scholarly journals Design of novel hybrid secondary metabolite targets to diguanylate cyclase of Acinetobacter baumannii

FEMS Microbes ◽  
2021 ◽  
Vol 2 ◽  
Author(s):  
Monalisa Tiwari ◽  
Richa Joshi ◽  
Vishvanath Tiwari
Keyword(s):  
Secondary Metabolites ◽  
Acinetobacter Baumannii ◽  
Active Site ◽  
Solvent Accessibility ◽  
Plant Secondary Metabolites ◽  
Positive Control ◽  
Dynamics Simulation ◽  
Diguanylate Cyclase ◽  
Active Site Residues ◽  
Hybrid Molecule

Abstract Biofilm formation in bacteria is a resistance determinant and is positively regulated by cyclic diguanylate signaling. This signaling is a near universal signaling, and c-di-GMP produced by diguanylate cyclase (DGC) in this signaling is involved in different bacterial behaviors. The present study aims to find a plant-based novel hybrid therapeutic agent that can target the DGC of Acinetobacter baumannii. In this study, we have tried to design a hybrid molecule from the anti-biofilm plant secondary metabolites and screened its binding with the DGC of A. baumannii. The modeled and validated DGC was used to identify the active site and docking grid. Designed hybrid compounds were analysed for their interaction with the active site residues of DGC of A. baumannii. Further, the binding free energies of the docked complexes obtained from the Generalized Born model and Solvent Accessibility (MMGBSA) were analysed. The results indicated that VR-QEg-180 has a predicted high binding affinity with enzyme DGC as compared to other hybrids, parent secondary metabolites and positive control. Molecular dynamics simulation (MDS) analysis confirmed the interaction of VR-QEg-180 with DGC of the A. baumannii. The designed lead has favorable ADMET properties, has no human off-targets and has no predicted cytotoxicity in cell lines. Therefore, the designed hybrid molecule (VR-QEg-180) targeting the DGC of A. baumannii may play a very significant role in controlling this pathogen.

scholarly journals Activation and selectivity of OTUB-1 and OTUB-2 deubiquitinylases

2020 ◽  
Vol 295 (20) ◽  
pp. 6972-6982
Author(s):  
Dakshinamurthy Sivakumar ◽  
Vikash Kumar ◽  
Michael Naumann ◽  
Matthias Stein
Keyword(s):  
Active Site ◽  
Electrostatic Interactions ◽  
Active Form ◽  
Cysteine Proteases ◽  
Binding Pocket ◽  
Catalytic Triad ◽  
Catalytic Site ◽  
Dynamics Simulation ◽  
Active Site Residues ◽  
Catalytically Active

The ovarian tumor domain (OTU) deubiquitinylating cysteine proteases OTUB1 and OTUB2 (OTU ubiquitin aldehyde binding 1 and 2) are representative members of the OTU subfamily of deubiquitinylases. Deubiquitinylation critically regulates a multitude of important cellular processes, such as apoptosis, cell signaling, and growth. Moreover, elevated OTUB expression has been observed in various cancers, including glioma, endometrial cancer, ovarian cancer, and breast cancer. Here, using molecular dynamics simulation approaches, we found that both OTUB1 and OTUB2 display a catalytic triad characteristic of proteases but differ in their configuration and protonation states. The OTUB1 protein had a prearranged catalytic site, with strong electrostatic interactions between the active-site residues His265 and Asp267. In OTUB2, however, the arrangement of the catalytic triad was different. In the absence of ubiquitin, the neutral states of the catalytic-site residues in OTUB2 were more stable, resulting in larger distances between these residues. Only upon ubiquitin binding did the catalytic triad in OTUB2 rearrange and bring the active site into a catalytically feasible state. An analysis of water access channels revealed only a few diffusion trajectories for the catalytically active form of OTUB1, whereas in OTUB2 the catalytic site was solvent-accessible, and a larger number of water molecules reached and left the binding pocket. Interestingly, in OTUB2, the catalytic residues His224 and Asn226 formed a stable hydrogen bond. We propose that the observed differences in activation kinetics, protonation states, water channels, and active-site accessibility between OTUB1 and OTUB2 may be relevant for the selective design of OTU inhibitors.

scholarly journals Computational Elucidation of Structural Basis for Ligand Binding withLeishmania donovaniAdenosine Kinase

2013 ◽  
Vol 2013 ◽  
pp. 1-14 ◽  
Author(s):  
Rajiv K. Kar ◽  
Md. Yousuf Ansari ◽  
Priyanka Suryadevara ◽  
Bikash R. Sahoo ◽  
Ganesh C. Sahoo ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Active Site ◽  
Protein Complex ◽  
Leishmania Donovani ◽  
Homology Model ◽  
Adenosine Kinase ◽  
Dynamics Simulation ◽  
Structural Basis ◽  
Active Site Residues ◽  
Drug Candidates

Enzyme adenosine kinase is responsible for phosphorylation of adenosine to AMP and is crucial for parasites which are purine auxotrophs. The present study describes development of robust homology model ofLeishmania donovaniadenosine kinase to forecast interaction phenomenon with inhibitory molecules using structure-based drug designing strategy. Docking calculation using reported organic small molecules and natural products revealed key active site residues such as Arg131 and Asp16 for ligand binding, which is consistent with previous studies. Molecular dynamics simulation of ligand protein complex revealed the importance of hydrogen bonding with active site residues and solvent molecules, which may be crucial for successful development of drug candidates. Precise role of Phe168 residue in the active site was elucidated in this report that provided stability to ligand-protein complex via aromatic-πcontacts. Overall, the present study is believed to provide valuable information to design a new compound with improved activity for antileishmanial therapeutics development.

scholarly journals Crystal Structure of Carbapenemase OXA-58 from Acinetobacter baumannii

2014 ◽  
Vol 58 (4) ◽  
pp. 2135-2143 ◽  
Author(s):  
Clyde A. Smith ◽  
Nuno Tiago Antunes ◽  
Marta Toth ◽  
Sergei B. Vakulenko
Keyword(s):  
Water Molecule ◽  
Acinetobacter Baumannii ◽  
Active Site ◽  
Bacterial Infections ◽  
Surrounding Medium ◽  
Active Site Residues ◽  
Content Type ◽  
Class D ◽  
Enzyme Complexes ◽  
Wide Dissemination

ABSTRACTClass D β-lactamases capable of hydrolyzing last-resort carbapenem antibiotics represent a major challenge for treatment of bacterial infections. Wide dissemination of these enzymes inAcinetobacter baumanniielevated this pathogen to the category of most deadly and difficult to treat. We present here the structure of the OXA-58 β-lactamase, a major class D carbapenemase ofA. baumannii, determined to 1.30-Å resolution. Unlike two otherAcinetobactercarbapenemases, OXA23 and OXA-24, the OXA-58 enzyme lacks the characteristic hydrophobic bridge over the active site, despite conservation of the residues which participate in its formation. The active-site residues in OXA-58 are spatially conserved in comparison to those in other class D β-lactamases. Lys86, which activates water molecules during the acylation and deacylation steps, is fully carboxylated in the OXA-58 structure. In the absence of a substrate, a water molecule is observed in the active site of the enzyme and is positioned in the pocket that is usually occupied by the 6α-hydroxyethyl moiety of carbapenems. A water molecule in this location would efficiently deacylate good substrates, such as the penicillins, but in the case of carbapenems, it would be expelled by the 6α-hydroxyethyl moiety of the antibiotics and a water from the surrounding medium would find its way to the vicinity of the carboxylated Lys86 to perform deacylation. Subtle differences in the position of this water in the acyl-enzyme complexes of class D β-lactamases could ultimately be responsible for differences in the catalytic efficiencies of these enzymes against last-resort carbapenem antibiotics.

scholarly journals In silico studies evidenced the role of structurally diverse plant secondary metabolites in reducing SARS-CoV-2 pathogenesis

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Hariprasad Puttaswamy ◽  
Hittanahallikoppal Gajendramurthy Gowtham ◽  
Monu Dinesh Ojha ◽  
Ajay Yadav ◽  
Gourav Choudhir ◽  
...  
Keyword(s):  
Secondary Metabolites ◽  
Active Site ◽  
Plant Secondary Metabolites ◽  
Natural Occurrence ◽  
Primary Concern ◽  
In Vivo Evaluation ◽  
Target Proteins ◽  
In Silico Studies

AbstractPlants are endowed with a large pool of structurally diverse small molecules known as secondary metabolites. The present study aims to virtually screen these plant secondary metabolites (PSM) for their possible anti-SARS-CoV-2 properties targeting four proteins/ enzymes which govern viral pathogenesis. Results of molecular docking with 4,704 ligands against four target proteins, and data analysis revealed a unique pattern of structurally similar PSM interacting with the target proteins. Among the top-ranked PSM which recorded lower binding energy (BE), > 50% were triterpenoids which interacted strongly with viral spike protein—receptor binding domain, > 32% molecules which showed better interaction with the active site of human transmembrane serine protease were belongs to flavonoids and their glycosides, > 16% of flavonol glycosides and > 16% anthocyanidins recorded lower BE against active site of viral main protease and > 13% flavonol glycoside strongly interacted with active site of viral RNA-dependent RNA polymerase. The primary concern about these PSM is their bioavailability. However, several PSM recorded higher bioavailability score and found fulfilling most of the drug-likeness characters as per Lipinski's rule (Coagulin K, Kamalachalcone C, Ginkgetin, Isoginkgetin, 3,3′-Biplumbagin, Chrysophanein, Aromoline, etc.). Natural occurrence, bio-transformation, bioavailability of selected PSM and their interaction with the target site of selected proteins were discussed in detail. Present study provides a platform for researchers to explore the possible use of selected PSM to prevent/ cure the COVID-19 by subjecting them for thorough in vitro and in vivo evaluation for the capabilities to interfering with the process of viral host cell recognition, entry and replication.

scholarly journals Clinical Variants of the Native Class D β-Lactamase of Acinetobacter baumannii Pose an Emerging Threat through Increased Hydrolytic Activity against Carbapenems

2016 ◽  
Vol 60 (10) ◽  
pp. 6155-6164 ◽  
Author(s):  
Emma C. Schroder ◽  
Zachary L. Klamer ◽  
Aysegul Saral ◽  
Kyle A. Sugg ◽  
Cynthia M. June ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Active Site ◽  
Hydrolytic Activity ◽  
Single Amino Acid ◽  
Kinetic Properties ◽  
Active Site Residues ◽  
Content Type ◽  
Class D ◽  
Clinical Variants ◽  
Dynamics Simulations

ABSTRACTThe threat posed by the chromosomally encoded class D β-lactamase ofAcinetobacter baumannii(OXA-51/66) has been unclear, in part because of its relatively low affinity and turnover rate for carbapenems. Several hundred clinical variants of OXA-51/66 have been reported, many with substitutions of active-site residues. We determined the kinetic properties of OXA-66 and five clinical variants with respect to a wide variety of β-lactam substrates. The five variants displayed enhanced activity against carbapenems and in some cases against penicillins, late-generation cephalosporins, and the monobactam aztreonam. Molecular dynamics simulations show that in OXA-66, P130 inhibits the side-chain rotation of I129 and thereby prevents doripenem binding because of steric clash. A single amino acid substitution at this position (P130Q) in the variant OXA-109 greatly enhances the mobility of both I129 and a key active-site tryptophan (W222), thereby facilitating carbapenem binding. This expansion of substrate specificity represents a very worrisome development for the efficacy of β-lactams against this troublesome pathogen.

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