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VIRTUAL SCREENING OF SUBSTANCES WITH POTENTIAL ANTIVIRAL ACTIVITY AGAINST THREE FLAVIVIRUSES: dengue virus, yellow fever virus and Zika virus

VIRTUAL SCREENING OF SUBSTANCES WITH POTENTIAL ANTIVIRAL ACTIVITY AGAINST THREE FLAVIVIRUSES: dengue virus, yellow fever virus and Zika virus

Mateus Serafim, Thales Kronenberger, Rafael Rocha, Rafaela Ferreira, Vinícius Maltarollo, Bruno Mota and Erna Kroon

Approximately three billion people live in regions at risk of infections by flaviviruses. Dengue virus (DENV), Zika virus (ZIKV) and Yellow fever virus (YFV) presents outbreaks and severe complications. Currently, there are no antivirals available to treat these diseases. We screened and evaluated the potential antiviral activity of small molecules against these viruses, targeting the viral protease NS2B-NS3 (NS3PRO). We used a combination of HQSAR models and structural molecular modelling, based on structures of peptidomimetic DENV-3 NS3PRO inhibitors and molecular docking studies to screen for new compounds. Binding sites of DENV-3 and ZIKV NS3PRO were assessed to build a pharmacophoric model for virtual screening. Hits were selected after molecular dynamics simulations, with predictions of toxicity and biological activity. Biological activities were evaluated by the MTT assay. Antiviral activity was evaluated by plaque reduction, pre-treatment and virucide activity assays. Enzymatic inhibition assays against ZIKV NS3PRO were carried out. An optimal HQSAR model (q2 = 0.67; r2 = 0.87) was selected. A virtual screening of ~7,600,000 compounds was conducted (pharmacophore, docking and molecular dynamics), identifying eight potential inhibitors to the NS3PRO, with favorable biological activity (5/8) and toxicity (8/8) predictions. Five were active against ZIKV, YFV, DENV-2 or DENV-3 (EC50 from 4.21 ± 0.14 to 37.51 ± 0.8 µM, with selective indexes from 1.42 to 3.74), with one being active against all viruses. In plaque reduction assays, two substances reduced about 1.0 to 1.5 log10 of the viral titer of ZIKV, YFV and DENV-2. One also reduced about 1.0 log10 of YFV titer in pre-treatment assays. We have identified five compounds with antiviral activity, with one showing a potential panflavivirus activity. Preliminary ZIKV NS3PRO inhibition assays showed three active compounds with IC50 values between 28 and 69 µM.

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Virtual screening suggest potential affinity between Corynebacterium ulcerans essential proteins and inedited synthetic derivatives of tetraisoquinoline alkaloids

Virtual screening suggest potential affinity between Corynebacterium ulcerans essential proteins and inedited synthetic derivatives of tetraisoquinoline alkaloids

Luis Felipe de Morais Melo, Gustavo Andrew Mahon Mendes Pereira, Luis Cezar Rodrigues and Edson Luiz Folador

Corynebacterium ulcerans is aerobic, gram-positive bacteria that causes diphtheria, by infecting several hosts have a larger reservoir than the other causative agents. Considered reemergent, isolated cases due C. ulcerans diphtheria have increased even in immunized nations, highlighting the importance to seek new drugs and treatments. In previous work, we applied the interolog mapping method to generate the interactome, identifying the conserved hub proteins for 10 C. ulcerans strains, whose Database of Essential Genes (DEG) validation, COG classification and GO analysis, were confirmed the essentiality of 457 hub proteins, 351 having less than 30% identity against the host, being potential pharmacological targets. Here, we submitted the 351 non-host homologous hub proteins to Phyre2, resulting in 119 viable three-dimensional structure (more than 90% of the amino acids in Ramachandran plot favorable regions). Submitted to fpocket, 145 pockets with drugability score >= 0.5 were identified, which after being subjected to molecular docking in Autodock Vina against a library containing 42 inedited synthetic derivatives of tetraisoquinolinic alkaloid molecules resulted in 6,090 complex, 2,864 getting energy <= -6, considered relevant. The UvrABC system protein B, essential in the DNA repair process, formed the best complex with molecule23 reaching binding energy of -9.9, performing favorable interactions precisely with the protein residues binding to DNA, such as: hydrogen bonds (ARG379, LYS380 and SER166), Van der Waals interactions (ARG146, ASP376, ASP396, GLU122, GLU32, LYS134, MET372 and TYR116), pi-electron interactions (TYR119, TYR119 and TYR169), among others. Additionally, the molecule41 complexed with Bifunctional RNase H/acid phosphatase protein (-9.6); the molecule34 competes for the ADP binding site on Bifunctional protein (-9.5); the molecule20 competes for the uridina-difosfato-n-acetilglicosanima binding site on UDP-N-acetylglucosamine 1-carboxyvinyltransferase protein (-9.4). The results make it possible to understand the molecular binding mechanisms, enabling the rational optimization of molecules, reducing costs associated with synthesis and in-vitro or in-vivo tests.

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In Silico Evaluation of Some Flavonoids Honeybee Constituents as SARS-CoV-2 Main Protease (COVID-19) Inhibitors

In Silico Evaluation of Some Flavonoids Honeybee Constituents as SARS-CoV-2 Main Protease (COVID-19) Inhibitors

Heba Hashem

The huge attack of coronavirus disease (COVID-19) over all the world forces the researcher around the world to study the crystal structure of the main protease Mpro (3-chymotrypsin-like cysteine enzyme) which is the essential enzyme for coronavirus. The inhibition of this enzyme active site becomes the target of all scientists of drug discovery to overcome this disease. On the bases of this view, using the molecular modeling approach to evaluate the effect of different flavonoids compounds from honeybee and propolis as SARS-CoV-2 main protease inhibition using Schrodinger Maestro v10.1.
The presented study resulted in six main compounds possess high binding energy with the receptor active site of COVID-19 main protease.
Developing this study aim to be an effective way for the honeybee constitution as an inhibitors ligand for SARS-CoV-2 main protease inhibition and be in the medicinal study of anti-COVID-19 therapeutic drugs.

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MOLECULAR MODELING OF BUTYRYLCHOLINESTERASE INHIBITORS AS POTENTIAL DRUGS AGAINST ALZHEIMER’S DISEASE

MOLECULAR MODELING OF BUTYRYLCHOLINESTERASE INHIBITORS AS POTENTIAL DRUGS AGAINST ALZHEIMER’S DISEASE

Bárbara B. Novo, Joelma F. de Mesquita, Camilo H. S. Lima and Magaly G. Albuquerque

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease worldwide. According to the World Health Organization (WHO), it is estimated 152 million people worldwide will be affected by AD in 2050. Memory loss, a symptom of AD, is the result of a decrease of acetylcholine level in the brain, due to the increase in cholinesterases, mainly butyrylcholinesterase (BChE). Our study targets new potential BChE inhibitors, by molecular modeling, aiming to alleviate the symptoms from the acetylcholine deficit. We used two 3D structures of human BChE complexes with potent inhibitors, resolved by X-ray diffraction and available in the Protein Data Bank (PDB): 5DYW and 5NN0 (Košak et al., 2016, 2018). The inhibitors have a piperidine heterocycle showing (R) configuration at C3 of the piperidine ring, whose amino group is protonated, according to Košak et al. (2016, 2018). The construction of the 3D structures of the inhibitors (5HF601 in the 5DYW complex and 92H627 in the 5NN0 complex) was carried out in the Spartan’14, followed by geometry optimization and conformational analysis (systematic and random), using the MMFF94 force field. Molecular docking/redocking was performed on the DockThor server (https://dockthor.lncc.br/v2/), where the C-alpha from Gly116 (chain A) at the active site, was chosen as the center of the 20x20x20 Å box. The preliminary results indicate that, for both ligands, the poses with the best score refer to the structures where the absolute configurations of both, C3 and N of piperidine, are (S). In the case of C3, according to Košak et al., the configuration is (R), while the configuration of the protonated N is not described, probably due to the possibility of both configurations coexisting in equilibrium. Thus, our study suggests re-evaluating the configuration of these stereogenic centers. As a perspective, we will study the binding modes of other inhibitors.