, schizophrenia, obesity, anxiety, etc. Fourteen serotonin receptor (5-HTR) subtypes are known, among which the 5-HT1A/5-HT7 subtypes are the most studied. Agonists of the 5-HT1AR/5-HT7R have neuroprotective properties, whilst antagonists are helpful in the therapy of neurological diseases. Four (arylpiperazinyl-butyl) benzothiazolone (APBBT) derivatives, abbreviated as L1-L4, which are well established ligands for serotonin receptors. The protein–ligand interaction analysis was performed to determine the extent to which the synthesized APBBT derivatives bind to serum proteins for transport to the target organ.The binding affinity of bovine serum albumin (BSA) was evaluated using a computational technique. An enzyme activity assay specific for esterase confirmed its potential tobecome a new marker for 5-HT7. The quenching of fluorescence and details about the change in protein’s confirmation were provided by synchronous fluorescence spectroscopy. In this study, different spectroscopic methodologies were used, which included UV–visible spectroscopy, fluorescence spectroscopy, and circular dichroism (CD) spectroscopy. An enzymatic activity assay was done to assess the binding affinities of four (arylpiperazinyl-butyl)benzothiazolone derivatives with bovine serum albumin. Finally, molecular docking was used to deduce the primary intermolecular forces involved in the binding process between the synthesisedAPBBT derivatives and the BSA structure. On the basis of Glide score, ligand L3 was the most efficient for Sudlow Site I, followed by L1 > L2 > L4. All studies indicated the effective binding of serotonin derivatives with BSA, thus showing the role of BSA in the transport and metabolism of serotonin derivatives.

In Silico Evaluation of Bioactive Compounds of Artemisia pallens Targeting the Efflux Protein of Multidrug-Resistant Acinetobacter baumannii (LAC-4 Strain).

Acinetobacter baumannii (A. baumannii) is one of the major representative aetiologies of recalcitrant nosocomial infections. Genotypic and phenotypic alterations in A. baumannii have resulted in a significant surge in multidrug resistance (MDR). Of all the factors responsible for the development of antimicrobial resistance (AMR), efflux protein pumps play a paramount role. In pursuit of a safe alternative for the prevention and control of A. baumannii infections, bioactive compounds from the aerial parts of the medicinal plant Artemisia pallens were studied. GC-MS analysis of the ethanol extract of A. pallens detected five major compounds: lilac alcohol A, spathulenol, lilac alcohol C, n-hexadecanoic acid, and vulgarin. In silico examinations were performed using the Schrödinger suite. Homology modelling was performed to predict the structure of the efflux protein of A. baumannii-LAC-4 strain (MDR Ab-EP). The identified bioactive compounds were analysed for their binding efficiency with MDR Ab-EP. High binding efficiency was observed with vulgarin with a glide score of −4.775 kcal/mol and stereoisomers of lilac alcohol A (−3.706 kcal/mol) and lilac alcohol C (−3.706 kcal/mol). Our molecular dynamic simulation studies unveiled the stability of the ligand–efflux protein complex. Vulgarin and lilac alcohol A possessed strong and stable binding efficiency with MDR Ab-EP. Furthermore, validation of the absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of the ligands strongly suggested that these compounds could serve as a lead molecule in the development of an alternate drug from A. pallens.

Evaluation of novel L-histidine-based Schiff base derivatives as microbial-HO inhibitors and their antimicrobial and molecular docking studies

Amino acid-derived Schiff base complexes had been well explored as antimicrobial agents and the imidazole-based Heme oxygenase (HO) inhibitors were proposed as novel antimicrobial agents with a novel mechanism of action i.e., inhibition of microbial-HO, an enzyme essential for microbial survival in the human host. In line with this, we have synthesized and characterized three novel L-Histidine-based Schiff base derivatives (HKA-1,2 and 3) as inhibitors of microbial-HO. All the compounds were confirmed to be non-hemolytic and possess microbial-HO inhibitory activity against the microbial-HO's tested. HKA-1 showed good antimicrobial activity against Bacillus subtilis (6.25 µM), Escherichia coli (0.78 µM), Candida albicans (3.125 µM), and Saccharomyces cerevisiae (0.78 µM) whereas HKA-2 and HKA-3 showed good antimicrobial activity against Pseudomonas aeruginosa (3.125 µM) and Staphylococcus aureus (0.78 µM) respectively. According to molecular docking analysis, the HKA-1 with quinoline moiety showed better interaction with all the microbial HO's tested with a Glide Score extending from -9.71 to -5.51 Kcal/Mol whereas HKA-2 and HKA-3 with bi-phenyl moiety showed interaction with certain microbial-HO's with a Glide Score extending from -7.9 to -2.22 Kcal/Mol and -8.49 to -3.14 Kcal/Mol respectively. The formation of hydrogen bonds between ligand-protein interactions confirmed the stability of the complexes and the compounds reported in the present study could be used to treat drug-resistant pathogens.

Antioxidant, Anti-Proliferative Activity and Chemical Fingerprinting of Centaurea calcitrapa against Breast Cancer Cells and Molecular Docking of Caspase-3.

Centaurea calcitrapa has been intensively utilized in ethnomedicinal practices as a natural therapeutic recipe to cure various ailments. The current study aimed to chemically characterize ethanolic extract of C. calcitrapa (EECC) aerial parts (leaves and shoots) by use of gas chromatography-mass spectrometry analyses (GC-MS) and investigate its antioxidant and in vitro anticancer activities, elucidating the underlying molecular mechanism by use of flow cytometry-based fluorescence-activated cell sorting (FACS) and conducting in silico assessment of binding inhibitory activities of EECC major compounds docked to caspase-3. CG-MS profiling of EECC identified a total of 26 major flavonoids and polyphenolic compounds. DPPH and ABTS assays revealed that EECC exhibits potent antioxidant activity comparable to standard reducing agents. Results of the proliferation assay revealed that EECC exhibit potent, dose-dependent cytotoxic activities against triple-positive (MCF-7) and triple-negative (MDA-MB-231) breast cancer cell models, with IC50 values of 1.3 × 102 and 8.7 × 101 µg/mL, respectively. The observed cytotoxic effect was specific to studied cancer cells since EECC exhibited minimal (~<10%) cytotoxicity against MCF-12, a normal breast cell line. FACS analysis employing annexin V-FITC/propidium iodide double labeling demonstrated that the observed anti-proliferative activity against MCF-7 and MDA-MB-231 was mediated via apoptotic as well as necrotic signaling transduction processes. The increase in fluorescence intensity associated with DCFH oxidation to DCF, as reported by FACS, indicated that apoptosis is caused by generation of ROS. The use of caspase-3-specific fluorogenic substrate revealed a dose-dependent elevation in caspase-3 substrate-cleavage activity, which further supports EECC-mediated apoptosis in MCF-7 cells. The major EECC compounds were examined for their inhibitory activity against caspase-3 receptor (1HD2) using molecular docking. Three compounds exhibited the highest glide score energy of −5.156, −4.691 and −4.551 kcal/mol, respectively. Phenol, 2,6-dimethoxy established strong binding in caspase-3 receptor of hydrogenic type, with residue ARG 207 and of PI-PI stacking type with residue HIS 121. By contract, hexadecenoic acid showed 3 H-bond with the following residues: ASN 615, ASN 616a and THR 646. Taken together, the current findings reveal that EECC exhibits significant and specific cytotoxicity against breast cancer cells mediated by the generation of ROS and culminating into necrosis and apoptosis. Further investigations of the phytoconstituents-rich C. calcitrapa are therefore warranted against breast as well as other human cancer cell models.

Neurological and Molecular Interactions of Phytoconstituents from Ricinus communis Root Extract- A Pharmacological and Computational Approach

The majority of epileptic patients takes numerous anticonvulsant medications and is still not treated successfully. These medications' produce chronic side effects and drug interactions, which restrict their use, constitute their major drawback. On the other hand, the fact that nature has given us plants that can be used as safe, all-natural treatments for illnesses with little side effects and minimal drug interactions has prompted researchers to focus on herbal remedies with anticonvulsant potential. The antiepileptic potential of the methanolic root extract of Ricinus communis was investigated in rodent models. Molecular docking studies using Schrodinger software was employed to study interactions with active site using PDB ID: 4MS4 (GABA agonist’s), 3WFG (glutamate antagonist), 5HCV (aspartate antagonist), 6J8G (sodium channel antagonist). At 30 and 60 minutes, MERC effectively diminished various convulsive phases and provided strong defence against the MES model. In PTZ, MERC extract treated groups at a dose (200 mg/kg and 400 mg/kg) showed significant antiepileptic activity with percentage protection of 24% and 33% respectively against seizures and significantly (* = p&lt;0.0001) increased the latency of the seizures. Molecular docking studies confirmed the GABA agonist’s effects, and the results revealed that quercetin. gallic acid, luteolic acid, gentixic acid, catechin, vanillic acid, ricinoilc acid and standard phenytoin, clonazepam has highest Glide scores against all the selected proteins which indicates a stronger receptor -ligand binding affinity. From in vivo and molecular docking results it is clear that methanolic root extract of Ricinus communis possessed significant antiepileptic activity.

In silico and in vivo Biological Evaluation of Chenopodium quinoa on Scopolamine Induced Memory Impairment in Mice

Aims: The present research is focused on screening in vivo and insilico anti- amnesic activity of the ethanolic extract of seeds of Chenopodium quinoa. To establish the exact the mechanism of action, the phytochemical constituents of the extract were subjected to in silico studies using schrodinger and pass software.&#x0D; Methodology: The powdered material of seeds of Chenopodium quinoa were dried and extracted with ethanol by soxhlation technique. In vivo evaluation of anti- amnesic activity of the ethanolic extract of seeds of Chenopodium quinoa was carried using Transfer latency by Elevated plus maze, Novel object recognition test and Passive avoidance time by cook’s pole climbing apparatus. The major phytoconstituents were subjected to molecular docking using PDB ID: 1EVE, 6N33, 2FV5 and 6W2X. Prediction studies for biological activities, adverse effects, direct and possible targets and using PASS (Predictions of activity spectra for substances) online software.&#x0D; Results: The extract was administered at doses (200 mg/kg and 400 mg/kg) showed significant anti- amnesic activity. The prolongation of the transfer latency time (secs) in the elevated plus-maze test is as an indicator for impairment of learning and memory. In Novel objective recognition test the time of memorizing the familiar object with that of the novel object and time taken for each animal to recognize the novel object compare to familiar object is noted. The results revealed that Quercetin, Beta sitosterol, Kaempferol, Dimethyl sulphide, Myristic acid, Palmitic acid, Stigmasterol, Lenolenic acid, Pentadecanoic acid, Tocopherols, Arachidonic acid and standard Donepezil have got highest glide scores against PDB ID: 1EVE, 6N33, 2FV5 and 6W2X. The ADME results revealed the higher oral bioavailability. The major phytoconstituents were subjected to prediction studies for biological activities, adverse effects, direct and possible targets and using PASS (Predictions of activity spectra for substances) online software.&#x0D; Conclusion: From in vivo and in silico results it is evident that ethanolic extract seeds of Chenopodium quinoa possessed significant anti- amnesic activity.

Prediction of novel and potent inhibitors of lanosterol 14-α demethylase

Lanosterol 14-α demethylase (LDM) is one of the promising drug targets of azoles antifungal. In this study, we have screened a large number of small molecules from different chemical databases (ZINC, DrugBank, ChEMBL, and ChemDiv) to find out novel and potential inhibitors of LDM. As a result, from more than a hundred thousand molecules, the two best candidates, C1 (ZINC000299817826) and C3 (ZINC000095786149), were selected from the top-scoring compounds and further validated in Molecular Dynamic (MD) simulation. The Glide scores of C1 and C3 were −19.33 kcal/mol and −19.13 kcal/mol, suggesting that these compounds bind with LDM with higher binding affinity than the benchmark compound (itraconazole), which has a Glide score of −6.85 kcal/mol. Docking poses reveal that the compounds C1 and C3 bind to the outermost region of the LDM binding site, which can prevent the lanosterol from getting into the catalytic pocket. Furthermore, MD simulation studies were performed to assess the stability of C1 and C3 in complex with LDM and were found to be stable over the 100 nanosecond simulation time. Binding free energy calculated by the MMPBSA method suggested that the C3 forms a more stable complex with the LDM as close to the benchmark compounds. Among the top selected molecules, C1 and C3 were predicted to be the significant inhibitors of LDM. Communicated by Ramaswamy H. Sarma

Dual Acting Immuno-Antibiotics: Computational Investigation on Antibacterial Efficacy of Immune Boosters Against Isoprenoid H Enzyme.

Drug-resistant infections have become a serious threat to human health in the past two decades. Global Antimicrobial Surveillance (GLASS) in January 2018 reported widespread antibiotic resistance among 1.5 million people infected with bacteria across 22 countries. According to prominent economist Jim O'Neil, antimicrobial resistance is estimated to kill ∼10 million people affected by microorganisms each year by 2050. Even though multiple therapeutics are now available to treat the infections, more and more bacterial strains have acquired resistance to these treatments through various techniques. Moreover, the decrease in the pipeline of antibacterial medicines under clinical development has become a significant problem. In this scenario, the development of novel antibiotics that act on untapped pathways is necessary to combat the bacterial infections. Isoprenoid H (IspH) synthetase has become an attractive antibacterial target as there is no human homologue. IspH is an enzyme involved in methyl-d-erythritol phosphate (MEP) pathway of isoprenoid synthesis and is conserved in gram-negative bacteria, mycobacteria, and apicomplexans. Since, IspH is a novel therapeutic target, explorations are only just beginning, and despite the progress made in this area, no single IspH inhibitor is available in the market for therapeutic use. In this article, we have repurposed 35 immune boosters against IspH enzyme using methods such as extra-precision docking and Molecular Mechanics Generalized Born Surface Area (MMGBSA). Among them, 4'-fluorouridine was found to be active because of its glide score and significant binding affinity with IspH enzyme. Furthermore, this study requires more in vitro, in vivo, and molecular dynamics studies to support our findings.

Docking, ADMET and Molecular Dynamics Studies of Plant-Based Phenolics as Tumor Pyruvate Kinase M2 Modulators

The drug discovery is presently threatened by exorbitant costs and is less productive. To challenge the deterioration in the throughput curve, pharmaceutical corporations, and academic scientists are leaning towards plant-based molecules to ascertain new molecules to convert them into pharmacotherapies, and phenolics are the molecules of choice. Natural products, specifically phenolics are undoubtedly explicit sources for development of effective drugs either totally or in a semi-synthetic way and there are numerous examples to support this statement. Molecular docking is chiefly employed to predict novel lead compounds for drug discovery. In this study, phenolics known to act as tumor pyruvate kinase M2 (PKM2) modulators and considered as anticancer agents were subjected to docking studies using Glide and rigorous in silico ADMET studies using the Qikprop suite. In silico investigations were carried out to find out the explicit interactions of the phenolics with PKM2 (PDB IDs 3GR4 and 4B2D) modulators. The docking studies were carried out on phenolics reported as PKM2 modulators. Myricetin was found to be the most suitable anticancer agent for the PKM2 modulation acting on the DASA-binding site with a glide score of -10.746. In addition, the effectiveness of the study was further validated by performing ADMET studies of all the modulators which again established myricetin to be the most favourable one among the selected compounds. It suggested that amongst the “hit list”, myricetin shares the best features to be considered ahead for drug discovery. The results of molecular dynamics simulation studies of myricetin with the DASA-binding pocket of human pyruvate kinase M2 (PDB ID- 3GR4) are strongly in concert with complementary experimental methods discussed above.

In silico Approach and Molecular Docking Studies of Potent Bioactive Compounds of Carica papaya as Anti-breast Cancer Agents.

Breast cancer is one of the greatest global dilemmas, and the current treatment option is to target hormone receptors with partial agonists/antagonists. Estrogen and aromatase enzymes play important roles in breast cancer. Excessive estrogen activity or inadequate estrogen production leads to various hormonal issues, including breast cancer. Potent breast cancer drugs are Tamoxifen, Paclitaxel, Cyclophosphamide, Trastuzumab, etc., and aromatase inhibitors, include Anastrozole, Letrozole, and Exemestane, etc. In general, breast cancer drugs cause numerous adverse effects in humans. This study has attempted to identify alternative drug candidates from Carica papaya for treating breast cancer with fewer side effects. To achieve this, we have utilized computational methods to predict the characteristics of bioactive compounds from Carica papaya and determine the target binding affinities using the Schrödinger suite (Maestro 9.5). The target protein and ligands were obtained from the well-known database. Carica papaya has 35 identified bioactive compounds that were drawn using ChemDraw software and performed Ligand preparation wizard. Absorption, Distribution, Metabolism, and Excretion (ADME) analysis is performed with QikProp. From the docking studies, the phytocompounds such as Chlorogenic acid, Myricetin, Quercetin, Isorhamnetin, and Catechin showed the highest Glide scores (G Score). Among the five bioactive phytocompounds, Chlorogenic acid has a higher G Score with good binding energy than Tamoxifen, Anastrozole, and Letrozole standards. The pharmacokinetic properties and drug-likeness of phytocompounds were determined using ADME profiling. Carica papaya phytocompounds serve as an antiestrogen or aromatase inhibitor that regulates estrogen levels to reduce the risk of breast cancer in postmenopausal women. As a result, we recommend that these top five bioactive phytocompounds be investigated further in in vitro and in vivo studies.

Identification of novel HDAC8 selective inhibitors through ligand and structure based studies: Exploiting the acetate release channel differences among class I isoforms

Histone deacetylases (HDACs) are key regulators of gene expression and have emerged as crucial therapeutic targets for cancer. Among the HDACs, inhibition of HDAC8 enzyme has been reported to be a novel strategy in the treatment of female-specific cancers. Most of the HDAC inhibitors discovered so far inhibit multiple HDAC isoforms causing toxicities in the clinic thus limiting their potential. Therefore, the discovery of isoform-selective HDAC8 inhibitors is highly desirable. In the present study, a combination of ligand and structure based drug design tools were utilized to build a statistically significant pharmacophore based 3D QSAR model with statistical parameters R 2 : 0.9964, and Q 2 : 0.7154, from a series of 31 known HDAC8 inhibitors. Top 1000 hits obtained from Virtual screening of Phase database were subjected to docking studies against HDAC8. Top 100 hits obtained were redocked into HDAC Class I (HDAC 1,2,3) and Class II isoforms (HDAC 4, 6) and rescored with XP Glide Score. Based on fitness score, XP glide score and interacting amino acid residues, five HDAC8 inhibitors ( 1 – 5 ) were selected for in vitro studies. The HDAC8 activity assay followed by enzyme kinetics clearly indicated Compounds 1 , 2 and 3 to be potent HDAC8 selective inhibitors with IC 50 of 126 pM, 112 nM, and 442 nM respectively. These compounds were cytotoxic to HeLa cells where HDAC8 is overexpressed but not to normal cells, HEK293. Also, they were able to induce apoptosis by modulating Bax/Bcl2, cleavage of PARP and release of Cytochrome C . Molecular Dynamics simulations observed most favorable interaction patterns and presented a rationale for the activities of the identified compounds. Selectivity against HDAC8 was due to exploitation of the architectural difference in the acetate release channel among class I HDAC isoforms.

Targeting tribbles homolog 3 (TRIB3) protein against type 2 diabetes for the identification of potential inhibitors by in silico screening

Tribbles homolog 3 (TRIB3) protein is inhibiting the insulin signaling by directly binding to the Akt/PKB leading to insulin resistance in the pancreas causing type 2 diabetes mellitus. Hence, TRIB3 protein is considered as a possible drug target for the new lead identification against type 2 diabetes. In the present study, the homology model of TRIB3 protein was generated to explore its biochemical function and molecular interactions in the new lead identification. The energy minimization of TRIB3 protein was carried out and evaluated by validation protocols for structure reliability. The druggable binding site of TRIB3 protein was identified for the virtual screening and molecular docking studies. The Asinex-fragments library of 22634 small molecules was docked at TRIB3 active site using the Glide module to identify new chemical entities. A total of 9 molecules were identified as final hits from virtual screening and their potency was ranked using Glide score, Glide energies, and residues interactions. The 6 prioritized lead molecules were further optimized using AutoDock, Prime MM/GBSA, and percentage of human oral absorption for the identification of potential leads. The molecules L2, L5, and L6 are identified as lead inhibitors and are showing consistent interactions with key residues Glu194 and Lys196 of TRIB3 protein. The identified potential leads were analyzed by ADME properties for their drug likeness and HergIC50 values are predicted for the prevention of preclinical failures. The present work sheds light on the identification of the best lead molecules against TRIB3 protein and offers a route to design as novel potential drug candidates for T2DM.

Molecular docking analysis of mTOR protein kinase with chromatographically characterized compounds from Clerodendrum inerme L. leaves extract.

The mTOR protein is known to be linked with cancer. Therefore, it is of interest to document the molecular docking analysis of mTOR protein kinase with chromatographically characterized compounds from Clerodendrum inerme L. leaves extract. The GC-MS analysis suggested that, totally 25 bioactive compounds were present in the extract of Clerodendrum inerme. Molecular docking analysis show that the bioactive compounds such as Triethoxysilanol, Piperazine dihydrochloridehydrate, 2,4(1H,3H)-Pyrimidinedione, 5-methyl and 4',7-Dihydroxyflavanone showed good glide score and glide energy within the acceptable and permissible limits of ADME properties for further consideration in drug discovery.