Prediction Of Pharmacokinetic Properties Research Articles

Design of new α-glucosidase inhibitors based on the bis-4-hydroxycoumarin skeleton: Synthesis, evaluation, and in silico studies

In this work, we have reported the design, synthesis, in vitro, and in silico enzymatic evaluation of new bis-4-hydroxycoumarin-based phenoxy-1,2,3-triazole-N-phenylacetamide derivatives 5a-m as potent α-glucosidase inhibitors. All the synthesized analogues showed high inhibition effects against α-glucosidase (IC50 values ranging between 6.0 ± 0.2 and 85.4 ± 2.3 µM) as compared to the positive control acarbose (IC50 = 750.0 ± 0.6 µM). Among the newly synthesized compounds 5a-m, 2,4-dichloro-N-phenylacetamide derivative 5i with inhibition effect around 125-folds more than the acarbose was identified as the most potent entry. A structure–activity relationship (SAR) study about the title compounds 5a-m demonstrated that the inhibition effects of these compounds depend on the pattern of substitution on the N-phenylacetamide ring. The interaction modes and binding energies in the active site of enzyme of the important analogues (in term of SAR study) were evaluated through molecular docking study. Molecular dynamics and prediction of pharmacokinetic properties and toxicity of the most potent compound 5i also evaluated and the obtained data was compared with the acarbose.

Synthesis, In vivo, and In silico Evaluation of New Pyrazoline-Benzothiazole Conjugates as Antiepileptic Agents.

New 2-(4-benzothiazol-2-yl-phenoxy)-1-(3,5-diphenyl-4,5-dihydro-pyrazol-1-yl)-ethanones (9a-o) have been designed and synthesized. All the synthesized compounds were characterized by thin layer chromatography and spectral analysis. The antiepileptic potential of the synthesized compounds has been tested by following standard animal screening models, including maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) models. The neurotoxic and antidepression effects of the synthesized compounds were checked by utilizing rotarod apparatus, and motor impairment test (by actophotometer) respectively. The study concluded that compounds 9c, 9d, 9f, 9i, 9n, and 9o possessed good antiepileptic potential compared to standard drugs like carbamazepine and phenytoin. The results of the rotarod performance test also established them without any neurotoxicity. The motor impairment test revealed that the synthesized compounds are also good antidepressants. In-silico studies have been performed for calculation of pharmacophore pattern, prediction of pharmacokinetic properties which determine the eligibility of synthesized compounds as orally administered molecules and interactions with the target proteins. The result of in-silico studies reinforced results obtained by in vivo study of the synthesized compounds and their possible mechanism of antiepileptic action i. e. via inhibiting voltage-gated sodium channels (VGSCs) and gamma-aminobutyric acid-A receptor.

Computational Insight into the Mechanism of Action of DNA Gyrase Inhibitors; Revealing a New Mechanism.

Discovery of novel antimicrobial agents is in need to deal with antibiotic resistance. Elucidating the mechanism of action for established drugs contributes to this endeavor. DNA gyrase is a therapeutic target used in the design and development of new antibacterial agents. Selective antibacterial gyrase inhibitors are available; however, resistance development against them is a big challenge. Hence, novel gyrase inhibitors with novel mechanisms are required. In this study, the mechanism of action for selected DNA gyrase inhibitors available was carried out through molecular docking and molecular dynamics (MD) simulation. In addition, pharmacophore analysis, density functional theory (DFT) calculations, and computational pharmacokinetics analysis of the gyrase inhibitors were performed. This study demonstrated that all the DNA gyrase inhibitors investigated, except compound 14, exhibit their activity by inhibiting gyrase B at a binding pocket. The interaction of the inhibitors at Lys103 was found to be essential for the binding. The molecular docking and MD simulation results revealed that compound 14 could act by inhibiting gyrase A. A pharmacophore model that consisted of the features that would help the inhibition effect was generated. The DFT analysis demonstrated 14 had relatively high chemical stability. Computational pharmacokinetics analysis revealed that most of the explored inhibitors were estimated to have good drug-like properties. Furthermore, most of the inhibitors were found to be non-mutagenic. In this study, mode of action elucidation through molecular docking and MD simulation, pharmacophore model generation, pharmacokinetic property prediction, and DFT study for selected DNA gyrase inhibitors were carried out. The outcomes of this study are anticipated to contribute to the design of novel gyrase inhibitors.

Abstract 4496: A computational initiative to determine the role of dietary polyphenols against oncogenic KRAS mutants

Abstract Introduction: Two oncogenic driver mutants (G12C and G14D) of KRAS have been reported to drive tumorigenesis in several cancers and targeting the switch I/II domain of mutant KRAS oncoprotein can be an efficient strategy for inhibiting the mutated KRAS-driven tumors. Modern clinical therapeutics are often associated with several adverse side effects and the eventual development of multi-drug resistance. Herein, exhaustive computational strategies are employed in designing dietary polyphenol-based small molecule inhibitors against such oncogenic KRAS tumors. Methodology: Integrated bioinformatics strategies such as pharmacokinetic property prediction, analysis of medicinal chemistry profile, density functional theory (DFT) study, molecular docking, molecular dynamics simulation (MDS) and principal component analysis were performed to screen 930 dietary polyphenols to identify potent inhibitors against the G12C and G14D mutants. Sotorasib, an FDA-approved KRAS chemotherapeutic inhibitor was used as a reference drug in this study. Results: Out of the 930 dietary polyphenols screened, based on the properties of pharmacokinetic descriptors and medicinal chemistry profile, 512 molecules were shortlisted for further studies. Five dietary polyphenols viz. Quercetin, Luteolin, Peonidin 3-O-glucoside, Myricetin, and Kaempferol identified via DFT and MDS exhibited the highest binding affinity and optimum energy profiles with our selected mutants G12C and G14D. An all-atom MDS study executed over 200 ns each revealed that Quercetin, Luteolin, and Peonidin 3-O-glucoside show favorable thermodynamic stability with significantly less conformational perturbations with G12C mutant. By contrast, mutant G12D complexed with Kaempferol and Myricetin exhibited the least thermodynamic flexibility and stable backbone trajectory, when compared to clinically standardized KRAS inhibitor Sotorasib. The efficient and higher binding stability of the polyphenols targeting the KRAS mutants, G12C and G14D switches I/II is mainly attributed to the formation of hydrogen bonds and other hydrophobic interactions at the molecular level. All five evaluated polyphenols qualified the parameters of cell-line cytotoxicity hinting at remarkable chemotherapeutic efficacy. Conclusion: Computer-aided drug designing performed here aided the identification of natural dietary polyphenolic inhibitors as potential drug candidates exhibiting stable binding dynamics like Sotorasib, which thus awaits validation through further in-vitro analyses in inhibiting KRAS-driven tumorigenesis. Citation Format: Prarthana Chatterjee, Rohit Karn, Sohini Chakraborty, Saptarshi Sinha, Pradipta Ghosh, Satarupa Banerjee. A computational initiative to determine the role of dietary polyphenols against oncogenic KRAS mutants [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4496.

Antioxidant and antidiabetic activity and phytoconstituents of lichen extracts with temperate and polar distribution.

The objective of this research was to characterize the chemical composition of ethanolic extracts of the lichen species Placopsis contortuplicata, Ochrolechia frigida, and Umbilicaria antarctica, their antioxidant activity, and enzymatic inhibition through in vitro and molecular docking analysis. In total phenol content, FRAP, ORAC, and DPPH assays, the extracts showed significant antioxidant activity, and in in vitro assays for the inhibition of pancreatic lipase, α-glucosidase, and α-amylase enzymes, together with in silico studies for the prediction of pharmacokinetic properties, toxicity risks, and intermolecular interactions of compounds, the extracts evidenced inhibitory potential. A total of 13 compounds were identified by UHPLC-ESI-QTOF-MS in P. contortuplicata, 18 compounds in O. frigida, and 12 compounds in U. antarctica. This study contributes to the knowledge of the pool of bioactive compounds present in lichens of temperate and polar distribution and biological characteristics that increase interest in the discovery of natural products that offer alternatives for treatment studies of diseases related to oxidative stress and metabolic syndrome.

Benzenesulfonamide based 1,3,4-oxadiazole derivatives: synthesis, pharmacokinetic property prediction, bovine carbonic anhydrase activity and molecular docking studies

Sulphur-containing compounds are highly significant as they can possess a variety of biological activities that make them useful for pharmacological purposes and for the mechanism by which drugs such as antibiotics bind to and disrupt bacterial cell walls. In this study, novel thioalkyl substituted-1,3,4 oxadiazole-bearing sulfonamide compounds have been successfully synthesized and characterized by 1HNMR, 13CNMR, IR and elemental analysis. The effects of different thioalkyl groups on the 1,3,4 oxadiazole group, the IC50 value for Bovine Carbonic Anhydrase (BCA) found by in vitro, density functional theory (DFT) calculations, pharmacokinetics prediction and molecular docking are aimed to reveal the interactions on BCA. Firstly, pharmacokinetic predictions of thioalkyl substituted 1,3,4-oxadiazole compounds were generated to predict their potential hazards. Secondly, the predicted molecular docking data and 2D interaction were analyzed based on the best configuration from DFT optimization. Finally, the inhibition against BCA was analyzed in vitro and compared with the theoretical data. The compound (5o) has the best value such as IC50 = 51.80 µM, HOMO–LUMO (ΔE 4.488 Ev), ΔG −7.69 kcal/mol, Full fitness −2152.72 FF and predicted toxicity results showed no significant results except hepatotoxicity.

Analisis interaksi senyawa guvakolin dan homoarekolin terhadap MAO-A secara in silico

This study was aimed to conduct the inhibitory activity of the MAO-A enzyme (PDB ID: 2Z5Y) by the active compounds of Areca catechu L. The method used is in silico approach using AutoDock Vina, PyMol, and Discovery Studio (DSV). The prediction of pharmacokinetic properties and drug-likeness used the Swiss-ADME online website. The docking results exhibited guvacoline has a binding free energy value of -5.9 kcal / mol compared to homoarecoline (-5.4 kcal / mol), and positive control (-5.7 kcal / mol). Guvacoline compounds have a hydrogen bond in the active site of the enzyme. Areca nut compounds obtained good results on pharmacokinetic properties, but not so good on the BBB parameter. The compounds obtained good results for the parameters of the Lipinski, Veber rule, bioavailability score, but the guvacoline compounds could not meet Ghose's rule. The results of the bioavailability radar showed that the compounds have properties as oral drug.

Analisis Potensi Farmakokinetik dan Toksisitas Pada Curcumin (Curcuma xanthorrhiza) Sebagai Brightening Terhadap Reseptor Protein Tirosinase Secara in Silico

Tyrosinase enzyme is an enzyme that plays an important role in melanin synthesis. This enzyme will oxidize the amino acid L-tyrosine into L- 3,4 dihydroxyphenylalanine (L-DOPA) and convert L-DOPA into DOPAquinone. Tyrosinase protein from Bacillus megaterium in complex with inhibitor kojic acid is the target protein that will interact with the ligand (Drug Candidate), Temulawak (Curcuma xanthorrhiza) is one of the medicinal plants of the Zingiberaceae family which is widely grown and used as a raw material for traditional medicine in Indonesia, the main content in Temulawak is curcumin which has antioxidant properties. Antioxidants in curcumin content can be used as ingredients for whitening preparations. In silico tests are used to predict pharmacokinetic activity and toxicity by docking using the Molegro Virtual Docker computer program. The receptor used was Protein Tyrosinase PDB code 3NQ1 with ligand KOJ_B_1351. Prediction of pharmacokinetic properties (ADME) and toxicity of Curcumin and Kojic Acid was performed using the pkCSM online tool program. Data analysis was performed by comparing the binding energy of docking results between Curcumin, Kojic Acid, and ligand on the target receptor. The in silico test results showed that the binding energy of Kurkumin =-142.766 kcal/mol, Kojic Acid = -60.6899 kcal/mol, and KOJ_B_1351 ligand =-62.266 kcal/mol. The results of in silico tests using the pkCSM online tool program show that Kurkumin compounds have good pharmacokinetic properties, and cause relatively low toxicity, and can be used as candidates for whitening materials.

An investigation of binding interactions of tumor-targeted peptide conjugated polyphenols with the kinase domain of ephrin B4 and B2 receptors.

Recent studies have shown that Ephrin receptors may be upregulated in several types of cancers including breast, ovarian and endometrial cancers, making them a target for drug design. In this work, we have utilized a target-hopping approach to design new natural product-peptide conjugates and examined their interactions with the kinase-binding domain of EphB4 and EphB2 receptors. The peptide sequences were generated through point mutations of the known EphB4 antagonist peptide TNYLFSPNGPIA. Their anticancer properties and secondary structures were analyzed computationally. Conjugates of most optimum of peptides were then designed by binding the N-terminal of the peptides with the free carboxyl group of the polyphenols sinapate, gallate and coumarate, which are known for their inherent anticancer properties. To investigate if these conjugates have a potential to bind to the kinase domain, we carried out docking studies and MMGBSA free energy calculations of the trajectories based on the molecular dynamics simulations, with both the apo and the ATP bound kinase domains of both receptors. In most cases binding interactions occurred within the catalytic loop region, while in some cases the conjugates were found to spread out across the N-lobe and the DFG motif region. The conjugates were further tested for prediction of pharmacokinetic properties using ADME studies. Our results indicated that the conjugates were lipophilic and MDCK permeable with no CYP interactions. These findings provide an insight into the molecular interactions of these peptides and conjugates with the kinase domain of the EphB4 and EphB2 receptor. As a proof of concept, we synthesized and carried out SPR analysis with two of the conjugates (gallate-TNYLFSPNGPIA and sinapate-TNYLFSPNGPIA). Results indicated that the conjugates showed higher binding with the EphB4 receptor and minimal binding to EphB2 receptor. Sinapate-TNYLFSPNGPIA showed inhibitory activity against EphB4. These studies reveal that some of the conjugates may be developed for further investigation into in vitro and in vivo studies and potential development as therapeutics.

QSAR Study, Molecular Docking, and Pharmacokinetic Analysis of Substituted Dihydropyrimidinone as ErbB2 Inhibitors

ErbB2 is considered to be the preferred dimerization partner among the ErbB receptor tyrosine kinase (RTK) family. They are implicated in the development and progression of several cancer types, majorly breast cancer-related maladies. In the current study, quantitative structure-activity relationship (QSAR), molecular docking approaches and prediction of pharmacokinetic properties were utilized to identify promising ErbB2 inhibitors from a series of dihydropyrimidinone (DHPM) derivatives. The results indicated that the QSAR models of ErbB2 inhibitory activity is robust and has a very good prediction capacity, as exhibited by the value of R which is 0.9194. Furthermore, 6 compounds were shortlisted with potentially high biological activity. These compounds were subjected to drug likeliness, molecular docking and pharmacokinetic evaluations which indicated that the compounds are orally bioavailable and exhibit suitable proficiency as ErbB2 antagonists.

MOLECULAR DOCKING AND COMPUTATIONAL PHARMACOKINETIC STUDY OF SOME NOVEL COUMARIN–BENZOTHIAZOLE SCHIFF’S BASE FOR ANTIMICROBIAL ACTIVITY

Objective: The present study discusses molecular docking of some novel coumarin–benzothiazole Schiff bases and the prediction of pharmacokinetic properties of potent molecules by the computational method. Methods: Five protein targets were selected for the study and their structures were taken from RCSB Protein Data Bank in PDB format. Preparation of proteins was done using Discovery Studio 2021 Client. A total of twenty derivatives were drawn using ChemDraw 20.0 and saved in Mol format. Molecular docking was performed using PyRx software. Docking results were visualized by Discovery Studio 2021 Client. The pharmacokinetic properties of the best compounds were determined using the pkCSM tool. Results: All twenty derivatives were docked against the five proteins, namely DNA Ligase (PDB ID: 3PN1), Topoisomerase (PDB ID: 3TTZ), Sterol demethylase (PDB ID: 5FSA), Enoyl-acyl-carrier protein (PDB ID: 1BVR) and Glutamate racemase (PDB ID: 5HJ7). The compound JJB18 has shown the best binding score against DNA ligase (-10.7 kcal/mol), Glutamate racemase (-8.4 kcal/mol), and Enoyl-acyl-carrier protein (-10.8 kcal/mol). Further, compound JJB19 has shown the best score for fungal sterol demethylase (-10.6 kcal/mol) and compound JJB20 towards topoisomerase (-9.4 kcal/mol) than the standard drugs. The physicochemical properties of potent derivatives were also reported. Conclusion: Molecular Docking study indicates that coumarin–benzothiazole Schiff bases may be effective inhibitors for the different microbial proteins. Additionally, in silico ADMET studies predicts drug-like features. Hence, these compounds may be considered lead molecules and further investigation of their analogues may help in the development of novel drugs for the treatment of microbial diseases.

Potensi Senyawa Turunan Xanton dari Kulit Buah Manggis (Garcinia mangostana L.) Sebagai Inhibitor Protein Mycobacterium tuberculosis: Studi In Silico

Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis infection that attacks the lungs. Tuberculosis is a dangerous disease that can cause death. In overcoming it, a safe and effective treatment is needed so that this disease can be cured. The purpose of this study was to determine the potential activity of the active compounds derived from xanthones contained in the mangosteen rind as an inhibitor of Mycobacterium tuberculosis protein with the comparison compound Isoniazid. The active compounds used in this study were α-mangostin, β-mangostin, γ-mangostin, garsinon, gartanin, and 8-deoxygartanin. This research uses the molecular docking method with Yasara, MarvinSketch, PubChem, PDB, and Plants 1.1 software. The results showed that the Gibss energy produced by each test ligand had a difference value, either lower or higher than the native ligand protein of Mycobacterium tuberculosis. Lipinski screening was done to make it easier to determine a molecule or compound based on its permeability and absorption properties. The results showed that gartanin and 8-deoxygartanin complied with Lipinski's rules. Prediction of pharmacokinetic properties and toxicity was carried out using the pkCSM website and can be concluded that gartanin and 8-deoxygartanin compounds have good pharmacokinetic properties and low toxicity.

Chromatographic profile, in silico and in vivo study of the pharmacokinetic and toxicological properties of major constituent present in kefir, the kefiran.

Kefiran is a polysaccharide present in kefir grains that have been widely explored due to its potential health benefits. The objective of this work was to characterize and quantify the components present in the ethanolic extract of milk kefir grains; to study its pharmacokinetic and toxicological properties in silico and evaluate the acute toxicity of the kefiran in zebrafish. The prediction of pharmacokinetic properties was performed by QikProp software. In silico toxicity assessment was performed using the DEREK (deductive estimate of risk from existing knowledge) software. In the chromatographic, kefiran was identified as the major component. Results showed that the kefiran had low human oral absorption and intestinal absorption its due poor solubility profile; low logP value, indicating its lipophilicity and the low MDCK and Caco-2 cells permability, and unable to cross the blood-brain barrier. Kefiran did not present any structural warning for in silico toxicity. In zebrafish, the dose of 2,000mg/kg of kefiran produced nonsignificant alterations in the analyzed organs. It can be said then that kefiran has an acceptable degree of safety for use in the development of drugs or functional foods. Further research such as in vivo testing to confirm its pharmacological potential is currently underway.

Potential Biological Targets Prediction, ADME Profiling, and Molecular Docking Studies of Novel Steroidal Products from Cunninghamella blakesleana.

New potential biological targets prediction through inverse molecular docking technique is another smart strategy to forecast the possibility of compounds being biologically active against various target receptors. In this case of designed study, we screened our recently obtained novel acetylenic steroidal biotransformed products [(1) 8-β-methyl-14-α-hydroxyΔ4tibolone (2) 9-α-HydroxyΔ4 tibolone (3) 8-β-methyl-11-β-hydroxyΔ4tibolone (4) 6-β-hydroxyΔ4tibolone, (5) 6-β-9-α-dihydroxyΔ4tibolone (6) 7-β-hydroxyΔ4tibolone)] from fungi Cunninghemella Blakesleana to predict their possible biological targets and profiling of ADME properties. The prediction of pharmacokinetic properties, membrane permeability, and bioavailability radar properties was carried out by using Swiss target prediction and Swiss ADME tools, respectively. These metabolites were also subjected to predict the possible mechanism of action along with associated biological network pathways by using Reactome database. All the six screened compounds possessed excellent drug ability criteria and exhibited exceptionally excellent non-inhibitory potential against all five isozymes of the CYP450 enzyme complex, including CYP1A2, CYP2C19, CYP2C9, CYP2D6, and CYP3A4. All the screened compounds are lying within the acceptable pink zone of bioavailability radar and showing excellent descriptive properties. Compounds [1-4 & 6] are showing high BBB (Blood Brain Barrier) permeation, while compound 5 is exhibiting high HIA (Human Intestinal Absorption) property of (Egan Egg). In conclusion, the results of this study smartly reveal that in-silico based studies are considered to provide robustness towards a rational drug design and development approach; therefore, in this way, it helps to avoid the possibility of failure of drug candidates in the later experimental stages of drug development phases.

New Pharmacokinetic and Microbiological Prediction Equations to Be Used as Models for the Search of Antibacterial Drugs.

Currently, the development of resistance of Enterobacteriaceae bacteria is one of the most important health problems worldwide. Consequently, there is a growing urge for finding new compounds with antibacterial activity. Furthermore, it is very important to find antibacterial compounds with a good pharmacokinetic profile too, which will lead to more efficient and safer drugs. In this work, we have mathematically described a series of antibacterial quinolones by means of molecular topology. We have used molecular descriptors and related them to various pharmacological properties by using multilinear regression (MLR) analysis. The regression functions selected by presenting the best combination of a number of quality and validation metrics allowed for the reliable prediction of clearance (CL), and minimum inhibitory concentration 50 against Enterobacter aerogenes (MIC50Ea) and Proteus mirabilis (MIC50Pm). The obtained results clearly reveal that the combination of molecular topology methods and MLR provides an excellent tool for the prediction of pharmacokinetic properties and microbiological activities in both new and existing compounds with different pharmacological activities.

In silico screening-based discovery of inhibitors against glycosylation proteins dysregulated in cancer

Targeting enzymes associated with the biosynthesis of aberrant glycans is an under-utilized strategy in discovering potential inhibitors or drugs against cancer. The formation of cancer-associated glycans is mainly due to the dysregulated expression of glycosyltransferases and glycosidases, which play crucial roles in maintaining cellular structure and function. We screened a database of more than 14,000 compounds consisting of natural products and drugs for inhibition against four glycosylation enzymes - Alpha1-6FucT, ST6Gal1, ERMan1, and GlcNAcT-V. The top inhibitors identified against each enzyme were subsequently analyzed for potential binding against all four enzymes. In silico screening results show several promising candidates that could potentially inhibit all four enzymes: (1) Amb20622156 (demethylwedelolactone) [ERMan1: −9.3 kcal/mol; Alpha1-6FucT: −7.3 kcal/mol; ST6Gal1: −8.4 kcal/mol; GlcNAcT-V: −7.2 kcal/mol], (2) Amb22173588 (1,2-dihydrotanshinone I) [ERMan1: −9.3 kcal/mol; Alpha1-6FucT: −6.1 kcal/mol; ST6Gal1: −9.2 kcal/mol; GlcNAcT-V: −7.9 kcal/mol], and (3) Amb22173591 (tanshinol B) [ERMan1: −9.3 kcal/mol; Alpha1-6FucT: −6.0 kcal/mol; ST6Gal1: −9.8 kcal/mol; GlcNAcT-V: −7.7 kcal/mol]. Drug-enzyme active site residue interaction analyses show that the putative inhibitors form non-covalent bonding interactions with key active site residues in each enzyme, suggesting critical target residues in the four enzymes’ active sites. Furthermore, pharmacokinetic property prediction analysis using pkCSM indicates that all of these inhibitors have good ADMETox properties (i.e., log P < 5, Caco-2 permeability > 0.90, intestinal absorption > 30%, skin permeability>-2.5, CNS permeability <-3, maximum tolerated dose < 0.477, minnow toxicity<-0.3). The in silico docking approach to glycosylation enzyme inhibitor prediction could help guide and streamline the discovery of novel inhibitors against enzymes involved in aberrant protein glycosylation. Communicated by Ramaswamy H. Sarma

Comparative Study for Prediction of Low and High Plasma Protein Binding Drugs by Various Machine Learning-Based Classification Algorithms

&lt;p&gt;In the drug discovery path, most drug candidates failed at the early stages due to their pharmacokinetic behavior in the system. Early prediction of pharmacokinetic properties and screening methods can reduce the time and investment for lead discoveries. Plasma protein binding is one of these properties which has a vital role in drug discovery and development. The focus of the current study is to develop a computational model for the classification of Low Plasma Protein Binding (LPPB) and High Plasma Protein Binding (HPPB) drugs using machine learning methods for early screening of molecules through WEKA. Plasma protein binding drugs data was collated from the Drug Bank database where 617 drug candidates were found to interact with plasma proteins, out of which an equal proportion of high and low plasma protein binding drugs were extracted to build a training set of ~300 drugs. The machine learning algorithms were trained with a training set and evaluated by a test set. We also compared various machine learning-based classification algorithms i.e., the Naïve Bayes algorithm, Instance-Based Learner (IBK), multilayer perceptron, and random forest to determine the best model based on accuracy. It was observed that the random forest algorithm-based model outperforms with an accuracy of 99.67% and 0.9933 kappa value on training set and on test set as compared to other classification methods and can predict drug plasma binding capacity in the given data set using the WEKA tool.&lt;/p&gt;

Antidepressant-like effect of dehydrozingerone from Zingiber officinale by elevating monoamines in brain: in silico and in vivo studies

BackgroundDehydrozingerone (DHZ) is an active ingredient of Zingiber officinale and structural half analogue of curcumin. In the present study, DHZ was evaluated for monoamine oxidase (MAO) inhibitory activity in silico and antidepressant activity in vivo.MethodThe binding affinity of DHZ with MAO-A (PDB ID: 2Z5Y) was assessed using Schrodinger's Maestro followed by free energy calculation, pharmacokinetic property prediction using Qikprop and Molecular dynamics simulation using Desmond. In vivo antidepressant activity of DHZ was evaluated on C57 BL/6 male mice using Escilatopram as the standard antidepressant. Open field test (OFT), forced swimming test (FST) and tail suspension test (TST) were used to evaluate the antidepressant effect of the drugs on days 1 and 7. Following the behavioural study, neurotransmitters (noradrenaline, dopamine and serotonin) were estimated using liquid chromatography–mass spectrometry.ResultsDHZ demonstrated a greater binding affinity for the MAO-A enzyme compared to moclobemide in silico. Immobility in TST and FST were significantly (p < 0.05) reduced in vivo with 100mg/kg DHZ as compared to respective controls. DHZ treatment was more effective 1 h post treatment compared to vehicle control. A significant increase in levels of neurotransmitters was observed in mice brain homogenate in response to DHZ treatment, reassuring its antidepressant-like potential.ConclusionDHZ demonstrated MAO-A inhibition in silico, and the increased neurotransmitter levels in the brain in vivo were associated with an antidepressant-like effect.

Successful and Unsuccessful Prediction of Human Hepatic Clearance for Lead Optimization.

Development of new chemical entities is costly, time-consuming, and has a low success rate. Accurate prediction of pharmacokinetic properties is critical to progress compounds with favorable drug-like characteristics in lead optimization. Of particular importance is the prediction of hepatic clearance, which determines drug exposure and contributes to projection of dose, half-life, and bioavailability. The most commonly employed methodology to predict hepatic clearance is termed in vitro to in vivo extrapolation (IVIVE) that involves measuring drug metabolism in vitro, scaling-up this in vitro intrinsic clearance to a prediction of in vivo intrinsic clearance by reconciling the enzymatic content between the incubation and an average human liver, and applying a model of hepatic disposition to account for limitations of protein binding and blood flow to predict in vivo clearance. This manuscript reviews common in vitro techniques used to predict hepatic clearance as well as current challenges and recent theoretical advancements in IVIVE.

Phytochemistry, Bioactivities, Pharmacokinetics and Toxicity Prediction of Selaginella repanda with Its Anticancer Potential against Human Lung, Breast and Colorectal Carcinoma Cell Lines.

In this study, we investigated the bioactive potential (antibacterial and antioxidant), anticancer activity and detailed phytochemical analysis of Selaginella repanda (S. repanda) ethanolic crude extract for the very first time using different in vitro approaches. Furthermore, computer-aided prediction of pharmacokinetic properties and safety profile of the identified phytoconstituents were also employed in order to provide some useful insights for drug discovery. S. repanda, which is a rich source of potent natural bioactive compounds, showed promising antibacterial activity against the tested pathogenic bacteria (S. aureus, P. aeruginosa, E. coli and S. flexneri). The crude extract displayed favorable antioxidant activity against both 2,2-diphenyl-1-picrylhydrazyl (DPPH) (IC50 = 231.6 μg/mL) and H2O2 (IC50 = 288.3 μg/mL) molecules. S. repanda also showed favorable and effective anticancer activity against all three malignant cancer cells in a dose/time dependent manner. Higher activity was found against lung (A549) (IC50 = 341.1 μg/mL), followed by colon (HCT-116) (IC50 = 378.8 μg/mL) and breast (MCF-7) (IC50 = 428.3 μg/mL) cancer cells. High resolution-liquid chromatography–mass spectrometry (HR-LC–MS) data of S. repanda crude extract revealed the presence of diverse bioactive/chemical components, including fatty acids, alcohol, sugar, flavonoids, alkaloids, terpenoids, coumarins and phenolics, which can be the basis and major cause for its bioactive potential. Therefore, achieved results from this study confirmed the efficacy of S. repanda and a prospective source of naturally active biomolecules with antibacterial, antioxidant and anticancer potential. These phytocompounds alone with their favorable pharmacokinetics profile suggests good lead and efficiency of S. repanda with no toxicity risks. Finally, further in vivo experimental investigations can be promoted as probable candidates for various therapeutic functions, drug discovery and development.