Drug-likeness Score Research Articles

Pharmacokinetic and toxicological in silco profiling of pluchine from the medicinal plant – Pluchea lanceolata

Background: Pluchea lanceolata belongs to the genus Pluchea (family: Asteraceae). The medicinal herb has been used for various ailments to prevent joint swelling in arthritic disorders, rheumatism, and other neurological-inflammatory disorders. Pluchine, which in our review was found to be a compound from P. Lanceolata, is explored for possible pharmacokinetic and toxicological properties by in silico computational predictive tools. Aims and Objectives: The aim of the study is to profile the pharmacokinetic, toxicological, and drug likeness scores of pluchine’s active principle using computational analysis and prediction tools. Materials and Methods: The authenticated and validated chemical structure of pluchine with its chemical formula will be extracted from standard web-based tools PubChem and ChemSpider. The two-dimensional to three-dimensional (3D) structure conversion will be processed with ChemSketchonline software; the 3D structure output will be processed further to be screened for molecular and pharmacokinetic properties for absorption, distribution, metabolism, and elimination, followed by toxicity profiling through AdmetSAR software. Results: Pluchine active principle from P. lanceolata had a predictive pharmacokinetic profile of human intestinal absorption of <30%, Human skin permeability coefficients (log k p) of pluchine were −6.75 cm/s, and the blood–brain barrier were predicted to be positive with a probability score of 0.65. Drug likeness lipinskiscore is positive with -0- violations. Acute oral toxicity testing for pluchine predicts it to be placed in category III with LD50 values >500 mg/kg but <5000 mg/kg. Conclusion: The pluchineactive principle from P. lanceolata is predicted to have a favorable pharmacokinetic and drug-like property profile for lead compound development.

Computational Prediction of Pharmacokinetic and Toxicological Properties of Rotenoids Present in Roots of Boerhavia Diffusa L.

Background Commonly referred to as Punarnava Boerhavia diffusa Linn. family Nyctaginaceae is a plant that is widely cultivated across India particularly abundant during the rainy season. Aim A computational attempt has been made in this study to predict the pharmacokinetic and toxicological characteristics of a subset of the rotenoids present in roots of Boerhavia diffusa L. Methodology BoeravinoneA-N 10-O-Demethylboeravinone C Coccineone-B Coccineone-E 6-O-De methyl boeravinone H and 2rsquo -O-methylabronisoflavone are the rotenoids chosen for the study. The canonical smiles have been obtained by employing the ChemDraw Software. Selected phytochemicalsrsquo drug similarity was evaluated using the Molsoft server. Toxicology and pharmacokinetic features were determined using the admetSAR Structure Activity Relationship server. Results The information gathered throughout the study included the pharmacokinetic and toxicological characteristics of a number of rotenoids as well as their drug-likeness score. Among the selected rotenoids 2rsquo-O-methylabronisoflavone showed the highest drug-likeness score. However many other rotenoids also were found to be better drug-like candidates.Conclusion The present in-silico research found that the assisted prediction and server-based research were crucial and instructive in gathering information about drug candidates pharmacokinetics and the harmfulness of bioactive substances from Boerhavia diffusa L.

Synthesis, crystallographic, quantum chemical and molecular docking studies of 4-benzoyl-1,2,3,11a-tetrahydro-6H-chromeno[3,2-e]imidazo[1,2-a]pyridin-6-one

The synthesis of pyridine derivatives is an active area of research in the development of new drugs. In view of the above importance, a novel compound with fused rings of derivatives of biologically active imidazole, pyridine and chromanone was synthesized. The crystal structure was analysed by single crystal X-ray diffraction method. The quantum chemical parameters of the molecule in the gaseous state were calculated by semi-empirical method using restricted Hartree-Fock wavefunction. The physicochemical properties such as druglikeness and bioactive scores were predicted to understand the drug transport and receptor interactions. Molecular docking studies were performed to analyze the binding of this compound with various bacterial and fungal pathogens. This study points out the potential of this compound to act as an antimicrobial agent. Comparison with related compounds shows that the addition of more number of biologically active groups enhances the activity.

Citrus nutraceutical eriocitrin and its metabolites are partial agonists of peroxisome proliferator-activated receptor gamma (PPARγ): a molecular docking and molecular dynamics study

Peroxisome proliferator-activated receptor gamma (PPARγ) agonists are potent insulin sensitizers in treating type 2 diabetes. Despite being very effective in the fight against diabetes-mediated complications, PPARγ agonists are accompanied by severe side effects leading to complicated health problems, making the discovery of novel safe ligands highly pertinent. A significant intense research effort is in progress to explore the PPARγ activating potential of a wide range of natural compounds. Lemon (Citrus limon) contains various bioactive flavonoids, and eriocitrin is the major flavonoid. It possesses substantial antioxidant and anticancer, lipid-lowering activities and prevents obesity-associated metabolic diseases. Eriocitrin is metabolized to eriodictyol in the intestine, and the absorbed eriodictyol undergoes conversion to numerous metabolites in vivo. It is unclear if eriocitrin or its metabolites are responsible for their beneficial effects. We have used molecular docking, ADMET properties, drug-likeness score and molecular dynamics simulation study to find if eriocitrin and its metabolites are potent binders for PPARγ. Docking studies revealed that eriocitrin binds to PPARγ with the highest binding energy, but ADMET properties and in vivo studies show that the bioavailability of eriocitrin is very poor. Molecular dynamics studies were carried out to validate the docking results, and multiple parameters like RMSD, RMSF, Radius of gyration, SASA, hydrogen bond analysis, interaction energy, principal component analysis, Gibbs free energy and MM-PBSA were calculated. Based on our studies, eriodictyol, eriodictyol 7-O-glucuronide, eriodictyol 3′-O-glucuronide, homoeriodictyol and homoeriodictyol 7-O-glucuronide which are metabolites of eriocitrin appear to be potent partial agonists of PPARγ under physiological conditions. Communicated by Ramaswamy H. Sarma

A series of 1,2,3-triazole compounds: Synthesis, characterization, and investigation of the cholinesterase inhibitory properties via in vitro and in silico studies

A series of 1,2,3-triazole compounds derived from a salicylaldehyde moiety were synthesized in high yields using copper (I)-catalyzed azide-alkyne cycloaddition (CuAAC) reactions. The structures of the newly synthesized 1,2,3-triazole compounds were characterized by FT-IR, NMR, and HRMS analyses. The inhibitory activities of all the target compounds were investigated against electric eel acetylcholinesterase (eeAChE) and equine serum butyrylcholinesterase (eqBChE) enzymes. The activity results were compared with galantamine used as a reference compound. The in vitro biological assays showed that most of the target compounds had quite good inhibition activities for eeAChE, while weaker towards eqBChE. Among them, compound 23f exhibited better activity than both other target compounds and galantamine against both eeAChE (IC50: 0.458 µM) and eqBChE (IC50:1.721 µM). Molecular docking studies of all target compounds were performed on the 3D crystallographic structures of eeAChE, Homo sapiens AChE, and BChE enzymes. The binding energies appear to be consistent with the activity results. Moreover, it was determined that 23f interacted with crucial residues of the catalytic active site (CAS) and peripheral anionic site (PAS) of both AChE and BChE due to its dual binding feature. Finally, in silico ADME and toxicity properties of the compounds were investigated using the Swiss ADME and ProTox-II websites. The compounds have appropriate drug-likeness scores, Additionally, it has been estimated that 23f, the most active compound, and 23c are within the best limits in terms of oral bioavailability and exhibit low levels of toxicity. Consequently, the target compounds, especially 23f, can be considered promising inhibitors for the cholinesterase enzymes.

Biginelli Reaction Synthesis of Novel Multitarget-Directed Ligands with Ca2+ Channel Blocking Ability, Cholinesterase Inhibition, Antioxidant Capacity, and Nrf2 Activation.

Novel multitarget-directed ligands BIGI 4a-d and BIGI 5a-d were designed and synthesized with a simple and cost-efficient procedure via a one-pot three-component Biginelli reaction targeting acetyl-/butyrylcholinesterases inhibition, calcium channel antagonism, and antioxidant ability. Among these multitarget-directed ligands, BIGI 4b, BIGI 4d, and BIGI 5b were identified as promising new hit compounds showing in vitro balanced activities toward the recognized AD targets. In addition, these compounds showed suitable physicochemical properties and a good druglikeness score predicted by Data Warrior software.

Synthesis, Physicochemical Properties and Molecular Docking of New Benzothiazole Derivatives as Antimicrobial Agents Targeting DHPS Enzyme.

The drug-resistance problem is widely spread and becoming more common in community-acquired and nosocomial strains of bacteria. Therefore, finding new antimicrobial agents remains an important drug target. From this perspective, new derivatives of benzothiazole were synthesized and evaluated for their antimicrobial activity and ability to inhibit the DHPS enzyme. The synthesis was carried out by the reaction of benzothiazole N-arylsulphonylhydrazone with N-aryl-2-cyano-3-(dimethylamino)acrylamide, N-aryl-3-(dimethylamino)prop-2-en-1-one, arylaldehydes or diazonium salt of arylamine derivatives, which led to the formation of N-arylsulfonylpyridones 6a-d (yield 60-70%) and 12a-c (yield 50-60%),N-(2-(benzo[d]thiazole-2-yl)-3-arylacryloyl-4-methylsulfonohydrazide 14a-c (yield 60-65%), 4-(benzo[d]thiazole-2-yl)-5-aryl-1H-pyrazol-3(2H)-one 16a-c (yield 65-75%), and N'-(2-(benzo[d]thiazol-2-yl)-2-(2-arylhydrazono)acetyl)-4-arylsulfonohydrazide 19a-e (yield 85-70%). The antimicrobial evaluations resulted into a variety of microbial activities against the tested strains. Most compounds showed antimicrobial activity against S. aureus with an MIC range of 0.025 to 2.609 mM. The most active compound, 16c, exhibited superior activity against the S. aureus strain with an of MIC 0.025 mM among all tested compounds, outperforming both standard drugs ampicillin and sulfadiazine. The physicochemical-pharmacokinetic properties of the synthesized compounds were studied, and it was discovered that some compounds do not violate rule of five and have good bioavailability and drug-likeness scores. The five antimicrobial potent compounds with good physicochemical-pharmacokinetic properties were then examined for their inhibition of DHPS enzyme. According to the finding, three compounds, 16a-c, had IC50 values comparable to the standard drug and revealed that compound 16b was the most active compound with an IC50 value of 7.85 μg/mL, which is comparable to that of sulfadiazine (standard drug) with an IC50 value of 7.13 μg/mL. A docking study was performed to better understand the interaction of potent compounds with the binding sites of the DHPS enzyme, which revealed that compounds 16a-c are linked by two arene-H interactions with Lys220 within the PABA pocket.

Strychnos alkaloids: total synthesis, characterization, DFT investigations, and molecular docking with AChE, BuChE, and HSA

An efficient five steps, the protection-deprotection synthetic a novel synthetic routes to(±) noruleine (±)-uleine, are reported starting from tetrahydrocarbazole fused monoalkyl nitrile at C-2 position that is prepared on multigram scale from 2-(3-ethyl-1-oxo-2,3,4,9-tetrahydro-1H-carbazol-2-yl)acetonitrile (1) as well as the key azocino[4,3-b]indole skeleton is constructed via the tetrafluoro-1,4-benzoquinone (TFB)-mediated cyclization of a tetrahydrocarbazole derivative possessing direct amide synthesis from nitrile. As a result, Total synthesis of noruleine and uleine has been developed, which is accomplished in 4 and 5- steps synthesis of the ABCD tetracyclic of the strychnos alkaloids with an overall yield of 44% and 39%, respectively. The DFT computations were performed with B3LYP/6-311g(d,p) level to determine inter and intramolecular interactions and reactivity features of the compound 3–6. Also, TD-DFT computations were performed to characterize the electronic absorption spectra of all compounds. Last, the interactions of compounds 3–6 with selected targets AChE, BuChE, and HSA were evaluated in light of the molecular dockings. The bioactivity and drug-likeness scores revealed that compound 6 3–6 can be proper candidate for future drug-design studies more than the other compounds.

Exploring the mechanism of Tengli Kangliu Decoction in the prevention and treatment of colorectal cancer precancerous based on network pharmacology.

This study aimed to predict the targets and signaling pathways affected by Tengli Kangliu Decoction (TKD) in the treatment of colorectal cancer (CRC) precursor lesions and to determine TKDs mechanism of action based on previous experimental results using network pharmacology techniques and methods. Using the traditional Chinese medicine systems pharmacology database (TCMSP) and UniProt database, the active ingredients and potential targets of TKD were identified. Human colorectal adenoma (CRA) targets were analyzed using the GeneCards database, the Online mendelian inheritance in man (OMIM) database, and the NCBI database. The common targets of drug-disease interactions were input into the String database to construct a protein-protein interaction (PPI) network. These data were then used to construct the network diagram. Gene ontology (GO) function analysis and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis were performed on the target genes. Finally, the component-disease-pathway-target network file was imported into Cytoscape 3.8.0 and used to construct the pathway network diagram. Compounds with a drug-likeness (DL) score ≥ 0.18 and an oral bioavailability (OB) ≥ 30% were selected as the active constituents of TKD. Two hundred eighty eight chemical constituents were screened and 305 chemical drug targets were predicted. After further screening, 1942 disease-related targets, which are hypothesized to be the main chemical components of TKD, were obtained. When comparing the targets of action and CRA treatment targets, 172 common targets were identified. Using GO enrichment analysis of common targets of drug diseases, 2550 biological processes (BP) were predicted, 164 items of which were related to molecular functioning (MF), and 67 items related to cell composition. KEGG pathway analysis was performed on the common targets of drug diseases, and a total of 178 signaling pathways were enriched. Using network pharmacology research, this study reports on the synergistic effect of the multiple components of TKD on the multi-target, and multiple pathways of colorectal precancerous lesions. These findings lay a theoretical foundation for further colorectal precancerous lesions research.

Design, Synthesis, Kinetic Analysis and Pharmacophore-Directed Discovery of 3-Ethylaniline Hybrid Imino-Thiazolidinone as Potential Inhibitor of Carbonic Anhydrase II: An Emerging Biological Target for Treatment of Cancer.

Carbonic anhydrases (CA), having Zn2+ metal atoms, are responsible for the catalysis of CO2 and water to bicarbonate and protons. Any abnormality in the functioning of these enzymes may lead to morbidities such as glaucoma and different types of cancers including brain, renal and pancreatic carcinomas. To cope with the lack of presence of a promising therapeutic agent against these cancers, searching for an efficient and suitable carbonic anhydrase inhibitor is crucial. In the current study, ten novel 3-ethylaniline hybrid imino-thiazolidinones were synthesized and characterized by FTIR, NMR (1H, 13C), and mass spectrometry. Synthesis was carried out by diethyl but-2-ynedioate cyclization and different acyl thiourea substitutions of 3-ethyl amine. The CA (II) enzyme inhibition profile for all synthesized derivatives was determined. It was observed that compound 6e demonstrated highest inhibition of CA-II with an IC50 value of 1.545 ± 0.016 µM. In order to explore the pharmacophoric properties and develop structure activity relationship, in silico screening was performed. In silico investigations included density functional theory (DFT) studies, pharmacophore-guided model development, molecular docking, molecular dynamic (MD) simulations, and prediction of drug likeness scores. DFT investigations provided insight into the electronic characteristics of compounds, while molecular docking determined the binding orientation of derivatives within the CA-II active site. Compounds 6a, 6e, and 6g had a reactive profile and generated stable protein-ligand interactions with respective docking scores of -6.12, -6.99, and -6.76 kcal/mol. MD simulations were used to evaluate the stability of the top-ranked complex. In addition, pharmacophore-guided modeling demonstrated that compound 6e produced the best pharmacophore model (HHAAARR) compared to standard brinzolamide. In vitro and in silico investigations anticipated that compound 6e would be an inhibitor of carbonic anhydrase II with high efficacy. Compound 6e may serve as a potential lead for future synthesis that can be investigated at the molecular level, and additional in vivo studies are strongly encouraged.

Low-Molecular Weight Small Molecules Can Potently Bind RNA and Affect Oncogenic Pathways in Cells.

RNA is challenging to target with bioactive small molecules, particularly those of low molecular weight that bind with sufficient affinity and specificity. In this report, we developed a platform to address this challenge, affording a novel bioactive interaction. An RNA-focused small-molecule fragment collection (n = 2500) was constructed by analyzing features in all publicly reported compounds that bind RNA, the largest collection of RNA-focused fragments to date. The RNA-binding landscape for each fragment was studied by using a library-versus-library selection with an RNA library displaying a discrete structural element, probing over 12.8 million interactions, the greatest number of interactions between fragments and biomolecules probed experimentally. Mining of this dataset across the human transcriptome defined a drug-like fragment that potently and specifically targeted the microRNA-372 hairpin precursor, inhibiting its processing into the mature, functional microRNA and alleviating invasive and proliferative oncogenic phenotypes in gastric cancer cells. Importantly, this fragment has favorable properties, including an affinity for the RNA target of 300 ± 130 nM, a molecular weight of 273 Da, and quantitative estimate of drug-likeness (QED) score of 0.8. (For comparison, the mean QED of oral medicines is 0.6 ± 0.2). Thus, these studies demonstrate that a low-molecular weight, fragment-like compound can specifically and potently modulate RNA targets.

Design, synthesis, cytotoxicity, and molecular docking studies of 1-(4-methoxyphenyl)-N-substituted phenyl-1H-1,2,3-triazole-4-carboxamide derivatives

A new series of 1-(4-methoxyphenyl)-N-substituted phenyl-1H-1,2,3-triazole-4-carboxamide derivates (4A–4N) have been synthesized in excellent yields and structures were characterized by spectral techniques like 1H-NMR, 13C-NMR, LC-MS, and FT-IR. The newly synthesized derivatives were evaluated for anticancer activity against breast cancer cell lines MCF-7 and MDA-MB-231. Among them, compound 4H (IC50 = 13.11 and 23.61 μM) and compound 4M (IC50 = 11.55–31.87 μM) shows good cytotoxicity activity toward both cell line, while compounds 4B (IC50 = 9.48 μM), 4I (IC50 = 7.11 μM), and 4J (IC50 = 8.27 μM) showed promising cytotoxicity against MCF-7 cell line as compared with standard (Doxorubicin). Also explored docking study with binding mode of interactions and active site in EGFR tyrosinse (PDB ID: 2J5F) proteins and molecular docking study shows very good interaction with the tyrosine kinase active site. In addition to this targeted compounds were studied the pharmacokinetics and the compounds were follow Lipinski’s rule of five as well as compounds have acceptable good drug-likeness score properties.

In vitro and in silico binding studies of phytochemical isochroman with calf thymus DNA using multi-spectroscopic and computational modelling techniques

A wide range of therapeutic molecules uses deoxyribonucleic acid (DNA) as an intracellular target. The interaction of small molecules to DNA is a key feature in pharmacology and plays a vital role in the development of novel and more efficient drugs with increased selective activity and enhanced therapeutic effectiveness. Isochroman (IC) is a constituent of Olea europea plant, which has been shown to exhibit several beneficial pharmacological activities. At present, its interaction studies using calf thymus DNA (ct-DNA) have not been explained. A set of multi-spectroscopic techniques has been performed to determine the interaction mechanism of isochroman with ct-DNA. Absorption spectra and quenching in fluorescence studies show that isochroman and ct-DNA form a complex. The static mode of quenching was determined by the Stern-Volmer plot. The value of binding constant, Kb = 4.0 × 103 M−1 revealed moderate type of binding. Effects of single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) and ionic strength were studied to examine the isochroman binding to ct-DNA. Potassium iodide (KI) quenching effects and competitive binding studies clearly showed that isochroman binds in the minor groove of ct-DNA. Circular dichroic and DNA melting experiments also confirmed these results. The experimental outputs were further corroborated via in silico computational modelling studies. Lipinski’s rule of 5 and SwissADME showed drug-likeness and oral bioavailability scores. Protox ІІ online software predicts oral and organ toxicity. Communicated by Ramaswamy H. Sarma

In-silico design and screening of cephalosporin derivatives for their inhibitory potential against Haemophilus influenza

Antibiotics kill bacteria by blocking essential metabolic processes which prevent them from reproducing thereby allowing the immune system to fight bacterial infections. However, the emergence and the quick spread of bacterial resistance against clinically approved antibiotics have become alarming. This necessitates the development of novel treatment options and alternative antimicrobial therapies in the fight against bacterial infections. In this study, we aim to virtually design and carry out in-silico studies to identify a cephalosporin derivative with inhibitory potential against Haemophilus influenza. Data Warrior software, Discovery studio software, PyRx tool, Swiss ADME web tool, and ProTox-II web tool were used to screen the cephalosporin derivatives. Initially, 17 cephalosporin derivatives were preliminarily screened for their toxicity followed by in-silico ADME studies. Among the cephalosporin derivatives, C1, C6, and C12 were found to be the potential drug-like molecules with binding energies of -7.4 kcal/mol, -7.1 kcal/mol, and -7.1 kcal/mol, respectively. In particular, C1 was predicted to have a moderate biological activity with a high bioavailability score. Based on the ADME profile, toxicity, binding energy, drug-likeness, and drug score, we conclude C1 (‘F’ at the 3rd position) as the potential lead molecule to inhibit H. influenza.

In silico Toxicity Prediction on Novel Antiobesity Drug Using Cheminformatics Approaches

Background: Obesity is a major problem that many individuals suffer presently. Using in silico Tools and Servers, we propose to build a novel chemical drug and validate its oral toxicity effect. Our strategy entails first picking an existing anti-obesity drug 2-methyl-1-phenylpropan-2- amine as well as an agent which is then coupled with the existing drug lithium; bis(trimethylsilyl) utilizing cheminformatics software and tools. Materials and Methods: Pharmacokinetic studies of the compounds were analyzed to show Lipinski’s rules via in silico methods of Molinspiration. The drug likeness calculations were also carried out in Molinspiration analyses. Some toxicity risk parameters were quantified using ProTox II. The results will be thoroughly examined, including calculations of the intended compound’s molecular characteristics and bioactivity. Results: The calculations obtained through Molinspiration show that it has a good drug likeness score with the LogP value of 2.34 and TPSA valued at 26.02. The toxicity prediction was done with the help of the website ProTox II, the website was used to examine toxicology in organisms, organs, cells, and genes, as well as molecular mechanisms of toxicity. The drug compound according to the projected LD50 values, it is non-toxic and safe for various organs and pathways. The mechanism of toxicity of the compound was obtained as class III. The drug has good Lipophilicity and acceptable ADMET properties; The projected developed drug compound demonstrates that the intended molecule has no hazardous effect. Advanced molecular imaging technologies will be used to visualise the structures in 3D. Conclusion: In silico study indicates that the proposed chemical compounds had no negative effects and has the potential to be used as an obesity therapy agent. This medicine can also be utilised to conduct more docking research on human protein targets associated with obesity.

Synthesis and biological evaluation of substituted aurone derivatives as potential tyrosinase inhibitors: in vitro, kinetic, QSAR, docking and drug-likeness studies

Tyrosinase enzyme plays an essential role in melanin biosynthesis and enzymatic browning of fruits and vegetables. To discover potent tyrosinase inhibitors, the present studies were undertaken. In this context, synthetic aurone derivatives 26–50 were designed, synthesized, and structurally elucidated by various spectroscopic techniques including IR, UV, 1H- & 13C-NMR and mass spectrometry. The target compounds 26–50 were screened for their anti-tyrosinase inhibitory potential, and thus kinetic mechanism was analyzed by Lineweaver-Burk plots. All target compounds exhibited good to excellent IC50 values in the range of 7.12 ± 0.32 μM to 66.82 ± 2.44 μM. These synthesized aurone derivatives were found as potent tyrosinase inhibitors relative to the standard kojic acid (IC50 = 16.69 ± 2.81 μM) and the compound 39 inhibited tyrosinase non-competitively (Ki = 11.8 μM) by forming an enzyme-inhibitor complex. The binding modes of these molecules were ascribed through molecular docking studies against tyrosinase protein (PDB ID: 2Y9X). The quantitative structure-activity relationship studies displayed a good correlation between 26–50 structures and their anti-tyrosinase activity (IC50) with a correlation coefficient (R2) of 0.9926. The computational studies were coherent with experimental results and these ligands exhibited good binding values against tyrosinase and interacted with core residues of target protein. Moreover, the drug-likeness analysis also showed that some compounds have a linear correlation with Lipinski’s rule of five, indicating good drug-likeness and bioactivity scores for pharmacological targets. Communicated by Ramaswamy H. Sarma

Hydroxyalkynyl uracil derivatives as NNRTIs against HIV-1: in silico predictions, synthesis, docking and molecular dynamics simulation studies

To improve rationally the efficacy of the non-nucleoside human immunodeficiency virus (HIV-1) inhibitors, it is important to have a precise and detailed understanding of the HIV-1 reverse transcriptase (RT) and inhibitor interactions. For the 1-[(2-hydroxyethoxy) methyl]-6-(phenylthio) thymine (HEPT) type of nucleoside reverse transcriptase inhibitors (NNRTIs), the H-bond between the N-3H of the inhibitor and the backbone carbonyl group of K101 represents the major hydrophilic interaction. This H-bond contributes to the NNRTI binding affinity. The descriptor analyses of different uracil derivatives proved their good cell internalization. The bioactivity score reflected higher drug likeness score and the ligands showed interesting docking results. All molecules were deeply buried and stabilized into the allosteric site of HIV-1 RT. For majority of molecules, residues Lys101, Lys103, Tyr181 and Tyr188 were identified as key protein residues responsible for generation of H-bond and major interactions were similar to all known NNRTIs while very few molecules interacted with residues Phe227 and Tyr318. The TOPKAT protocol available in Discovery Studio 3.0 was used to predict the pharmacokinetics of the designed uracil derivatives in the human body. The molecular dynamics (MD) and post-MD analyses results reflected that the complex HIVRT:5 appeared to be more stable than the complex HIVRT:HEPT, where HEPT was used as reference. Different uracil derivatives have been synthesized by using uracil as starting material and commercially available propargyl bromide. The N-1 derivative of uracil was further reacted with sodamide and different aldehydes/ketones bearing alkyl and phenyl ring to obtain hydroxyalkynyl uracil derivatives as NNRTIs. Communicated by Ramaswamy H. Sarma

Rutin bioconjugates as potential nutraceutical prodrugs: An in vitro and in ovo toxicological screening.

Rutin (RUT) is considered one the most attractive flavonoids from a therapeutic perspective due to its multispectral pharmacological activities including antiradical, anti-inflammatory, antiproliferative, and antimetastatic among others. Still, this compound presents a low bioavailability what narrows its clinical applications. To overcome this inconvenience, the current paper was focused on the synthesis, characterization, and toxicological assessment of two RUT bioconjugates obtained by enzymatic esterification with oleic acid (OA) and linoleic acid (LA)—rutin oleate (RUT-O) and rutin linoleate (RUT-L), as flavonoid precursors with improved physicochemical and biological properties. Following the enzymatic synthesis in the presence of Novozyme® 435, the two bioconjugates were obtained, their formation being confirmed by RAMAN and FT-IR spectroscopy. The in vitro and in ovo toxicological assessment of RUT bioconjugates (1–100 µM) was performed using 2D consecrated cell lines (cardiomyoblasts - H9c2(2-1), hepatocytes—HepaRG, and keratinocytes—HaCaT), 3D reconstructed human epidermis tissue (EpiDerm™), and chick chorioallantoic membranes, respectively. The results obtained were test compound, concentration—and cell-type dependent, as follows: RUT-O reduced the viability of H9c2(2-1), HepaRG, and HaCaT cells at 100 µM (to 77.53%, 83.17%, and 78.32%, respectively), and induced cell rounding and floating, as well as apoptotic-like features in the nuclei of all cell lines, whereas RUT-L exerted no signs of cytotoxicity in all cell lines in terms of cell viability, morphology, and nuclear integrity. Both RUT esters impaired the migration of HepaRG cells (at 25 µM) and lack irritative potential (at 100 µM) in vitro (tissue viability >50%) and in ovo (irritation scores of 0.70 for RUT-O, and 0.49 for RUT-L, respectively). Computational predictions revealed an increased lipophilicity, and reduced solubility, drug-likeness and drug score of RUT-O and RUT-L compared to their parent compounds—RUT, OA, and LA. In conclusion, we report a favorable toxicological profile for RUT-L, while RUT-O is dosage-limited since at high concentrations were noticed cytotoxic effects.

Identification of novel mycocompounds as inhibitors of PI3K/AKT/mTOR pathway against RCC

PI3K/AKT/mTOR pathway is one of the frequently disrupted signaling pathways in renal cell carcinoma (RCC) that plays a significant role in tumor formation, disease progression and therapeutic resistance. Therefore, novel natural molecules targeting the critical proteins of this pathway will provide the best alternative to existing drugs, which are toxic and develops resistance. Recent studies have recognized the anti-cancer therapeutic potential of mycocompounds. The current study is focused on screening various mycocompounds from Astraeus hygrometricus against key cancer signaling proteins phosphoinositide 3‐kinase (PI3K), protein kinase B, PKB (AKT1) and mammalian target of rapamycin (mTOR). We also studied in-silico cancer cells cytotoxicity and ADMET (absorption, distribution, metabolism, excretion and toxicity) profiles to elucidate the molecular mechanism against RCC and also to uncover the pharmacokinetic profile of these compounds. Astrakurkurone and Ergosta-4,6, 8-(14) 22-tetraene-3-one were the two most efficacious compounds with highest interaction scores and bonding. These compounds were both active against RCC4 and VMRC-RCZ cell lines of RCC. The ADME profiles of both were satisfactory based on druglikeness and bioavailability score criteria. Thus, this proposed study identified astrakurkurone and ergosta-4,6, 8-(14) 22-tetraene-3-one as potential anticancer drug candidates, and provides comparative structural insight into their binding to the 3 protein kinases.

Virtual screening of flavonoids from Chamaecrista genus: ADME and pharmacokinetic properties, interactions of flavonoid–DNA complex by molecular docking and molecular dynamics

This research aimed to conduct an in silico study of compounds, mainly flavonoids, that are found in several plants, including the species of the Chamaecrista genus. The ADME properties, the drug-likeness score and properties of Lipinski and Veber rules of the molecules were determined using online databases. Based on the predicted properties, four flavonoids, apigenin, fisetin, luteolin and ononin were selected for molecular docking and dynamic simulations to study their interactions with DNA (PDB ID: 1BNA). The molecular docking showed that ononin has a high affinity for B-DNA, exhibiting a ΔG value of −9.3 kcal mol−1, compared with the other flavonoids. The molecular dynamic simulations of the flavonoid–DNA complexes showed that the flavonoids interacted with DNA by hydrogen bonding, hydrophobic interaction and π-stacking. The flavonoid ononin showed the best interaction energy value of −291.3490 kJ mol−1, compared with the other flavonoids. Communicated by Ramaswamy H. Sarma