scholarly journals In silico analysis of interaction of compounds, containing photoactivatable groups,with human CYP7 enzymes

2020 ◽  
Vol 64 (5) ◽  
pp. 558-566
Author(s):  
Ya. U. Dzichenka ◽  
M. S. Horetski ◽  
Ya. V. Faletrov ◽  
A. V. Yantsevich ◽  
V. M. Shkumatov ◽  
...  
Keyword(s):  
In Silico ◽  
Binding Mode ◽  
Amino Acid Residues ◽  
Structural Peculiarities ◽  
Close Proximity ◽  
Mechanism Of Interaction ◽  
Covalent Adducts ◽  
Steroid Hydroxylases ◽  
Shed Light

In silico analysis of “protein-ligand” complexes of human CYP7 enzymes with modified borondipyrrome-tene (BODIPY) and steroids, containing photo-activated crosslinking groups, wasperformed in order to identify structural peculiarities of their interaction. It was found that BODIPY molecules and DHEA derivative with diazirine group are able to bind tightly with human steroid-hydroxylases. Binding affinity is comparable with corresponding values for essential ligands of the enzymes. Binding mode of the modified steroid corresponds to the binding mode of essential CYP7 ligands, so formation of hydroxylated products is possible. It was found that presence of both diazirine and NBD groups in a molecule significantly increases affinity of the compound in case of CYP7A1 and, especially, CYP7B1. Amino acid residues, located in a close proximity with photo-activated groups were detected, that can form covalent adducts with them. The obtained results can shed light on the mechanism of interaction of the compounds with recombinant human CYP7 enzymes in vitro. The results can also be used for the identification of modified amino acids of the proteins that are formed under photoactivation of the compounds in vitro.

scholarly journals Distinct Subregions of Swi1 Manifest Striking Differences in Prion Transmission and SWI/SNF Function

2010 ◽  
Vol 30 (19) ◽  
pp. 4644-4655 ◽  
Author(s):  
Zhiqiang Du ◽  
Emily T. Crow ◽  
Hyun Seok Kang ◽  
Liming Li
Keyword(s):  
Chromatin Remodeling ◽  
De Novo ◽  
Amino Acid Residues ◽  
Coding Region ◽  
Conformational Switch ◽  
Amyloid Fibers ◽  
Aggregation Pattern ◽  
Prion Transmission ◽  
Shed Light

ABSTRACT We have recently reported that the yeast chromatin-remodeling factor Swi1 can exist as a prion, [SWI +], demonstrating a link between prionogenesis and global transcriptional regulation. To shed light on how the Swi1 conformational switch influences Swi1 function and to define the sequence and structural requirements for [SWI +] formation and propagation, we functionally dissected the Swi1 molecule. We show here that the [SWI +] prion features are solely attributable to the first 327 amino acid residues (N), a region that is asparagine rich. N was aggregated in [SWI+ ] cells but diffuse in [swi− ] cells; chromosomal deletion of the N-coding region resulted in [SWI +] loss, and recombinant N peptide was able to form infectious amyloid fibers in vitro, enabling [SWI +] de novo formation through a simple transformation. Although the glutamine-rich middle region (Q) was not sufficient to aggregate in [SWI +] cells or essential for SWI/SNF function, it significantly modified the Swi1 aggregation pattern and Swi1 function. We also show that excessive Swi1 incurred Li+/Na+ sensitivity and that the N/Q regions are important for this gain of sensitivity. Taken together, our results provide the final proof of “protein-only” transmission of [SWI +] and demonstrate that the widely distributed “dispensable” glutamine/asparagine-rich regions/motifs might have important and divergent biological functions.

Chemical synthesis and characterization of a new quinazolinedione competitive antagonist for strigolactone receptors with an unexpected binding mode

2019 ◽  
Vol 476 (12) ◽  
pp. 1843-1856 ◽  
Author(s):  
Cyril Hamiaux ◽  
Lesley Larsen ◽  
Hui Wen Lee ◽  
Zhiwei Luo ◽  
Prachi Sharma ◽  
...  
Keyword(s):  
In Silico ◽  
Binding Mode ◽  
Crystal Structure Analysis ◽  
Tolfenamic Acid ◽  
In Vitro Assays ◽  
Inhibition Mechanism ◽  
In Planta ◽  
Competitive Antagonist ◽  
In Silico Docking

Abstract Strigolactones (SLs) are multifunctional plant hormones regulating essential physiological processes affecting growth and development. In vascular plants, SLs are recognized by α/β hydrolase-fold proteins from the D14/DAD2 (Dwarf14/Decreased Apical Dominance 2) family in the initial step of the signaling pathway. We have previously discovered that N-phenylanthranilic acid derivatives (e.g. tolfenamic acid) are potent antagonists of SL receptors, prompting us to design quinazolinone and quinazolinedione derivatives (QADs and QADDs, respectively) as second-generation antagonists. Initial in silico docking studies suggested that these compounds would bind to DAD2, the petunia SL receptor, with higher affinity than the first-generation compounds. However, only one of the QADs/QADDs tested in in vitro assays acted as a competitive antagonist of SL receptors, with reduced affinity and potency compared with its N-phenylanthranilic acid ‘parent’. X-ray crystal structure analysis revealed that the binding mode of the active QADD inside DAD2's cavity was not that predicted in silico, highlighting a novel inhibition mechanism for SL receptors. Despite a ∼10-fold difference in potency in vitro, the QADD and tolfenamic acid had comparable activity in planta, suggesting that the QADD compensates for lower potency with increased bioavailability. Altogether, our results establish this QADD as a novel lead compound towards the development of potent and bioavailable antagonists of SL receptors.

Antiviral Potential of Spondias mombin L. Leaves Extract Against Herpes Simplex Virus Type-1 Replication Using In Vitro and In Silico Approaches

Planta Medica ◽  
2020 ◽  
Vol 86 (07) ◽  
pp. 505-515 ◽  
Author(s):  
Emerson M. da S. Siqueira ◽  
Tábata L. C. Lima ◽  
Laurita Boff ◽  
Sarah G. M. Lima ◽  
Estela M. G. Lourenço ◽  
...  
Keyword(s):  
In Silico ◽  
Therapeutic Potential ◽  
Binding Mode ◽  
Surface Glycoprotein ◽  
Viral Attachment ◽  
Docking Simulations ◽  
Simplex Virus ◽  
Hsv 1

Abstract Spondias mobin leaves have been traditionally used for treating cold sores. The study investigated the mechanism of antiherpes action of S. mombin extract, fractions, and geraniin. Different concentrations of samples were used to evaluate the in vitro antiherpes activity (anti-HSV-1) in virucidal, post-infection, attachment, and penetration assays. The mechanism of action of geraniin was investigated considering the glycoproteins gB and gD of HSV-1 surface as potential molecular targets. Molecular docking simulations were carried out for both in order to determine the possible binding mode position of geraniin at the activity sites. The binding mode position was posteriorly optimized considering the flexibility of the glycoproteins. The chemical analysis of samples was performed by LC-MS and revealed the presence of 22 substances, which are hydrolysable tannins, O-glycosylated flavonoids, phenolic acids, and a carbohydrate. The extract, tannin-rich fraction and geraniin showed important in vitro virucidal activity through blocking viral attachment but showed no relevant inhibition of viral penetration. The in silico approaches demonstrated a high number of potential strong intermolecular interactions as hydrogen bonds between geraniin and the activity site of the glycoproteins, particularly the glycoprotein gB. In silico experiments indicated that geraniin is at least partially responsible for the anti-herpes activity through interaction with the viral surface glycoprotein gB, which is responsible for viral adsorption. These results highlight the therapeutic potential of S. mombin anti-herpes treatment and provides support for its traditional purposes. However, further studies are required to validate the antiviral activities in vivo, as well as efficacy in humans.

scholarly journals Agent-based Models for Detecting the Driving Forces of Biomolecular Interactions

2021 ◽  
Author(s):  
Stefano Maestri ◽  
Emanuela Merelli ◽  
Marco Pettini
Keyword(s):  
In Silico ◽  
Autonomous Agents ◽  
High Efficiency ◽  
Driving Forces ◽  
Agent Based ◽  
Biochemical Processes ◽  
Agent Based Modelling ◽  
Electrodynamic Forces ◽  
Shed Light

Abstract Agent-based modelling and simulation have been effectively applied to the study of complex biological systems, especially when composed by a large number of interacting entities. Representing biomolecules as autonomous agents allows this approach to bring out the global behaviour of biochemical processes as resulting from local molecular interactions. In this paper, we leverage the capabilities of the agent paradigm to construct an in silico replica of the glycolytic pathway of baker’s yeasts; the aim is to detect the role that long-range electrodynamic forces might have on the rate of glucose oxidation. Experimental evidences have shown that random encounters and short-range potentials might not be sufficient to explain the high efficiency of biochemical reactions in living cells. However, while the latest in vitro studies are limited by the present-day technology, agent-based simulations provide an in silico support to the outcomes hitherto obtained and shed light on behaviours not yet well understood. Our results reveal to be able to grasp properties hard to uncover through other computational methods, such as the effect of electromagnetic potentials on glycolytic oscillations.

In Vitro, Molecular Docking, and In Silico Binding Mode Analysis of Organic Compounds for Antimicrobial and Anticancer Activity against Jurkat, HCT116, and A549 Cell Lines.

2020 ◽  
Vol 5 (41) ◽  
pp. 12807-12818
Author(s):  
Sanay Naha ◽  
Shivaraja Govindaiah ◽  
Swamy Sreenivasa ◽  
Jeevan Kallur Prakash ◽  
Sivan Velmathi
Keyword(s):  
Molecular Docking ◽  
Anticancer Activity ◽  
Organic Compounds ◽  
Cell Lines ◽  
A549 Cell ◽  
In Silico ◽  
Binding Mode ◽  
Mode Analysis

scholarly journals Discovery of Two Brominated Oxindole Alkaloids as Staphylococcal DNA Gyrase and Pyruvate Kinase Inhibitors via Inverse Virtual Screening

2020 ◽  
Vol 8 (2) ◽  
pp. 293 ◽  
Author(s):  
Ahmed M. Sayed ◽  
Hani A. Alhadrami ◽  
Seham S. El-Hawary ◽  
Rabab Mohammed ◽  
Hossam M. Hassan ◽  
...  
Keyword(s):  
Natural Products ◽  
Virtual Screening ◽  
Pyruvate Kinase ◽  
Inhibitory Activity ◽  
In Silico ◽  
Kinase Inhibitors ◽  
Enzyme Inhibitor ◽  
Dna Gyrase ◽  
Binding Mode

In the present study, a small marine-derived natural products library was assessed for antibacterial potential. Among 36 isolated compounds, a number of bis-indole derivatives exhibited growth-inhibitory activity towards Gram-positive strains (Bacillus subtilis and multidrug-resistant Staphylococcus aureus). 5- and 6-trisindoline (5-Tris and 6-Tris) were the most active derivatives (minimum inhibitory concentration, MIC, 4–8 µM) that were subsequently selected for anti-biofilm activity evaluation. Only 5-Tris was able to inhibit the staphylococcal biofilm formation starting at a 5 µM concentration. In order to investigate their possible molecular targets, both natural products were subjected to in silico inverse virtual screening. Among 20 target proteins, DNA gyrase and pyruvate kinase were the most likely to be involved in the observed antibacterial and anti-biofilm activities of both selected natural products. The in vitro validation and in silico binding mode studies revealed that 5-Tris could act as a dual enzyme inhibitor (IC50 11.4 ± 0.03 and 6.6 ± 0.05 µM, respectively), while 6-Tris was a low micromolar gyrase-B inhibitor (IC50 2.1 ± 0.08 µM), indicating that the bromine position plays a crucial role in the determination of the antibacterial lead compound inhibitory activity.

scholarly journals 4-Amino-1,2,4-triazole-3-thione as a Promising Scaffold for the Inhibition of Serine and Metallo-β-Lactamases

2020 ◽  
Vol 13 (3) ◽  
pp. 52 ◽  
Author(s):  
Pasquale Linciano ◽  
Eleonora Gianquinto ◽  
Martina Montanari ◽  
Lorenzo Maso ◽  
Pierangelo Bellio ◽  
...  
Keyword(s):  
In Silico ◽  
Binding Mode ◽  
Clinical Strains ◽  
Class A ◽  
Lactam Antibiotic ◽  
Inhibition Potency ◽  
In Silico Analyses

The emergence of bacteria that co-express serine- and metallo- carbapenemases is a threat to the efficacy of the available β-lactam antibiotic armamentarium. The 4-amino-1,2,4-triazole-3-thione scaffold has been selected as the starting chemical moiety in the design of a small library of β-Lactamase inhibitors (BLIs) with extended activity profiles. The synthesised compounds have been validated in vitro against class A serine β−Lactamase (SBLs) KPC-2 and class B1 metallo β−Lactamases (MBLs) VIM-1 and IMP-1. Of the synthesised derivatives, four compounds showed cross-class micromolar inhibition potency and therefore underwent in silico analyses to elucidate their binding mode within the catalytic pockets of serine- and metallo-BLs. Moreover, several members of the synthesised library have been evaluated, in combination with meropenem (MEM), against clinical strains that overexpress BLs for their ability to synergise carbapenems.

Oxasetin from Lophiostoma sp. of the Baltic Sea: Identification, in silico Binding Mode Prediction and Antibacterial Evaluation against Fish Pathogenic Bacteria

2013 ◽  
Vol 8 (9) ◽  
pp. 1934578X1300800 ◽  
Author(s):  
Muftah Ali M. Shushni ◽  
Faizul Azam ◽  
Ulrike Lindequist
Keyword(s):  
Baltic Sea ◽  
In Silico ◽  
Pathogenic Bacteria ◽  
Vibrio Anguillarum ◽  
Binding Mode ◽  
Docking Studies ◽  
The Baltic Sea ◽  
Minimal Inhibitory Concentrations ◽  
The Baltic

Because of the evolving resistance of microorganisms against existing antibiotics, there is an increasing need for new ones, not only in human, but also in veterinary medicine. The dichloromethane extract of a fungal strain of the genus Lophiostoma, isolated from driftwood collected from the coast of the Baltic Sea, displayed antibacterial activity against some fish pathogenic bacteria. Ergosterol epoxide (1), cerebroside C (2) and oxasetin (3) were isolated from the extract and structurally elucidated on the basis of spectroscopic data and chemical evidence. Compound 3 exhibited in vitro activity against Vibrio anguillarum, Flexibacter maritimus and Pseudomonas anguilliseptica with minimal inhibitory concentrations of 12.5, 12.5 and 6.25 μg/mL, respectively. Molecular docking studies were performed to understand the interaction of compound 3 with different macromolecular targets. Analysis of in silico results, together with experimental findings, validates the antimicrobial activity associated with compound 3. These results may be exploited in lead optimization and development of potent antibacterial agents.

scholarly journals Design, Synthesis, Antihyperglycemic Studies, and Docking Simulations of Benzimidazole-Thiazolidinedione Hybrids

2019 ◽  
Vol 2019 ◽  
pp. 1-8 ◽  
Author(s):  
Abraham Gutierréz-Hernández ◽  
Yelzyn Galván-Ciprés ◽  
Elix Alberto Domínguez-Mendoza ◽  
Yoshajandith Aguirre-Vidal ◽  
Samuel Estrada-Soto ◽  
...  
Keyword(s):  
Mrna Expression ◽  
In Silico ◽  
Knoevenagel Condensation ◽  
Binding Mode ◽  
Spectral Studies ◽  
Design Synthesis ◽  
Docking Simulations ◽  
Step Procedure

A simple and cheap three-step procedure for the synthesis of three (5Z)-5-[3(4)-(1H-benzimidazol-2-ylmethoxy)benzylidene]-1,3-thiazolidine-2,4-diones has been described via a SN2 reaction of generally recognized as safe hydroxybenzaldehydes and 2-(chloromethyl)-1H-benzimidazole, followed by a Knoevenagel condensation with thiazolidine-2,4-dione in moderated yields. All the newly synthesized compounds were characterized using analytical and spectral studies. In vitro treatment on adipocytes with compounds increased the mRNA expression of two proteins recognized as strategic targets in diabetes: PPARγ and GLUT-4. In silico studies were conducted in order to explain the interaction binding mode of the synthesized compounds on PPARγ. In vivo studies confirmed that compounds 1–3 have robust antihyperglycemic action linked to insulin sensitization mechanisms. The present study provides three compounds with a promising antidiabetic action.

scholarly journals SARS-CoV-2 Papain-Like Protease Potential Inhibitors—In Silico Quantitative Assessment

2021 ◽  
Vol 22 (8) ◽  
pp. 3957
Author(s):  
Adam Stasiulewicz ◽  
Alicja W. Maksymiuk ◽  
Mai Lan Nguyen ◽  
Barbara Bełza ◽  
Joanna I. Sulkowska
Keyword(s):  
In Silico ◽  
Multiple Linear Regression Model ◽  
Binding Mode ◽  
Host Proteins ◽  
Human Ubiquitin ◽  
Ic50 Values ◽  
Potential Activity ◽  
Carboxy Terminal ◽  
Potential Inhibitors

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) encodes the papain-like protease (PLpro). The protein not only plays an essential role in viral replication but also cleaves ubiquitin and ubiquitin-like interferon-stimulated gene 15 protein (ISG15) from host proteins, making it an important target for developing new antiviral drugs. In this study, we searched for novel, noncovalent potential PLpro inhibitors by employing a multistep in silico screening of a 15 million compound library. The selectivity of the best-scored compounds was evaluated by checking their binding affinity to the human ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), which, as a deubiquitylating enzyme, exhibits structural and functional similarities to the PLpro. As a result, we identified 387 potential, selective PLpro inhibitors, from which we retrieved the 20 best compounds according to their IC50 values toward PLpro estimated by a multiple linear regression model. The selected candidates display potential activity against the protein with IC50 values in the nanomolar range from approximately 159 to 505 nM and mostly adopt a similar binding mode to the known, noncovalent SARS-CoV-2 PLpro inhibitors. We further propose the six most promising compounds for future in vitro evaluation. The results for the top potential PLpro inhibitors are deposited in the database prepared to facilitate research on anti-SARS-CoV-2 drugs.

Sign in / Sign up

Export Citation Format

Share Document