30 research outputs found
Exploring the Antiviral Potential of Natural Compounds against Influenza: A Combined Computational and Experimental Approach
No full textThe influenza A virus nonstructural protein 1 (NS1), which is crucial for viral replication and immune evasion, has been identified as a significant drug target with substantial potential to contribute to the fight against influenza. The emergence of drug-resistant influenza A virus strains highlights the urgent need for novel therapeutics. This study proposes a combined theoretical criterion for the virtual screening of molecular libraries to identify candidate NS1 inhibitors. By applying the criterion to the ZINC Natural Product database, followed by ligand-based virtual screening and molecular docking, we proposed the most promising candidate as a potential NS1 inhibitor. Subsequently, the selected natural compound was experimentally evaluated, revealing measurable virus replication inhibition activity in cell culture. This approach offers a promising avenue for developing novel anti-influenza agents targeting the NS1 protei
On the relationship between molecular spectroscopy and statistical mechanics: Calculation of partition functions for triatomic molecules undergoing large-amplitude bending vibrations
No full textThe evaluation of partition functions for triatomic molecules undergoing
large-amplitude bending vibrations is discussed. It was supposed that the
needed molecular structure data were obtained by means of ab initio
calculations. Special attention is paid to the coupling between the bending
and stretching modes and the interplay between bending motions and rotations.
An appropriate scheme for variational computation of the energy levels is
developed.</jats:p
Direct-Acting Antiviral Drugs for Treatment of Hepatitis C Virus Infection-Clinical Trials Data and Chemistry of NS3/4a Protease Inhibitors
No full textThe hepatitis C virus (HCV) infection is a major and rising global health problem, affecting more than 71 million people worldwide. HCV is connected with several hepatic and extrahepatic disorders, containing several malignancies. Improved HCV detection with combined simple, well-tolerated treatments could reduce the need for liver transplantation and HCV related mortality. The latest therapeutic advances might convert chronic HCV into a routinely treatable disease. The introduction of direct-acting antivirals (DAAs) has improved efficacy and tolerance of treatments with high cure rates. DAAs target specific nonstructural proteins of the HCV with consequential interference with viral replication and consequently infection. The majority of the FDA approved drugs for HCV and those pending approval are small molecule drugs, especially those that utilize the viral inhibitor mechanisms of action and favor the HCV nonstructural proteins as their targets. Therefore, DAAs represent the most promising anti-HCV drugs that carry the least risk of drug failure during clinical trials. NS3/4a protease inhibitors have become the basis for HCV treatment as most new therapies contain an inhibitor from this class. It is reported that the approach for combating chronic viral infections is best achieved by a combination of several strategies, by means of inhibiting several targets. Moreover, the best promising strategy for fighting HCV is most similar to the anti-HIV therapy. A literature review was conducted to identify published clinical trial results regarding DAA combination therapy with third generation NS3/4a protease inhibitors. Detailed attention is given to the chemistry of the approved NS3/4a drugs and candidate therapeutics in the advanced stages of development. In this regard, a review of key drug design and organic synthesis stages is presented for anti-NS3/4A DAAs. © 2020 Bentham Science Publishers. All rights reserved
Influenza a Virus Inhibition: Evaluating Computationally Identified Cyproheptadine Through In Vitro Assessment
No full textInfluenza is still a chronic global health threat, inducing a sustained search for effective antiviral therapeutics. Computational methods have played a pivotal role in developing small molecule therapeutics. In this study, we applied a combined in silico and in vitro approach to explore the potential anti-influenza activity of cyproheptadine, a clinically used histamine H1 receptor antagonist. Virtual screening based on the average quasivalence number (AQVN) and electron–ion interaction potential (EIIP) descriptors suggests similarities between cyproheptadine and several established anti-influenza agents. The subsequent ligand-based pharmacophore screening of a focused H1 antagonist library was aligned with the bioinformatics prediction, and further experimental in vitro evaluation of cyproheptadine demonstrated its anti-influenza activity. These findings provide proof of concept for cyproheptadine’s in silico-predicted antiviral potential and underscore the value of integrating computational predictions with experimental validation. The results of the current study provide a preliminary proof of concept for the predicted anti-influenza potential based on computational analysis and emphasize the utility of integrating in silico screening with experimental validation in the early stages of drug repurposing efforts
In silico analysis suggests interaction between Ebola virus and the extracellular matrix
No full textabstract: The worst Ebola virus (EV) outbreak in history has hit Liberia, Sierra Leone and Guinea hardest and the trend lines in this crisis are grave, and now represents a global public health threat concern. Limited therapeutic and/or prophylactic options are available for people suffering from Ebola virus disease (EVD) and further complicate the situation. Previous studies suggested that the EV glycoprotein (GP) is the main determinant causing structural damage of endothelial cells that triggers the hemorrhagic diathesis, but molecular mechanisms underlying this phenomenon remains elusive. Using the informational spectrum method (ISM), a virtual spectroscopy method for analysis of the protein-protein interactions, the interaction of GP with endothelial extracellular matrix (ECM) was investigated. Presented results of this in silico study suggest that Elastin Microfibril Interface Located Proteins (EMILINs) are involved in interaction between GP and ECM. This finding could contribute to a better understanding of EV/endothelium interaction and its role in pathogenesis, prevention and therapy of EVD.View the article as published at http://journal.frontiersin.org/article/10.3389/fmicb.2015.00135/ful
Identification of SARS-CoV-2 Papain-like protease (PLpro) inhibitors using combined computational approach
No full textIn the current pandemic finding an effective drug to prevent or treat the infection is the highest priority. A rapid and safe approach to counteract COVID-19 is in silico drug repurposing. The SARS-CoV-2 PLpro promotes viral replication and modulates the host immune system, resulting in inhibition of the host antiviral innate immune response, and therefore is an attractive drug target. In this study, we used a combined in silico virtual screening for candidates for SARS-CoV-2 PLpro protease inhibitors. We used the Informational spectrum method applied for Small Molecules for searching the Drugbank database followed by molecular docking. After in silico screening of drug space, we identified 44 drugs as potential SARS-CoV-2 PLpro inhibitors that we propose for further experimental testing
Modelovanje konformacija µ- i δ-opioidnih receptora specifičnih za pojedine ligande
No full textAn automated docking procedure was applied to study the binding of a series of mu- and delta-selective ligands to ligand-specific mu- and delta-opioid receptor models. Short-time molecular dynamic simulations were used to obtain ligand-specific mu- and delta-opioid receptors from arbitrarily chosen models of the active form of these receptors. The quality of receptor model depended on the molecular volume of the ligand in the receptor-ligand complex used in the molecular dynamic simulations. Within a series of ligands of similar size (volume), the results of ligand docking to the obtained ligand-specific receptor conformation were in agreement with point mutation studies. The correlation of the calculated and the experimentally determined binding energies was improved in relation to the initial receptor conformation.Računska metoda automatizovanog dokiranja primenjena je na vezivanje serije liganada, specifičnih za µ- i δ-receptore, za modele ovih receptora. Kratkotrajna molekulsko dinamička simulacija je korišćena za dobijanje konformacija ovih receptora koje su specifične za pojedine ligande, polazeći od slučajno izabranog modela aktiviranog receptora. Kvalitet ovako dobijenog modela receptora zavisi od molekulske zapremine liganda u ligand-receptor kompleksu korišćenog u molekulsko-dinamičkoj simulaciji. Za seriju liganda slične zapremine rezultati dokiranja su u skladu sa eksperimentalnim rezltatima mutacija aminokiselina u receptoru. Korelacija izračunatih i merenih energija vezivanja je poboljšana u odnosu na rezultate dobijene sa polaznom konformacijom receptora
Drug Repurposing for Candidate SARS-CoV-2 Main Protease Inhibitors by a Novel in Silico Method
No full textThe SARS-CoV-2 outbreak caused an
unprecedented global public health threat, having a high transmission rate with
currently no drugs or vaccines approved. An alternative powerful additional
approach to counteract COVID-19 is in silico drug repurposing. The
SARS-CoV-2 main protease is essential for viral replication and an attractive
drug target. In this study, we used the virtual screening (VS) protocol with
both long-range and short-range interactions to select candidate SARS-CoV-2
main protease inhibitors. First, the ISM applied for Small Molecules was used
for searching the Drugbank database and further followed by molecular docking.
After in silico screening of drug space, we identified 57 drugs as
potential SARS-CoV-2 main protease inhibitors that we propose for further
experimental testing.</p
Critical impact of different conserved endoplasmic retention mofits and dopamine receptor interacting proteins (DRIPs) on intracellular localization and trafficking of the D dopamine receptor (D-R) isoforms
No full textThe type 2 dopamine receptor D (D-R), member of the G protein-coupled receptor (GPCR) superfamily, exists in two isoforms, short (D-R) and long (D-R). They differ by an additional 29 amino acids (AA) in the third cytoplasmic loop (ICL3) of the D-R. These isoforms differ in their intracellular localization and trafficking functionality, as D-R possesses a larger intracellular pool, mostly in the endoplasmic reticulum (ER). This review focuses on the evolutionarily conserved motifs in the ICL3 of the D-R and proteins interacting with the ICL3 of both isoforms, specifically with the 29 AA insert. These motifs might be involved in D-R exit from the ER and have an impact on cell-surface and intracellular localization and, therefore, also play a role in the function of dopamine receptor signaling, ligand binding and possible homo/heterodimerization. Our recent bioinformatic data on potential new interaction partners for the ICL3 of D-Rs are also presented. Both are highly relevant, and have clinical impacts on the pathophysiology of several diseases such as Parkinson’s disease, schizophrenia, Tourette’s syndrome, Huntington’s disease, manic depression, and others, as they are connected to a variety of essential motifs and differences in communication with interaction partners
On the relationship between molecular spectroscopy and statistical mechanics: Calculation of vibrational-rotational energy levels and partition functions in the ground electronic state of BC2
No full textThe results of extensive ab initio calculations of the vibrational-
rotational energy spectrum in the ground electronic state of the BC2 molecule
are presented. These data were employed to discuss the evaluation of the
corresponding partition functions. Special attention was paid to the problems
connected with the calculation of the partition functions for the bending
vibrations and rotations about the axis corresponding to the smallest moment
of inertia.</jats:p
