Synthesis and antimicrobial bioassays of 1,3,4-thiadiazole sulfone derivatives containing amide moiety: A study based on molecular dynamics (MD) simulations,MM/GBSA,and molecular docking

The backbone structure (1,3,4-thiadiazole sulfone derivatives containing amide moiety) of target compounds was determined by modification and optimization of the theoretical design based on commercial chemical carboxin, including molecular docking, scaffold hopping, ligand expansion, etc.In this paper, 23 target compounds were synthesized by the combination of theoretical design and chemical synthesis, and characterized by ¹H NMR, ¹³C NMR and HR MS. Addtionally, the antibacterical bioassay showed that most target compounds performed excellent inhibition on Xanthomonas axonopodis pv. citri (Xac) and Xanthomonas oryzae pv. oryzae (Xoo) in vitro. Meanwhile, molecular docking, molecular dynamics (MD) simulations, and studies on ligand/protein (carboxin/2FBW and 4n/2FBW) complex systems were displayed, and the interaction patterns of ligand/protein complex system were predicted by molecular docking. Besides, the ligand/protein complex system was subject to MD simulation. The analysis of molecular dynamics such as RMSD values suggested that compound/2FBW complexes were stable. MM/GBSA (Molecular mechanics generalized born surface area) dynamic binding affinity results revealed that the active residues (TYR58, HIS26, ARG43, SER39, etc.) played an essential part in the binding of the compound(s) to form a stable low-energy ligand/protein complex, while the MD trajectories demonstrated that the interactions of drugs with 2FBW affected the tertiary structure and increased the stability of protein. Besides, compound 4n also showed control efficacies (curative and protective) on Xoo in vivo, where the curative efficacy was 35.91% and the protective efficacy was 18.97%. In a word, this study showed that 1,3,4-thiadiazole sulfone derivatives containing amide moiety designed based on the structure of carboxin were promising agricultural antibacterial agents, featuring certain stability of binding affinity to proteins and carboxin.     

Molecular modeling and structural analysis of some tetrahydroindazole and cyclopentanepyrazole derivatives as COX-2 inhibitors

In an attempt to rationalize the search for new potential anti-inflammatory compounds on the COX-2 enzyme, we carried out an in silico protocol that successfully combines the prediction of physicochemical and pharmacokinetic properties, molecular docking, molecular dynamic simulation, and free energy calculation. Starting from a small library of compounds synthesized previously, it was found that 70% of the compounds analyzed satisfy with the associated values to physicochemical principles as key evaluation parameters for the drug-likeness; all the compounds presented good gastrointestinal absorption and cerebral permeability and they showed an interaction with the Arg 106 residue of the COX-2 isoenzyme. Finally, it was obtained that compound 3ab has a binding mode, binding energy, and stability in the active site of COX-2 like the reference drug celecoxib, suggesting that this compound could become a powerful candidate in the inhibition of the COX-2 enzyme. In addition, we realized the crystallographic analysis of compounds 3j, 3r, and 3t defining the crystal parameters and the Packing interactions.     

Molecular docking studies of some new imidazole derivatives for antimicrobial properties

In modern drug designing, molecular docking is routinely used for understanding drug-receptor interaction. In the present study six imidazole derivatives containing substituted pyrazole moiety (2a,b and 4a–d) were synthesized. Structures of the newly synthesized compounds were characterized by spectral studies. Compounds were screened for their antibacterial activity. Compound 4c was found to be potent antimicrobial against Pseudomonas aeruginosa at concentrations of 1 and 0.5 mg/mL compared to standard drug Streptomycin. All the compounds were subjected to molecular docking studies for the inhibition of the enzyme l-glutamine: d-fructose-6-phosphate amidotransferase[GlcN-6-P] (EC 2.6.1.16). The in silico molecular docking study results showed that, all the synthesized compounds having minimum binding energy and have good affinity toward the active pocket, thus, they may be considered as good inhibitor of GlcN-6-P synthase.     

New coumarin derivative with potential antioxidant activity: Synthesis,DNA binding and in silico studies (Docking,MD, ADMET)

A new coumarin derivative, 7-((8-(4-benzylpiperidin-1-yl)octyl)oxy)-4-methyl-2H-chromen-2-one (C3), was synthesized by two-step alkylation reaction of 7-hydroxy-4-methyl coumarin. The structure and purity of the compound were characterized by its ¹H and ¹³C NMR, FT-IR and LC-MS spectral data. The DNA binding interaction of C3 was evaluated using UV–vis spectrophotometric and viscosimetric methods. These experiments showed that C3 was bound in intercalative mode. The antioxidant activity of C3 was evaluated by the DPPH method, the antioxidant activity results displayed that C3 had DPPH radical scavenging effect. The possible mechanism of antioxidant and anticancer activity of C3 was investigated via molecular docking by using two enzymes CYP450 and EGFR as receptors. The C3 also tended a good antioxidant ability based on the result of the molecular docking analysis, with good binding affinity values (-7.82 kcal/mol) and binding site interactions. Molecular Dynamics (MD) simulation was implemented to elucidate the interactions with the protein–ligand complex in 20 ns. The ADMET analyzes which paved the way for us to predict C3 as a drug candidate were also performed. All experimental and theoretical results showed that the compound C3 was a potential drug candidate as an antioxidant and anticancer agent.     

Design,synthesis and anti-diabetic activity of chromen-2-one derivatives

DPP-IV inhibitors have been immersed as promising pathway to treat Type 2 diabetes. Here we have reported designing of coumarin derivatives as DPP-IV inhibitors. Designed compounds have been studied for their binding with DPP-IV enzyme through molecular docking followed by synthesis. All synthesized compounds have been fully characterized and screened for DPP-IV inhibition activity. Two compounds showed very good inhibition at 10 μM concentration.     

Phytochemical profiling,in vitro biological activities,and in-silico molecular docking studies of Typha domingensis

A comparative study between methanolic extract and n-hexane fraction of Typha domingensis (Typhaceae) was conducted for the evaluation of phytochemical potential, in vitro biological activities, and in-silico molecular docking studies. The phytochemical composition was estimated by total phenolic and total flavonoid contents, and by GC–MS analysis. Several biological activities were performed such as antioxidant assays (ABTS, FRAP, DPPH, & CUPRAC), enzyme inhibition activity (Tyrosinase, Acetylcholinesterase & Butyrylcholinesterase), thrombolytic activity, and antimicrobial activity (antibacterial & antiviral) to evaluate the medicinal importance of Typha domingensis. The results of the comparative study showed that methanolic extract has more total phenolic and total flavonoid contents (95.72 ± 5.76 mg GAE/g, 131.66 ± 7.92 mg QE/g, respectively) as compared to n-hexane fraction which confirms its maximum antioxidant potential (ABTS 114.31 ± 8.17, FRAP 116.84 ± 3.01, DPPH 283.54 ± 7.3 & CUPRAC 284.16 ± 6.5 mg TE/g). In the case of in vitro enzyme inhibition study and thrombolytic activity, better results were observed for methanolic extract. Almost similar antimicrobial patterns were observed for both methanolic extract and n-hexane fraction of Typha domingensis. The major bioactive phytochemicals identified by GC–MS were further analyzed for in-silico molecular docking studies to determine the binding affinity between ligands and the enzymes. The docking study indicated that most of the bioactive compounds showed a better binding affinity with enzymes as compared to the standard compounds (kojic acid & galantamine). The results of this study recommended that Typha domingensis has promising pharmaceutical importance and it should be further analyzed for the isolation of bioactive phytochemicals which may be useful for the treatment of several diseases.     

Antibacterial potential of N-(2-furylmethylidene)-1, 3, 4-thiadiazole-2-amine: Experimental and theoretical investigations

Recently, a lot of interest has been attributed to the Schiff base compound because of its wide range of biological activities which include: antibacterial, antifungal, antima larial, including; antiproliferative, antiviral, and antipyretic. In this research work, N-(2-furylmethylidene)-1, 3, 4-thiadiazole- 2-amine gotten from o-phenylenediamine and 5- methoxysalicaldehyde was produced and characterized using UV–Visible, FT-IR, ¹H NMR, ¹³C NMR, and GC-MS along with molecular modeling using density functional theory (DFT) and molecular docking approach. The results obtained indicated that the Schiff base exhibited antimicrobial action against all the tested microbes except Candidaalbicans isolate, which exhibited zero diameter zone of inhibition. The theoretical investigations of the synthesized compounds were computed applying density functional theory at the B3LYP/6–31++G (d, p) level of theory and in silico molecular docking simulation. In comparing binding affinity energies and binding poses of the studied compound and the standard drug (ampicillin), the deduction that the molecular docking analysis results are in good agreement with in vitro analysis of the synthesized compounds can be made.     

Chromenone-based GSK-3β inhibitors as potential therapeutic targets for cardiovascular diseases: In silico study,molecular dynamics,and ADMET profiles

Glycogen synthase kinase-3 beta (GSK-3β) regulates glycogen metabolism and many different cellulars, including apoptosis, signaling, and neural. It is a crucial therapeutic receptor in heart disease, type 2 diabetes, and Alzheimer's. In this study, using computational methods, flavonoid compounds were investigated for potential inhibitors against GSK-3β. Virtual screening was utilized to investigate flavonoid compounds obtained from the PubChem database. Structure of human heart mitochondria of GSK-3β receptor constructed by homology modeling. Best binding poses were discovered via in silico molecular docking simulation. We surveyed noncovalent interactions among amino acid residues involved in the active site of the modeled Protein and compounds via molecular docking and molecular dynamics (MD).Moreover, ADMET characteristics of best docking conformers have been investigated. The obtained results revealed that compound 1 containing chromenone moiety with binding energy H-bond ?11.4 kcal/mol inhibited effectively binding pocket of the GSK-3β receptor. Moreover, MD simulation analysis (RMSD and radius of gyration indicated complex of the compound and GSK-3β receptor remained stable throughout 100 ns MD simulation, and also analysis of ADMET profiles revealed that selected compounds had good drug-likeness and pharmacokinetic properties. Hence, it was suggested that compounds with chromenone scaffold could potentially inhibit GSK-3β. Structural modification of the chromenone derivatives may result in the discovery of promising candidates for identifying novel drugs as GSK-3β inhibitors.     

Towards further understanding the structural insights of isoxazoles analogues against leishmaniasis using QSAR,molecular docking and molecular dynamics model

Leishmaniasis is one of the most well-known neglected infectious diseases, which is severe problem for public health. Heterocyclic derivatives are known to displays wide range of pharmacology activities including isoxazole ring that exhibit antileishmanial activity. Quantitative structure-activity relationship (QSAR) molecular docking and molecular dynamics are computational approaches to identify the relationships between structural properties and binding affinity of compounds. In the given paper series of 59, 4-aminomethyl 5-aryl-3-substituted isoxazoles were used to identify the structural insights and to find the binding affinity with protein. The designed model produced statistically significant results with of R² = 0.72, R²_adj = 0.65, and Q²_LMO = 0.72. Structure activity relationship (SAR) revealed that substitution of hydrophobic and steric groups may enhance the biological activity of compounds as antiprotozoal agents. Most potent compound formed hydrogen bonds with active amino acids Arg 87, Arg 104, Gly 112, His 117, Gly 118 and Asp 120. Molecular dynamics simulation (150 ns) on the docked complex of most active compound 3ba and 6 ab supported in the exploration of binding. Further MMPBSA investigations utilising MD trajectories verified compound 3bc higher binding affinity for nucleoside diphosphate kinases. The given strategies of computational studies could be an encouraging way for designing therapeutic targets against leishmaniasis.     

Extra precision docking,free energy calculation and molecular dynamics studies on glutamic acid derivatives as MurD inhibitors

The binding modes of well known MurD inhibitors have been studied using molecular docking and molecular dynamics (MD) simulations. The docking results of inhibitors 1-30 revealed similar mode of interaction with Escherichia coli-MurD. Further, residues Thr36, Arg37, His183, Lys319, Lys348, Thr321, Ser415 and Phe422 are found to be important for inhibitors and E. coli-MurD interactions. Our docking procedure precisely predicted crystallographic bound inhibitor 7 as evident from root mean square deviation (0.96 Å). In addition inhibitors 2 and 3 have been successfully cross-docked within the MurD active site, which was pre-organized for the inhibitor 7. Induced fit best docked poses of 2, 3, 7 and 15/2Y1O complexes were subjected to 10 ns MD simulations to determine the stability of the predicted binding conformations. Induce fit derived docked complexes were found to be in a state of near equilibrium as evident by the low root mean square deviations between the starting complex structure and the energy minimized final average MD complex structures. The results of molecular docking and MD simulations described in this study will be useful for the development of new MurD inhibitors with high potency.     

The novel 4-hydroxyphenylpyruvate dioxygenase inhibitors in vivo and in silico approach: 3D-QSAR analysis,molecular docking,bioassay and molecular dynamics

4-Hydroxyphenylpyruvate dioxygenase (HPPD) is not only an important target enzyme for the treatment of type I tyrosinemia, but also a new target for design bleaching herbicides, and it plays key role in the biosynthesis of tocopherol and plastoquinone. Thirty-six known active pyridine derivatives were collected, and comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) models based on common skeleton were constructed to obtain novel HPPD herbicides with higher activity. Two new HPPD inhibitors were rationally designed and synthesized according to the CoMFA and CoMSIA models and verified by enzyme activity, biological assays, and molecular docking. The promising compound W1 ((E)-5-(3-(4-bromophenyl)acryloyl)-6-hydroxy-2,3-dihydropyridin-4(1H)-one) showed better AtHPPD inhibitory activity, and the bioassay results revealed that some weeds showed bleaching symptoms. The good binding stability of W1 and protein was confirmed by molecular dynamics simulation in 100 ns. These results would be highly useful in the progress of new HPPD inhibitors discovery.     

Prediction of COVID-19 manipulation by selective ACE inhibitory compounds of Potentilla reptant root: In silico study and ADMET profile

In the novel SARS-CoV-2 (COVID-19) as a global emergency event, the main reason of the cardiac injury from COVID-19 is angiotensin-converting enzyme 2 (ACE2) targeting in SARS-CoV-2 infection. The inhibition of ACE2 induces an increase in the angiotensin II (Ang II) and the angiotensin II receptor type 1 (AT1R) leading to impaired cardiac function or cardiac inflammatory responses. The ethyl acetate fraction of Potentilla reptans L. root can rescue heart dysfunction, oxidative stress, cardiac arrhythmias and apoptosis. Therefore, isolated components of P. reptans evaluated to identify natural anti-SARS-CoV-2 agents via molecular docking.In silico molecular docking study were carried out using the Auto Dock software on the isolated compounds of Potentilla reptans root. The protein targets of selective ACE and others obtained from Protein Data Bank (PDB). The best binding pose between amino acid residues involved in active site of the targets and compounds was discovered via molecular docking. Furthermore, ADMET properties of the compounds were evaluated.The triterpenoids of P. reptans showed more ACE inhibitory potential than catechin in both domains. They were selective on the nACE domain, especially compound 5. Also, the compound 5 & 6 had the highest binding affinity toward active site of nACE, cACE, AT1R, ACE2, and TNF-α receptors. Meanwhile, compound 3 showed more activity to inhibit TXA2. Drug likeness and ADMET analysis showed that the compounds passed the criteria of drug likeness and Lipinski rules. The current study depicted that P. reptans root showed cardioprotective effect in COVID-19 infection and manipulation of angiotensin II-induced side effects.     

Indole-derived chalcones as anti-dermatophyte agents: In vitro evaluation and in silico study

A series of indole-derived methoxylated chalcones were described as anti-dermatophyte agents. The in vitro antifungal susceptibility testing against different dermatophytes revealed that most of compounds had potent activity against the dermatophyte strains. In particular, the 4-ethoxy derivative 4d with MIC values of 0.25−2 μg/ml was the most potent compound against Trichophyton interdigitale, Trichophyton veruccosum and Microsporum fulvum. Moreover, the 4-butoxy analog 4i displaying MIC values in the range of 1−16 μg/ml had the highest inhibitory activity against Trichophyton mentagrophytes, Microsporum canis, and Arthroderma benhamiae. To predict whether the synthesized compounds interact with tubulin binding site of dermatophytes, the 3D-structure of target protein was modeled by homology modeling and then used for molecular docking and molecular dynamics (MD) simulation studies. Docking simulation revealed that the promising compound 4d can properly bind with tubulin. The molecular dynamics analysis showed that interactions of compound 4d with the active site of target protein have binding stability throughout MD simulation. The results of this study could utilize in the design of more effective antifungal drugs with tubulin inhibition mechanism against keratinophilic fungi.     

Novel benzoxazole-based thiosemicarbazide derivatives as new inhibitors of urease and β-Glucuronidase: Synthesis,in vivo anti-nematodal activity and ADMET prediction along with in silico study

Here, we discuss the synthesis of thiosemicarbazide derivatives based on benzoxazole. These compounds were obtained via sequence of reactions. The targeted products were confirmed using a number of spectroscopic methods, including NMR (1H and 13C) and EI-MS. After spectral confirmation all the synthesized compounds were evaluated for urease and β-Glucuronidase inhibitory activity in order to explore their biological significances in the presence of standard drug thiourea (IC₅₀ = 21.86 ± 0.40) and D-saccharic acid 1,4-lactone (IC50 value 22.00 ± 1.10 µM) respectively. Among the evaluated series, compounds 14 and 15 (1.10 and 0.01 and 2.20 and 0.60) were shown to have slightly greater potential than standard drugs. Anti-nematodal activity was also employed to explore the cytotoxic nature of synthesized analogs. In order to establish the binding relationship with enzyme active sites, molecular docking experiments were done and directions for compound modification based on SAR features were addressed. In addition, ADMET prediction study also investigated to found drug like properties of the potential analogs.     

GC-MS,LC-MS/MS,Docking and Molecular Dynamics Approaches to Identify Potential SARS-CoV-2 3-Chymotrypsin-Like Protease Inhibitors from Zingiber officinale Roscoe

This study aims to identify and isolate the secondary metabolites of Zingiber officinale using GC-MS, preparative TLC, and LC-MS/MS methods, to evaluate the inhibitory potency on SARS-CoV-2 3 chymotrypsin-like protease enzyme, as well as to study the molecular interaction and stability by using docking and molecular dynamics simulations. GC-MS analysis suggested for the isolation of terpenoids compounds as major compounds on methanol extract of pseudostems and rhizomes. Isolation and LC-MS/MS analysis identified 5-hydro-7, 8, 2′-trimethoxyflavanone (9), (E)-hexadecyl-ferulate (1), isocyperol (2), N-isobutyl-(2E,4E)-octadecadienamide (3), and nootkatone (4) from the rhizome extract, as well as from the leaves extract with the absence of 9. Three known steroid compounds, i.e., spinasterone (7), spinasterol (8), and 24-methylcholesta-7-en-3β-on (6), were further identified from the pseudostem extract. Molecular docking showed that steroids compounds 7, 8, and 6 have lower predictive binding energies (MMGBSA) than other metabolites with binding energy of −87.91, −78.11, and −68.80 kcal/mole, respectively. Further characterization on the single isolated compound by NMR showed that 6 was identified and possessed 75% inhibitory activity on SARS-CoV-2 3CL protease enzyme that was slightly different with the positive control GC376 (77%). MD simulations showed the complex stability with compound 6 during 100 ns simulation time.     

Structural and energetic insight into the interactions between the benzolactam inhibitors and tumor marker HSP90α

The heat shock protein 90α (HSP90α) provides a promising molecular target for cancer therapy. A series of novel benzolactam inhibitors exhibited distinct inhibitory activity for HSP90α. However, the structural basis for the impact of distinct R₁ substituent groups of nine benzolactam inhibitors on HSP90α binding affinities remains unknown. In this study, we carried out molecular docking, molecular dynamics (MD) simulations, and molecular mechanics and generalized Born/surface area (MM–GBSA) binding free energy calculations to address the differences. Molecular docking studies indicated that all nine compounds presented one conformation in the ATP-binding site of HSP90α N-terminal domain. MD simulations and subsequent MM–GBSA calculations revealed that the hydrophobic interactions between all compounds and HSP90α contributed the most to the binding affinity and a good linear correlation was obtained between the calculated and the experimental binding free energies (R = 0.88). The per residue decomposition revealed that the most remarkable differences of residue contributions were found in the residues Ala55, Ile96, and Leu107 defining a hydrophobic pocket for the R₁ group, consistent with the analysis of binding modes. This study may be helpful for the future design of novel HSP90α inhibitors.     

Development of energetic pharmacophore for the designing of 1,2,3,4-tetrahydropyrimidine derivatives as selective cyclooxygenase-2 inhibitors

We present here the Energetic pharmacophore model representing complementary features of the 1,2,3,4-tetrahydropyrimidine for selective cyclooxygenase-2 (COX-2) inhibition. For the development of pharmacophore hypothesis, a total of 43 previously reported compounds were docked on active site of COX-2 enzyme. The generated pharmacophore features were ranked using energetic terms of Glide XP docking for 1,2,3,4-tetrahydropyrimidine scaffold to optimize its structure requirement for COX-2 inhibition. The thirty new 4,5,6-triphenyl-1,2,3,4-tetrahydropyrimidine derivatives were synthesized and assessed for selective COX-2 inhibitory activity. Two compounds 4B1 and 4B11 were found to be potent and selective COX-2 inhibitors. The molecular docking studies revealed that the newly synthesized compounds can be docked into COX-2 binding site and also provide the molecular basis for their activity.     

Disruption of redox catalytic functions of peroxiredoxin-thioredoxin complex in Mycobacterium tuberculosis H37Rv using small interface binding molecules

Mycobacterium tuberculosis has distinctive ability to detoxify various microbicidal superoxides and hydroperoxides via a redox catalytic cycle involving thiol reductants of peroxiredoxin (Prx) and thioredoxin (Trx) systems which has conferred on it resistance against oxidative killing and survivability within host. We have used computational approach to disrupt catalytic functions of Prx-Trx complex which can possibly render the pathogen vulnerable to oxidative killing in the host. Using protein–protein docking method, we have successfully constructed the Prx-Trx complex. Statistics of interface region revealed contact area of each monomer less than 1500 Å² and enriched in polar amino acids indicating transient interaction between Prx and Trx. We have identified ZINC40139449 as a potent interface binding molecule through virtual screening of drug-like compounds from ZINC database. Molecular dynamics (MD) simulation studies showed differences in structural properties of Prx-Trx complex both in apo and ligand bound states with regard to root mean square deviation (RMSD), radius of gyration (Rg), root mean square fluctuations (RMSF), solvent accessible surface area (SASA) and number of hydrogen bonds (NHBs). Interestingly, we found stability of two conserved catalytic residues Cys61 and Cys174 of Prx and conserved catalytic motif, WCXXC of Trx upon binding of ZINC40139449. The time dependent displacement study reveals that the compound is quite stable in the interface binding region till 30 ns of MD simulation. The structural properties were further validated by principal component analysis (PCA). We report ZINC40139449 as promising lead which can be further evaluated by in vitro or in vivo enzyme inhibition assays.