scholarly journals Virtual Screening of FDA-Approved Drugs against LasR of Pseudomonas aeruginosa for Antibiofilm Potential

Molecules ◽  
2020 ◽  
Vol 25 (16) ◽  
pp. 3723
Author(s):  
Suhaib Sadiq ◽  
Nosheen Fatima Rana ◽  
Muhammad Ammar Zahid ◽  
Muhammad Kazim Zargaham ◽  
Tahreem Tanweer ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Drug Resistance ◽  
Virtual Screening ◽  
Binding Pocket ◽  
Multi Drug Resistance ◽  
Binding Affinities ◽  
Binding Modes ◽  
Gastrointestinal Infections ◽  
The Stability ◽  
Approved Drugs

Pseudomonas aeruginosa is a Gram-negative pathogenic bacterium that is present commonly in soil and water and is responsible for causing septic shock, pneumonia, urinary tract and gastrointestinal infections, etc. The multi-drug resistance (MDR) phenomenon has increased dramatically in past years and is now considered a major threat globally, so there is an urgent need to develop new strategies to overcome drug resistance by P. aeruginosa. In P. aeruginosa, a major factor of drug resistance is associated to the formation of biofilms by the LasR enzyme, which regulates quorum sensing and has been reported as a new therapeutic target for designing novel antibacterial molecules. In this study, virtual screening and molecular docking were performed against the ligand binding domain (LBD) of LasR by employing a pharmacophore hypothesis for the screening of 2373 FDA-approved compounds to filter top-scoring hit compounds. Six inhibitors out of 2373 compounds were found to have binding affinities close to that of known LasR inhibitors. The binding modes of these compounds to the binding site in LasR-LBD were analyzed to identify the key interactions that contribute to the inhibition of LasR activity. Then, 50 ns simulations of top hit compounds were performed to elucidate the stability of their binding conformations with the LasR-LBD. This study, thus concluded that sulfamerazine showed the highest binding affinity for the LasR-LBD binding pocket exhibiting strong inhibitory binding interactions during molecular dynamics (MD) simulation.

Application of Molecular Docking for the Development of Improved HIV-1 Reverse Transcriptase Inhibitors

2020 ◽  
Vol 16 ◽  
Author(s):  
Arash Soltani ◽  
Seyed Isaac Hashemy ◽  
Farnaz Zahedi Avval ◽  
Houshang Rafatpanah ◽  
Seyed Abdolrahim Rezaee ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Binding Capacity ◽  
Binding Pocket ◽  
Ligand Docking ◽  
Binding Modes ◽  
Wild Type ◽  
Parent Molecule ◽  
Discovery Studio ◽  
Approved Drugs ◽  
Hiv 1

Introoduction: Inhibition of the reverse transcriptase (RT) enzyme of human immunodeficiency virus (HIV) by low molecular weight inhibitors is still an active area of research. Here, protein-ligand interactions and possible binding modes of novel compounds with the HIV-1 RT binding pocket (the wild-type as well as Y181C and K103N mutants) were obtained and discussed. Methods: A molecular fragment-based approach using FDA-approved drugs were followed to design novel chemical derivatives using delavirdine, efavirenz, etravirine and rilpivirine as the scaffolds. The drug-likeliness of the derivatives was evaluated using Swiss-ADME. Then the parent molecule and derivatives were docked into the binding pocket of related crystal structures (PDB ID: 4G1Q, 1IKW, 1KLM and 3MEC). Genetic Optimization for Ligand Docking (GOLD) Suite 5.2.2 software was used for docking and the results analyzed in the Discovery Studio Visualizer 4. A derivative was chosen for further analysis, if it passed drug-likeliness and the docked energy was more favorable than that of its parent molecule. Out of the fifty-seven derivatives, forty-eight failed in druglikeness screening by Swiss-ADME or in docking stage. Results: The final results showed that the selected compounds had higher predicted binding affinities than their parent scaffolds in both wild-type and the mutants. Binding energy improvement was higher for the structures designed based on second-generation NNRTIs (etravirine and rilpivirine) than the first-generation NNRTIs (delavirdine and efavirenz). For example, while the docked energy for rilpivirine was -51 KJ/mol, it was improved for its derivatives RPV01 and RPV15 up to -58.3 and -54.5 KJ/mol, respectively. Conclusion: In this study, we have identified and proposed some novel molecules with improved binding capacity for HIV RT using fragment-based approach.

scholarly journals Influence of the α-Methoxy Group on the Reaction of Temocillin with Pseudomonas aeruginosa PBP3 and CTX-M-14 β-Lactamase

2019 ◽  
Vol 64 (1) ◽  
Author(s):  
Michael D. Sacco ◽  
Kyle G. Kroeck ◽  
M. Trent Kemp ◽  
Xiujun Zhang ◽  
Logan D. Andrews ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Active Site ◽  
Methoxy Group ◽  
Complex Structure ◽  
Antibacterial Properties ◽  
Multidrug Resistant ◽  
Binding Modes ◽  
Content Type ◽  
The Stability ◽  
M 14

ABSTRACT The prevalence of multidrug-resistant Pseudomonas aeruginosa has led to the reexamination of older “forgotten” drugs, such as temocillin, for their ability to combat resistant microbes. Temocillin is the 6-α-methoxy analogue of ticarcillin, a carboxypenicillin with well-characterized antipseudomonal properties. The α-methoxy modification confers resistance to serine β-lactamases, yet temocillin is ineffective against P. aeruginosa growth. The origins of temocillin’s inferior antibacterial properties against P. aeruginosa have remained relatively unexplored. Here, we analyze the reaction kinetics, protein stability, and binding conformations of temocillin and ticarcillin with penicillin-binding protein 3 (PBP3), an essential PBP in P. aeruginosa. We show that the 6-α-methoxy group perturbs the stability of the PBP3 acyl-enzyme, which manifests in an elevated off-rate constant (koff) in biochemical assays comparing temocillin with ticarcillin. Complex crystal structures with PBP3 reveal similar binding modes of the two drugs but with important differences. Most notably, the 6-α-methoxy group disrupts a high-quality hydrogen bond with a conserved residue important for ligand binding while also being inserted into a crowded active site, possibly destabilizing the active site and enabling water molecule from bulk solvent to access and cleave the acyl-enzyme bond. This hypothesis is supported by the observation that the acyl-enzyme complex of temocillin has reduced thermal stability compared with ticarcillin. Furthermore, we explore temocillin’s mechanism of β-lactamase inhibition with a high-resolution complex structure of CTX-M-14 class A serine β-lactamase. The results suggest that the α-methoxy group prevents hydrolysis by locking the compound into an unexpected conformation that impedes access of the catalytic water to the acyl-enzyme adduct.

scholarly journals An usual approach to treatment of a case of multidrug resistance Pseudomonas aeruginosa peritonitis: parenteral and intraperitoneal aminoglycosides and parenteral colistin

2012 ◽  
Vol 4 (1) ◽  
pp. 36 ◽  
Author(s):  
Ian May ◽  
Maha Abu-Khdeir ◽  
Roland Alexander Blackwood
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Drug Resistance ◽  
Intensive Care ◽  
Multidrug Resistance ◽  
Pleural Cavity ◽  
Abdominal Cavity ◽  
Multi Drug Resistance ◽  
Clinical Settings ◽  
Intravenous Antibiotics ◽  
Polymyxin E

Infections caused by <em>Pseudomonas aeruginosa </em>are becoming more common and increasingly more difficult to treat due to the continued development of drug resistance. While sensitivity to colistin (polymyxin E) is well known, it is frequently avoided due to concerns of nephrotoxicity. Reported here is a case of a multi-drug resistance pseudomonal typhlitis, bacteremia and pleural cavity infection that required significant intensive care, and serial abdominal washouts. Intra-peritoneal tobramycin in combination with broad-spectrum intravenous antibiotics including colistin were used. Several instillations of tobramycin into the abdominal cavity along with concomitant IV administration of colistin, ceftazidime and tobramycin and<em> per os</em> colistin, tobramycin and nystatin resulted in the clearance of the pseudomonal infection without any evidence of toxicity from the treatment. Intra-abdominal tobramycin with parenteral colistin therapy can be used in complicated clinical settings with appropriate nephroprotection.

scholarly journals In SilicoInvestigation of Potential Pyruvate Kinase M2 Regulators from Traditional Chinese Medicine against Cancers

2014 ◽  
Vol 2014 ◽  
pp. 1-14 ◽  
Author(s):  
Kuan-Chung Chen ◽  
Kuen-Bao Chen ◽  
Hsin-Yi Chen ◽  
Calvin Yu-Chian Chen
Keyword(s):  
Virtual Screening ◽  
Drug Development ◽  
Pyruvate Kinase ◽  
Md Simulation ◽  
Docking Simulation ◽  
Target Protein ◽  
Binding Affinities ◽  
Pyruvate Kinase M2 ◽  
Lead Compounds ◽  
The Stability

A recent research in cancer research demonstrates that tumor-specific pyruvate kinase M2 (PKM2) plays an important role in chromosome segregation and mitosis progression of tumor cells. To improve the drug development of TCM compounds, we aim to identify potent TCM compounds as lead compounds of PKM2 regulators. PONDR-Fit protocol was utilized to predict the disordered disposition in the binding domain of PKM2 protein before virtual screening as the disordered structure in the protein may cause the side effect and downregulation of the possibility of ligand to bind with target protein. MD simulation was performed to validate the stability of interactions between PKM2 proteins and each ligand after virtual screening. The top TCM compounds, saussureamine C and precatorine, extracted fromLycium chinenseMill. andAbrus precatoriusL., respectively, have higher binding affinities with target protein in docking simulation than control. They have stable H-bonds with residues A:Lys311 and some other residues in both chains of PKM2 protein. Hence, we propose the TCM compounds, saussureamine C and precatorine, as potential candidates as lead compounds for further study in drug development process with the PKM2 protein against cancer.

DRUG TARGET PRIORITIZATION IN PLASMODIUM FALCIPARUM THROUGH METABOLIC NETWORK ANALYSIS, AND INHIBITOR DESIGNING USING VIRTUAL SCREENING AND DOCKING APPROACH

2013 ◽  
Vol 11 (04) ◽  
pp. 1350003 ◽  
Author(s):  
MANOJ KUMAR YADAV ◽  
SAURABH KUMAR PANDEY ◽  
D. SWATI
Keyword(s):  
Plasmodium Falciparum ◽  
Network Analysis ◽  
Virtual Screening ◽  
Metabolic Network ◽  
Pharmacophore Model ◽  
Binding Pocket ◽  
Binding Modes ◽  
Metabolic Network Analysis ◽  
Screening Experiments ◽  
Monophosphate Decarboxylase

The genome sequence of Plasmodium falciparum reveals that many metabolic pathways are unique as compared to its human host. Metabolic Network Analysis was carried out to find the essential enzymes critical for the survival of the pathogen. In the present study, choke point and load point analysis was used to locate putative targets. The identified targets were further checked to confirm that no alternate pathway or human homolog exists. Among the top 15 enzymes obtained from this analysis, we have selected P. falciparum orotidine-5'-monophosphate decarboxylase (PfODCase) enzyme as it is sequentially and structurally different from that of humans, for searching novel inhibitors. A five-point 3D pharmacophore was generated for the crystal structure of PfODCase complexes with uridine-5'-monophosphate (U5P). The binding site environment shows three H-bond acceptors, one H-bond donor and one negative ionizable feature. This pharmacophore model was used as a 3D query to perform virtual screening experiments against 2,664,779 standard lead compounds obtained from the freely available ZINC database. Top 10 hits obtained from virtual screening were selected for molecular docking experiments against PfODCase in order to verify their results and to have a better insight into their binding modes. Here, docking of U5P with PfODCase is used as a control. We have identified six compounds, among them, few are U5P analogs and others are novel ones with diverse scaffolds. The key residues: Lys42, Asp20, Lys72, Ser127, Ala184, Gln185 and Arg203 at the main binding pocket of PfODCase are responsible for better stability of diverse ligands. These compounds according to their free energy of binding could serve as potent leads for designing novel inhibitors against malarial ODCase enzyme.

scholarly journals Identification of floR Variants Associated With a Novel Tn4371-Like Integrative and Conjugative Element in Clinical Pseudomonas aeruginosa Isolates

2021 ◽  
Vol 11 ◽  
Author(s):  
Changrui Qian ◽  
Hongmao Liu ◽  
Jiawei Cao ◽  
Yongan Ji ◽  
Wei Lu ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Drug Resistance ◽  
Respiratory Diseases ◽  
Essential Role ◽  
Multi Drug Resistance ◽  
Clinical Samples ◽  
Integrative And Conjugative Elements ◽  
Intestinal Infections ◽  
Clinical Pathogens ◽  
Integrative And Conjugative Element

Florfenicol is widely used to control respiratory diseases and intestinal infections in food animals. However, there are increasing reports about florfenicol resistance of various clinical pathogens. floR is a key resistance gene that mediates resistance to florfenicol and could spread among different bacteria. Here, we investigated the prevalence of floR in 430 Pseudomonas aeruginosa isolates from human clinical samples and identified three types of floR genes (designated floR, floR-T1 and floR-T2) in these isolates, with floR-T1 the most prevalent (5.3%, 23/430). FloR-T2 was a novel floR variant identified in this study, and exhibited less identity with other FloR proteins than FloRv. Moreover, floR-T1 and floR-T2 identified in P. aeruginosa strain TL1285 were functionally active and located on multi-drug resistance region of a novel incomplete Tn4371-like integrative and conjugative elements (ICE) in the chromosome. The expression of the two floR variants could be induced by florfenicol or chloramphenicol. These results indicated that the two floR variants played an essential role in the host’s resistance to amphenicol and the spreading of these floR variants might be related with the Tn4371 family ICE.

Identification of FDA Approved Drugs Targeting COVID-19 Virus by Structure-Based Drug Repositioning (Version 2)

2020 ◽  
Author(s):  
Ayman Farag ◽  
Ping Wang ◽  
Mahmoud Ahmed ◽  
Hesham Sadek
Keyword(s):  
Drug Repositioning ◽  
Substrate Binding ◽  
Binding Pocket ◽  
Binding Energies ◽  
Binding Modes ◽  
Substrate Binding Pocket ◽  
Protease Enzyme ◽  
Starting Point ◽  
Approved Drugs ◽  
Fda Approved Drugs

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 against Covid-19 virus main protease enzyme (Mpro) substrate-binding pocket focusing on two potential sites (central and terminal sites) 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 substrate-binding pocket. The top hits bound to the central site of Mpro substrate-binding pocket include antiviral drugs such as Darunavir, Nelfinavir and 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. In addition, the top hits bound to the terminal site of Mpro substrate-binding pocket include the anti-asthma drug Montelukast and the anti-histaminic Fexofenadine among others. 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.<br>

scholarly journals Molecular simulations reveal the impact of RAMP1 on ligand binding and dynamics of CGRPR heterodimer

2021 ◽  
Author(s):  
Busecan Aksoydan ◽  
Serdar Durdagi
Keyword(s):  
Ligand Binding ◽  
Pain Perception ◽  
Md Simulations ◽  
Binding Pocket ◽  
Binding Modes ◽  
Cgrp Receptor ◽  
Tm Domain ◽  
The Stability ◽  
Global And Local ◽  
The Impact

The release of the neuropeptide of calcitonin gene-related peptide (CGRP) plays a key role in the mechanisms of migraine pathology and pain perception as it causes vasodilatation, neurogenic inflammation, mast cell degranulation, sensory signal activation and peripheral sensitivity. Although the findings on the effectiveness of CGRP-targeted therapies in migraine provide new information about the pathophysiology of migraine, questions remain on how the CGRP mechanisms fit into the overall migraine theory. The cryo-EM structure of Gs-protein complexed human CGRP receptor (CGRPR) with bound endogenous CGRP neuropeptide paved the way of understanding the insights into the CGRP receptor function. With several molecular modeling approaches, molecular dynamics (MD) simulations and post-MD analyzes, we aimed to investigate the importance of RAMP1 in the stability of calcitonin receptor-like receptor (CLR). Moreover, we compared the binding modes of the CGRP neuropeptide and CGRPR antagonists (i.e., telcagepant and rimegepant) within the presence or absence of RAMP1. We also investigated the global and local effects of bound molecules on CGRPR as well as their effects on the CLR-RAMP1 interaction interfaces. Results showed that although these molecules stay stable at the ectodomain binding site, they can also bind to the orthosteric ligand binding pocket and form the crucial interactions occurred in the CGRP agonism, which may be interpreted as non-specificity of the ligands, however, most of these interactions at orthosteric site are not sustainable or weak. Particularly, RAMP1 may also be important for the stability of TM domain of CLR hereby stabilizing the orthosteric binding pocket.

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