Biological and In silico Studies on Synthetic Analogues of Tyrosine Betaine as Inhibitors of Neprilysin - A Drug Target for the Treatment of Heart Failure

Background: Fungal secondary metabolites are important sources for the discovery of new pharmaceuticals, as exemplified by penicillin, lovastatin and cyclosporine. Searching for secondary metabolites of the fungi Metarhizium spp., we previously identified tyrosine betaine as a major constituent. Methods: Because of the structural similarity with other inhibitors of neprilysin (NEP), an enzyme explored for the treatment of heart failure, we devised the synthesis of tyrosine betaine and three analogues to be subjected to in vitro NEP inhibition assays and to molecular modeling studies. Results: In spite of the similar binding modes with other NEP inhibitors, these compounds only displayed moderate inhibitory activities (IC50 ranging from 170.0 to 52.9 µM). However, they enclose structural features required to hinder passive blood brain barrier permeation (BBB). Conclusions: Tyrosine betaine remains as a starting point for the development of NEP inhibitors because of the low probability of BBB permeation and, consequently, of NEP inhibition at the Central Nervous System, which is associated to an increment in the Aβ levels and, accordingly, with a higher risk for the onset of Alzheimer's disease.

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Antimicrobial Screening, in Silico Studies and QSAR of Chalcone-based 1,4-disubstituted 1,2,3-triazole Hybrids

Drug Research ◽

10.1055/a-1296-7751 ◽

2020 ◽

Author(s):

Pinki Yadav ◽

Kashmiri Lal ◽

Ashwani Kumar

Keyword(s):

Topoisomerase Ii ◽

Antimicrobial Properties ◽

Qsar Model ◽

Quantitative Structure Activity Relationship ◽

Binding Modes ◽

E Coli ◽

Structure Activity ◽

In Silico Studies ◽

Microbial Strains

AbstractThe in vitro antimicrobial properties of some chalcones (1a–1c ) and chalcone tethred 1,4-disubstituted 1,2,3-triazoles (2a–2u) towards different microbial strains viz. Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa, Aspergillus niger and Candida albicans are reported. Compounds 2g and 2u exhibited better potency than the standard Fluconazole with MIC values of 0.0063 µmol/mL and 0.0068 µmol/mL, respectively. Furthermore, molecular docking was performed to investigate the binding modes of two potent compounds 2q and 2g with E. coli topoisomerase II DNA gyrase B and C. albicans lanosterol 14α-demethylase, respectively. Based on these results, a statistically significant quantitative structure activity relationship (QSAR) model was successfully summarized for antibacterial activity against B. subtilis.

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Searching Hit Potential Antimicrobials in Natural Compounds Space against Biofilm Formation

Molecules ◽

10.3390/molecules25225334 ◽

2020 ◽

Vol 25 (22) ◽

pp. 5334

Author(s):

Roberto Pestana-Nobles ◽

Jorge A. Leyva-Rojas ◽

Juvenal Yosa

Keyword(s):

Natural Products ◽

Biofilm Formation ◽

Caulobacter Crescentus ◽

Resistant Bacteria ◽

Chronic Infections ◽

Aconitic Acid ◽

Starting Point ◽

In Silico Studies ◽

Biofilm Development

Biofilms are communities of microorganisms that can colonize biotic and abiotic surfaces and thus play a significant role in the persistence of bacterial infection and resistance to antimicrobial. About 65% and 80% of microbial and chronic infections are associated with biofilm formation, respectively. The increase in infections by multi-resistant bacteria instigates the need for the discovery of novel natural-based drugs that act as inhibitory molecules. The inhibition of diguanylate cyclases (DGCs), the enzyme implicated in the synthesis of the second messenger, cyclic diguanylate (c-di-GMP), involved in the biofilm formation, represents a potential approach for preventing the biofilm development. It has been extensively studied using PleD protein as a model of DGC for in silico studies as virtual screening and as a model for in vitro studies in biofilms formation. This study aimed to search for natural products capable of inhibiting the Caulobacter crescentus enzyme PleD. For this purpose, 224,205 molecules from the natural products ZINC15 database, have been evaluated through molecular docking and molecular dynamic simulation. Our results suggest trans-Aconitic acid (TAA) as a possible starting point for hit-to-lead methodologies to obtain new inhibitors of the PleD protein and hence blocking the biofilm formation.

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Molecular docking and molecular dynamics simulation study of inositol phosphorylceramide synthase – inhibitor complex in leishmaniasis: Insight into the structure based drug design

F1000Research ◽

10.12688/f1000research.9151.1 ◽

2016 ◽

Vol 5 ◽

pp. 1610 ◽

Cited By ~ 2

Author(s):

Vineetha Mandlik ◽

Shailza Singh

Keyword(s):

Molecular Dynamics ◽

Dynamics Simulation ◽

Sphingolipid Metabolism ◽

Drug Candidate ◽

Binding Modes ◽

Structure Based Drug Design ◽

Starting Point ◽

Synthase Inhibitor

Inositol phosphorylceramide synthase (IPCS) has emerged as an important, interesting and attractive target in the sphingolipid metabolism of Leishmania. IPCS catalyzes the conversion of ceramide to IPC which forms the most predominant sphingolipid in Leishmania. IPCS has no mammalian equivalent and also plays an important role in maintaining the infectivity and viability of the parasite. The present study explores the possibility of targeting IPCS; development of suitable inhibitors for the same would serve as a treatment strategy for the infectious disease leishmaniasis. Five coumarin derivatives were developed as inhibitors of IPCS protein. Molecular dynamics simulations of the complexes of IPCS with these inhibitors were performed which provided insights into the binding modes of the inhibitors. In vitro screening of the top three compounds has resulted in the identification of one of the compounds (compound 3) which shows little cytotoxic effects. This compound therefore represents a good starting point for further in vivo experimentation and could possibly serve as an important drug candidate for the treatment of leishmaniasis.

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Berberine Derivatives as Pseudomonas aeruginosa MexXY-OprM Inhibitors: Activity and In Silico Insights

Molecules ◽

10.3390/molecules26216644 ◽

2021 ◽

Vol 26 (21) ◽

pp. 6644

Author(s):

Giorgia Giorgini ◽

Gianmarco Mangiaterra ◽

Nicholas Cedraro ◽

Emiliano Laudadio ◽

Giulia Sabbatini ◽

...

Keyword(s):

Pseudomonas Aeruginosa ◽

In Silico ◽

Rational Design ◽

Specific Binding ◽

In Silico Analysis ◽

In Vitro Assays ◽

Binding Modes ◽

Starting Point ◽

Berberine Derivatives

The natural alkaloid berberine has been demonstrated to inhibit the Pseudomonas aeruginosa multidrug efflux system MexXY-OprM, which is responsible for tobramycin extrusion by binding the inner membrane transporter MexY. To find a structure with improved inhibitory activity, we compared by molecular dynamics investigations the binding affinity of berberine and three aromatic substituents towards the three polymorphic sequences of MexY found in P. aeruginosa (PAO1, PA7, and PA14). The synergy of the combinations of berberine or berberine derivatives/tobramycin against the same strains was then evaluated by checkerboard and time-kill assays. The in silico analysis evidenced different binding modes depending on both the structure of the berberine derivative and the specific MexY polymorphism. In vitro assays showed an evident MIC reduction (32-fold and 16-fold, respectively) and a 2–3 log greater killing effect after 2 h of exposure to the combinations of 13-(2-methylbenzyl)- and 13-(4-methylbenzyl)-berberine with tobramycin against the tobramycin-resistant strain PA7, a milder synergy (a 4-fold MIC reduction) against PAO1 and PA14, and no synergy against the ΔmexXY strain K1525, confirming the MexY-specific binding and the computational results. These berberine derivatives could thus be considered new hit compounds to select more effective berberine substitutions and their common path of interaction with MexY as the starting point for the rational design of novel MexXY-OprM inhibitors.

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In SilicoandIn VitroComparison of HIV-1 Subtypes B and CRF02_AG Integrases Susceptibility to Integrase Strand Transfer Inhibitors

Advances in Virology ◽

10.1155/2012/548657 ◽

2012 ◽

Vol 2012 ◽

pp. 1-13 ◽

Cited By ~ 3

Author(s):

Xiaoju Ni ◽

Safwat Abdel-Azeim ◽

Elodie Laine ◽

Rohit Arora ◽

Osamuede Osemwota ◽

...

Keyword(s):

Structural Features ◽

Strand Transfer ◽

Binding Modes ◽

Medical Treatments ◽

Sequence Variations ◽

Transfer Inhibitor ◽

Dna Substrate ◽

Integrase Strand Transfer Inhibitor ◽

Hiv 1

Most antiretroviral medical treatments were developed and tested principally on HIV-1 B nonrecombinant strain, which represents less than 10% of the worldwide HIV-1-infected population. HIV-1 circulating recombinant form CRF02_AG is prevalent in West Africa and is becoming more frequent in other countries. Previous studies suggested that the HIV-1 polymorphisms might be associated to variable susceptibility to antiretrovirals. This study is pointed to compare the susceptibility to integrase (IN) inhibitors of HIV-1 subtype CRF02_AG IN respectively to HIV-1 B. Structural models of B and CRF02_AG HIV-1 INs as unbound enzymes and in complex with the DNA substrate were built by homology modeling. IN inhibitors—raltegravir (RAL), elvitegravir (ELV) and L731,988—were docked onto the models, and their binding affinity for both HIV-1 B and CRF02_AG INs was compared. CRF02_AG INs were cloned and expressed from plasma of integrase strand transfer inhibitor (INSTI)-naïve infected patients. Ourin silicoandin vitrostudies showed that the sequence variations between the INs of CRF02_AG and B strains did not lead to any notable difference in the structural features of the enzyme and did not impact the susceptibility to the IN inhibitors. The binding modes and affinities of INSTI inhibitors to B and CRF02_AG INs were found to be similar. Although previous studies suggested that several naturally occurring variations of CRF02_AG IN might alter either IN/vDNA interactions or INSTIs binding, our study demonstrate that these variations do affect neither IN activity nor its susceptibility to INSTIs.

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Penicillins and cephalosporins are active site-directed acylating agents: evidence in support of the substrate analogue hypothesis

Philosophical Transactions of the Royal Society of London Series B Biological Sciences ◽

10.1098/rstb.1980.0044 ◽

1980 ◽

Vol 289 (1036) ◽

pp. 257-271 ◽

Cited By ~ 40

Keyword(s):

Cell Wall ◽

Active Site ◽

Structural Similarity ◽

Structural Features ◽

Covalent Modification ◽

Cross Linking ◽

Cell Wall Biosynthesis ◽

Substrate Analogue ◽

Bactericidal Effects

Penicillin and related β-lactam antibiotics are known to exert their bactericidal effects by inhibiting the cross-linking step (transpeptidation) of bacterial cell wall biosynthesis. Evidence is presented in support of the hypothesis that this inhibition results from covalent modification of the active site of sensitive enzymes as a consequence of the structural similarity between penicillin and the acyl-D-alanyl-D-alanine terminus of nascent peptidoglycan strands. Several predictions of this proposal have been verified experimentally. Penicillin-sensitive enzymes are inactivated, with the formation of a covalent, stoichiometric penicilloyl-enzyme complex in vitro . Acylenzyme intermediates have been trapped with several of these enzymes by using cell wall-related substrates. Sequence analysis of the peptides derived from active site-labelled enzymes has established that both penicilloyl and an acyl moiety derived from substrate are covalently bound to the same site, as an ester of serine 36, as predicted by the substrate analogue hypothesis. Sequences near the active site serine are homologous to sequences found in four β-lactamases, supporting the proposal that penicillinsensitive D-alanine carboxypeptidases and penicillin-inactivating β-lactamases are evolutionarily related. Structural features important for the specific and potent inhibitory properties of β-lactam antibiotics are discussed in terms of the original substrate analogue hypothesis.

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A Novel Series of [1,2,4]Triazolo[4,3-a]Pyridine Sulfonamides as Potential Antimalarial Agents: In Silico Studies, Synthesis and In Vitro Evaluation

Molecules ◽

10.3390/molecules25194485 ◽

2020 ◽

Vol 25 (19) ◽

pp. 4485

Author(s):

Veronika R. Karpina ◽

Svitlana S. Kovalenko ◽

Sergiy M. Kovalenko ◽

Oleksandr G. Drushlyak ◽

Natalya D. Bunyatyan ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Molecular Docking ◽

Virtual Screening ◽

Inhibitory Concentration ◽

Antimalarial Activity ◽

Virtual Library ◽

Antimalarial Agents ◽

Starting Point ◽

In Silico Studies

For the development of new and potent antimalarial drugs, we designed the virtual library with three points of randomization of novel [1,2,4]triazolo[4,3-a]pyridines bearing a sulfonamide fragment. The library of 1561 compounds has been investigated by both virtual screening and molecular docking methods using falcipain-2 as a target enzyme. 25 chosen hits were synthesized and evaluated for their antimalarial activity in vitro against Plasmodium falciparum. 3-Ethyl-N-(3-fluorobenzyl)-N-(4-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine-6-sulfonamide and 2-(3-chlorobenzyl)-8-(piperidin-1-ylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one showed in vitro good antimalarial activity with inhibitory concentration IC50 = 2.24 and 4.98 μM, respectively. This new series of compounds may serve as a starting point for future antimalarial drug discovery programs.

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Identification of FDA Approved Drugs Targeting COVID-19 Virus by Structure-Based Drug Repositioning

10.26434/chemrxiv.12003930.v1 ◽

2020 ◽

Cited By ~ 3

Author(s):

Ayman Farag ◽

Ping Wang ◽

Mahmoud Ahmed ◽

Hesham Sadek

Keyword(s):

Drug Repositioning ◽

Binding Energies ◽

Binding Modes ◽

Structure Based Drug Design ◽

Protease Enzyme ◽

Starting Point ◽

Approved Drugs ◽

Fda Approved Drugs

<div>The new strain of Coronaviruses (SARS-CoV-2), and the resulting Covid-19 disease has spread swiftly across the globe after its initial detection in late December 2019 in Wuhan, China, resulting in a pandemic status declaration by WHO within 3 months. Given the heavy toll of this pandemic, researchers are actively testing various strategies including new and repurposed drugs as well as vaccines. In the current brief report, we adopted a repositioning approach using insilico molecular modeling screening using FDA approved drugs with established safety profiles for potential inhibitory effects on Covid-19 virus. We started with structure based drug design by screening more than 2000 FDA approved drugs</div><div>against Covid-19 virus main protease enzyme (Mpro) substrate-binding pocket to identify potential hits based on their binding energies, binding modes, interacting amino acids, and therapeutic indications. In addition, we elucidate preliminary pharmacophore features for candidates bound to Covid-19 virus Mpro substratebinding pocket. The top hits include anti-viral drugs such as Darunavir, Nelfinavirand Saquinavir, some of which are already being tested in Covid-19 patients. Interestingly, one of the most promising hits in our screen is the hypercholesterolemia drug Rosuvastatin. These results certainly do not confirm or indicate antiviral activity, but can rather be used as a starting point for further in vitro and in vivo testing, either individually or in combination.</div>

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Searching Hit Potential Antimicrobials in Natural Compounds Space Against Biofilm Formation

10.20944/preprints202009.0046.v1 ◽

2020 ◽

Author(s):

Roberto Pestana ◽

Jorge Leyva ◽

Juvenal Yosa

Keyword(s):

Biofilm Formation ◽

Potential Method ◽

New Drugs ◽

Resistant Bacteria ◽

Chronic Infections ◽

Aconitic Acid ◽

Starting Point ◽

In Silico Studies ◽

Biofilm Development

Biofilms are communities of microorganisms that can colonize biotic and abiotic surfaces playing a significant role in the persistence of bacterial infection and antibiotic resistance. About 65% and 80% of microbial and chronic infections are produced by biofilm formation. The increase in infections by multi-resistant bacteria draws attention to the discovery of new drugs based on natural inhibitory molecules. The inhibition of diguanylate cyclases (DGCs), the enzyme implicated in the synthesis of the second messenger, cyclic diguanylate (c-di-GMP), involved the biofilm formation, represents a potential method for preventing the biofilm development. It has been extensively studied using PleD protein as a model of DGC for in silico studies as virtual screening and as a model for in vitro studies in biofilms formation. In the present study 224205 molecules from natural products database, ZINC15 has been evaluated through molecular docking and molecular dynamic simulation, our result suggests trans-Aconitic acid (TAA) as a possible starting point for hit-to-lead methodologies to obtain new molecules capable of inhibiting the PleD protein and hence blocking the biofilm formation.

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3-Methoxycarpachromene and Masticadienonic Acid as New Target Inhibitors from Pistacia atlantica Leaves against Trypanothione Reductase of Leishmania Parasites: In Vitro and In Silico Studies

10.20944/preprints202105.0348.v1 ◽

2021 ◽

Author(s):

Saarra Maamri ◽

Khedidja Benarous ◽

Mohamed Yousfi

Keyword(s):

Molecular Docking ◽

In Silico ◽

Leishmania Major ◽

Trypanothione Reductase ◽

Binding Modes ◽

Pistacia Atlantica ◽

In Silico Studies ◽

Ic50 Values ◽

Leishmania Parasites

This study aimed to identify new drug molecules against Leishmania parasites, leishmaniasis's causal agent, using Pistacia atlantica leaves as source. The evaluation of the anti-leishmania potential against the promastigote form of Leishmania. infantum and Leishmania. major was performed. A new in silico study was accomplished using molecular docking, with Autodock vina program, to find the binding affinity of two important phytochemical compounds from this plant (Masticadienonic acid, 3-Methoxycarpachromene) towards the trypanothione reductase as target drugs, responsible for defence mechanism against oxidative stress and virulence of this parasites. Results: Several concentrations showed a significant decrease in cell viability (P<0.0001), with IC50 values of 0.3 mg/ mL for L. infantum and 0.12 mg/ mL L. major; The molecular docking confirms the significant relationship between Leishmania survival and the inhibition of this crucial enzyme. There were promising and new positive results on binding modes of selected ligands and the trypanothione reductase for the first time. Through this work, we propose 3-Methoxycarpachromene and Masticadienonic acid as anti Trypanosomatidae species drug.

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