3-Oxoacyl-ACP Reductase from Schistosoma japonicum: Integrated In Silico-In Vitro Strategy for Discovering Antischistosomal Lead Compounds

AbstractBackgroundBrucellosis is an infectious disease caused by bacteria of the genus Brucella. Although it is the most common zoonosis worldwide, there are increasing reports of drug resistance and cases of relapse after long term treatment with the existing drugs of choice. This study therefore aims at identifying possible natural inhibitors of Brucella melitensis Methionyl-tRNA synthetase through an in-silico approach.MethodsUsing PyRx 0.8 virtual screening software, the target was docked against a library of natural compounds obtained from edible African plants. The compound, 2-({3-[(3,5-dichlorobenzyl) amino] propyl} amino) quinolin-4(1H)-one (OOU) which is a co-crystallized ligand with the target was used as the reference compound. Screening of the molecular descriptors of the compounds for bioavailability, pharmacokinetic properties, and bioactivity was performed using the SWISSADME, pkCSM, and Molinspiration web servers respectively. The Fpocket and PLIP webservers were used to perform the analyses of the binding pockets and the protein ligand interactions. Analysis of the time-resolved trajectories of the Apo and Holo forms of the target was performed using the Galaxy and MDWeb servers. The lead compounds, Strophanthidin and Isopteropodin are present in Corchorus olitorius and Uncaria tomentosa (cat-claw) plants respectively.ResultsIsopteropodin had a binding affinity score of -8.9 kcal / ml with the target and had 17 anti-correlating residues in pocket 1 after molecular dynamics simulation. The complex formed by Isopteropodin and the target had a total RMSD of 4.408 and a total RMSF of 9.8067. However, Strophanthidin formed 3 hydrogen bonds with the target at ILE21, GLY262 and LEU294, and induced a total RMSF of 5.4541 at Pocket 1.ConclusionOverall, Isopteropodin and Strophanthidin were found to be better drug candidates than OOU and they showed potentials to inhibit the Brucella melitensis Methionyl-tRNA synthetase at Pocket 1, hence abilities to treat brucellosis. In vivo and in vitro investigations are needed to further evaluate the efficacy and toxicity of the lead compounds.Author SummaryStrophanthidin and Isopteropodin showed potentials to inhibit the Brucella melitensis Methionyl-tRNA synthetase at Pocket 1Both compounds can be used to treat brucellosis.Both compounds showed potentials of being safe to use in humans.

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Design, Synthesis, and Preclinical Bio Evaluation of Chemical Conjugates Derived from Phytophenols and Nitrobenzoate as First Plausible Inhibitors of MPO Useful in CVD Treatment

Biointerface Research in Applied Chemistry ◽

10.33263/briac114.1163011652 ◽

2020 ◽

Vol 11 (4) ◽

pp. 11630-11652

Keyword(s):

In Silico ◽

Ex Vivo ◽

Radical Scavenging ◽

Building Blocks ◽

Xrd Analysis ◽

Positive Control ◽

In Silico Docking ◽

Lead Compounds ◽

Chemistry Research

Phytophenols are important phytonutrients and useful building blocks for medicinal chemistry research. Designed conjugates derived from phytophenols and nitrobenzoate were evaluated for MPO inhibition using in-silico docking and ADMET studies. Hit to lead compounds were prepared and confirmed by NMR, mass, and single-crystal XRD analysis. Based on the in-silico study, an in-vitro MPO inhibition assay was performed and identified two best compounds 1 and 2 (MPO-IC50 value is 12.88 and 14.97 µM respectively) lead molecules. An ex-vivo anti-inflammatory study was performed with human erythrocyte hemolysis using coagulated blood cells with increasing concentration (20 to 100 µM) of the lead molecules. The activity range was found to be ~85% and ~75% for compounds 1 and 2, respectively. DPPH and ABTS radical scavenging assays of the lead molecules were compared with ascorbic acid (positive control). MTT-cell line study shows that lead compounds were non-toxic even at higher concentrations. The outcome of this study demonstrated that conjugates 1 and 2 be considered potent inhibitors of MPO and useful cardiovascular therapeutic agents.

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In silico ADME in drug design – enhancing the impact

ADMET & DMPK ◽

10.5599/admet.6.1.470 ◽

2018 ◽

Vol 6 (1) ◽

pp. 15 ◽

Cited By ~ 3

Author(s):

Susanne Winiwarter ◽

Ernst Ahlberg ◽

Edmund Watson ◽

Ioana Oprisiu ◽

Mickael Mogemark ◽

...

Keyword(s):

In Silico ◽

In Vitro Assays ◽

Lead Compounds ◽

Human Dose ◽

Pharmacokinetic Properties ◽

In Silico Predictions ◽

In Silico Models ◽

The Impact ◽

Selection Of

<p>Each year the pharmaceutical industry makes thousands of compounds, many of which do not meet the desired efficacy or pharmacokinetic properties, describing the absorption, distribution, metabolism and excretion (ADME) behavior. Parameters such as lipophilicity, solubility and metabolic stability can be measured in high throughput in vitro assays. However, a compound needs to be synthesized in order to be tested. In silico models for these endpoints exist, although with varying quality. Such models can be used before synthesis and, together with a potency estimation, influence the decision to make a compound. In practice, it appears that often only one or two predicted properties are considered prior to synthesis, usually including a prediction of lipophilicity. While it is important to use all information when deciding which compound to make, it is somewhat challenging to combine multiple predictions unambiguously. This work investigates the possibility of combining in silico ADME predictions to define the minimum required potency for a specified human dose with sufficient confidence. Using a set of drug discovery compounds,in silico predictions were utilized to compare the relative ranking based on minimum potency calculation with the outcomes from the selection of lead compounds. The approach was also tested on a set of marketed drugs and the influence of the input parameters investigated.</p>

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Molecular Docking of Natural Phenolic Compounds for the Screening of Urease Inhibitors

Current Pharmaceutical Biotechnology ◽

10.2174/1389201020666190409110948 ◽

2019 ◽

Vol 20 (5) ◽

pp. 410-421 ◽

Cited By ~ 1

Author(s):

Ritu Kataria ◽

Anurag Khatkar

Keyword(s):

Phenolic Compounds ◽

In Silico ◽

Docking Study ◽

Peptic Ulcers ◽

Jack Bean Urease ◽

Jack Bean ◽

Lead Compounds ◽

Modelling Techniques ◽

Natural Phenolic Compounds

Background:Bacterial ureases have been the cause of various human and animal pathogenicity including hepatic encephalopathy, hepatic coma urolithiasis, gastric and peptic ulcers, pyelonephritis, and urinary catheter encrustation by the production of ammonia. Hence, in view of the side effects of existing drugs, there is a strong need to discover, more safe, effective and potent compounds for the treatment of infections caused by urease.Methods:For this purpose, several natural phenolic compounds have been screened by molecular modelling techniques, wherein the phenolic compounds were docked to the active site of Jack bean urease (PDB ID 3LA4) using the Schrodinger docking software.Results:The lead compounds were identified via in-silico screening technique where docking score, binding energy, ADME and toxicity data were considered to screen the lead compounds as compared with the available standard drugs. From the docking study of screened natural phenolic compounds, five compounds diosmin, morin, chlorogenic acid, capsaicin and resveratrol were selected based upon their better affinity towards the receptor and were considered for further wet lab studies.Conclusion:The in-silico results were confirmed by in vitro experiments by use of the Jack bean urease using Weatherburn method.

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In vitro and In silico Evaluation of Structurally Diverse Benzyl-pyrrolidine-3-ol Analogues as Apoptotic Agents via Caspase Activation

Acta Chimica Slovenica ◽

10.17344/acsi.2021.6684 ◽

2021 ◽

Vol 68 (3) ◽

pp. 667-682

Author(s):

Tahira Naqvi ◽

Asif Amin ◽

Shujat Ali ◽

Mohsin Y. Lone ◽

Nadeem Bashir ◽

...

Keyword(s):

Cell Lines ◽

In Silico ◽

Caspase 3 ◽

Human Cancer ◽

Md Simulations ◽

Human Cancer Cell Lines ◽

Lead Compounds ◽

Model Protein ◽

The Stability

The activation of caspases is central to apoptotic process in living systems. Defects in apoptosis have been implicated with carcinogenesis. Need to develop smart agents capable of inducing apoptosis in tumor cells is obvious. With this motive, diversity oriented synthesis of 1-benzylpyrrolidin-3-ol analogues was envisaged. The multi component Ugi reaction synthesized library of electronically diverse analogues was explored for cytotoxic propensity towards a panel of human cancer cell lines at 10 μM. The lead compounds exhibit a selective cytotoxicity towards HL-60 cells as compared to cell lines derived from solid tumors. Besides, their milder cytotoxic effect on non-cancerous cell lines reaffirm their selective action towards cancer cells only.The lead molecules were tested for their ability to target caspase-3, as a vital protease triggering apoptosis. The lead compounds were observed to induce apoptosis in HL-60 cells around 10 μM concentration. The lead compounds exhibited various non-covalent supra type interactions with caspase-3 key residues around the active site. The binding ability of lead compounds with caspase-3 was studied via molecular docking and molecular dynamic (MD) simulations. MD simulations indicated the stability of compound-caspase-3 complex throughout the 50 ns simulation run. The stability and bio-availability of the lead compounds under physiological conditions was assessed by their interaction with Bovine Serum Albumin (BSA) as model protein. BSA interactions of lead compounds were studied by various bio-physical methods and further substantiated with in silico MD simulations.

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Identification of new promising plant-based lead compounds for inhibition of prokaryotic replicative DNA polymerases: combination of in silico and in vitro studies

Journal of Biomolecular Structure and Dynamics ◽

10.1080/07391102.2018.1545701 ◽

2018 ◽

Vol 37 (16) ◽

pp. 4222-4237

Author(s):

Milad Lagzian ◽

Ali Qasemi ◽

Pegah Kaviani ◽

Malihe Mohammadi

Keyword(s):

In Silico ◽

Dna Polymerases ◽

In Vitro Studies ◽

Lead Compounds

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In Vitro and In Silico Acetylcholinesterase Inhibitory Activity of Thalictricavine and Canadine and Their Predicted Penetration across the Blood-Brain Barrier

Molecules ◽

10.3390/molecules24071340 ◽

2019 ◽

Vol 24 (7) ◽

pp. 1340 ◽

Cited By ~ 1

Author(s):

Jakub Chlebek ◽

Jan Korábečný ◽

Rafael Doležal ◽

Šárka Štěpánková ◽

Daniel Pérez ◽

...

Keyword(s):

Blood Brain Barrier ◽

In Silico ◽

Binding Mode ◽

Brain Barrier ◽

In Silico Docking ◽

Lead Compounds ◽

Blood Brain ◽

Type Pattern ◽

Ic50 Values

In recent studies, several alkaloids acting as cholinesterase inhibitors were isolated from Corydalis cava (Papaveraceae). Inhibitory activities of (+)-thalictricavine (1) and (+)-canadine (2) on human acetylcholinesterase (hAChE) and butyrylcholinesterase (hBChE) were evaluated with the Ellman’s spectrophotometric method. Molecular modeling was used to inspect the binding mode of compounds into the active site pocket of hAChE. The possible permeability of 1 and 2 through the blood–brain barrier (BBB) was predicted by the parallel artificial permeation assay (PAMPA) and logBB calculation. In vitro, 1 and 2 were found to be selective hAChE inhibitors with IC50 values of 0.38 ± 0.05 µM and 0.70 ± 0.07 µM, respectively, but against hBChE were considered inactive (IC50 values > 100 µM). Furthermore, both alkaloids demonstrated a competitive-type pattern of hAChE inhibition and bind, most probably, in the same AChE sub-site as its substrate. In silico docking experiments allowed us to confirm their binding poses into the active center of hAChE. Based on the PAMPA and logBB calculation, 2 is potentially centrally active, but for 1 BBB crossing is limited. In conclusion, 1 and 2 appear as potential lead compounds for the treatment of Alzheimer’s disease.

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Correlating In Vitro Target-Oriented Screening and Docking: Inhibition of Matrix Metalloproteinases Activities by Flavonoids

Planta Medica ◽

10.1055/s-0043-104775 ◽

2017 ◽

Vol 83 (11) ◽

pp. 901-911 ◽

Cited By ~ 8

Author(s):

Lucia Crascì ◽

Livia Basile ◽

Annamaria Panico ◽

Carmelo Puglia ◽

Francesco Bonina ◽

...

Keyword(s):

Active Site ◽

Inhibitory Activity ◽

In Silico ◽

In Silico Docking ◽

Lead Compounds ◽

Good Ability ◽

Metalloprotease Inhibitors ◽

Ic50 Values ◽

Further Development

AbstractMetalloproteases are a family of zinc-containing endopeptidases involved in a variety of pathological disorders. The use of flavonoid derivatives as potential metalloprotease inhibitors has recently increased.Particular plants growing in Sicily are an excellent yielder of the flavonoids luteolin, apigenin, and their respective glycoside derivatives (7-O-rutinoside, 7-O-glucoside, and 7-O-glucuronide).The inhibitory activity of luteolin, apigenin, and their respective glycoside derivatives on the metalloproteases MMP-1, MMP-3, MMP-13, MMP-8, and MMP-9 was assessed and rationalized correlating in vitro target-oriented screening and in silico docking.The flavones apigenin, luteolin, and their respective glucosides have good ability to interact with metalloproteases and can also be lead compounds for further development. Glycones are more active on MMP-1, -3, -8, and -13 than MMP-9. Collagenases MMP-1, MMP-8, and MMP-13 are inhibited by compounds having rutinoside glycones. Apigenin and luteolin are inactive on MMP-1, -3, and -8, which can be interpreted as a better selectivity for both -9 and -13 peptidases. The more active compounds are apigenin-7-O-rutinoside on MMP-1 and luteolin-7-O-rutinoside on MMP-3. The lowest IC50 values were also found for apigenin-7-O-glucuronide, apigenin-7-O-rutinoside, and luteolin-7-O-glucuronide. The glycoside moiety might allow for a better anchoring to the active site of MMP-1, -3, -8, -9, and -13. Overall, the in silico data are substantially in agreement with the in vitro ones (fluorimetric assay).

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