scholarly journals Strategy for Designing Selective Lysosomal Acid α-Glucosidase Inhibitors: Binding Orientation and Influence on Selectivity

Molecules ◽  
2020 ◽  
Vol 25 (12) ◽  
pp. 2843 ◽  
Author(s):  
Atsushi Kato ◽  
Izumi Nakagome ◽  
Mizuki Hata ◽  
Robert J. Nash ◽  
George W. J. Fleet ◽  
...  
Keyword(s):  
Alkyl Chain ◽  
Hydrophobic Interactions ◽  
Antiviral Agents ◽  
Design Strategy ◽  
Docking Study ◽  
Piperidine Ring ◽  
Hydroxyl Groups ◽  
Storage Site ◽  
Molecular Docking Study ◽  
Lysosomal Acid

Deoxynojirimycin (DNJ) is the archetypal iminosugar, in which the configuration of the hydroxyl groups in the piperidine ring truly mimic those of d-glucopyranose; DNJ and derivatives have beneficial effects as therapeutic agents, such as anti-diabetic and antiviral agents, and pharmacological chaperones for genetic disorders, because they have been shown to inhibit α-glucosidases from various sources. However, attempts to design a better molecule based solely on structural similarity cannot produce selectivity between α-glucosidases that are localized in multiple organs and tissues, because the differences of each sugar-recognition site are very subtle. In this study, we provide the first example of a design strategy for selective lysosomal acid α-glucosidase (GAA) inhibitors focusing on the alkyl chain storage site. Our design of α-1-C-heptyl-1,4-dideoxy-1,4-imino-l-arabinitol (LAB) produced a potent inhibitor of the GAA, with an IC50 value of 0.44 µM. It displayed a remarkable selectivity toward GAA (selectivity index value of 168.2). A molecular dynamic simulation study revealed that the ligand-binding conformation stability gradually improved with increasing length of the α-1-C-alkyl chain. It is noteworthy that α-1-C-heptyl-LAB formed clearly different interactions from DNJ and had favored hydrophobic interactions with Trp481, Phe525, and Met519 at the alkyl chain storage pocket of GAA. Moreover, a molecular docking study revealed that endoplasmic reticulum (ER) α-glucosidase II does not have enough space to accommodate these alkyl chains. Therefore, the design strategy focusing on the shape and acceptability of long alkyl chain at each α-glucosidase may lead to the creation of more selective and practically useful inhibitors.

scholarly journals Synthesis and Fungicidal Activity of Hydrated Geranylated Phenols against Botrytis cinerea

Molecules ◽  
2021 ◽  
Vol 26 (22) ◽  
pp. 6815
Author(s):  
Mauricio Soto ◽  
Ana Estevez-Braun ◽  
Ángel Amesty ◽  
Julia Kluepfel ◽  
Susana Restrepo ◽  
...  
Keyword(s):  
Botrytis Cinerea ◽  
Alkyl Chain ◽  
Reaction Times ◽  
Docking Study ◽  
Hydroxyl Group ◽  
Economic Losses ◽  
Hydroxyl Groups ◽  
Molecular Docking Study ◽  
Growth Inhibition Assay ◽  
Phenol Ring

Botrytis cinerea is a ubiquitous fungus that affects hundreds of plants, resulting in economic losses to the horticulture and fruit industry. The search for new antifungal agents is a matter of current interest. Thus, in this work a series of geranylated phenols in which the side alkyl chain has been hydrated have been synthesized, and their activity against B. cinerea has been evaluated. The coupling of phenol and geraniol has been accomplished under microwave irradiation obtaining the highest reaction yields in the shortest reaction times. Hydration of the side chain was carried out in dioxane with p-toluenesulfonic acid polymer-bound as the catalyst. All synthesized compounds were tested against B. cinerea using the growth inhibition assay and EC50 values were determined. The results show that activity depends on the number and nature of functional groups in the phenol ring and hydration degree of the geranyl chain. The most active compound is 1,4-dihydroquinone with one hydroxyl group attached at the end of the alkyl chain. Results from a molecular docking study suggest that hydroxyl groups in the phenol ring and alkyl chain are important in the binding of compounds to the active site, and that the experimental antifungal activity correlates with the number of H-bond that can be formed in the binding site.

scholarly journals Natural products as anti-COVID-19 agents: An in silico study

Coronaviruses ◽  
2020 ◽  
Vol 01 ◽  
Author(s):  
Chandan Sarkar ◽  
Sarmin Jamaddar ◽  
Milon Mondal ◽  
Abul Bashar Ripon Khalipha ◽  
Muhammad Torequl Islam ◽  
...  
Keyword(s):  
In Silico ◽  
Rna Virus ◽  
Antiviral Agents ◽  
Antiviral Agent ◽  
Docking Study ◽  
Asiatic Acid ◽  
Molecular Docking Study ◽  
Viral Protease ◽  
In Silico Study ◽  
To Come

Background: The coronavirus disease 2019 (COVID-19) is a life threatening viral infection caused by a positivestrand RNA virus belonging to Coronaviridae family called severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2). This virus has infected millions of peoples, and caused hundreds of thousands of deaths around the world. Unfortunately, to date, there is no specific cure for SARS-CoV-2 infection, although researchers are working tirelessly to come up with a drug against this virus. Recently, the main viral protease has been discovered, and is regarded as an appropriate target for antiviral agents in the search for treatment of SARS-CoV-2 infection, due to its role in polyproteins processing during coronavirus replication. Methodology: This investigation (an in silico study) explores the effectiveness of 16 natural compounds from a literature survey against the protease of SARS-CoV-2 in an attempt to identify a promising antiviral agent through a molecular docking study. Results: Among the 16 compounds studied, apigenin, alpha-hederin, and asiatic acid exhibited significant docking performance and interacted with several amino acid residues of the main protease of SARS-CoV-2. Conclusion: In summary, apigenin, alpha-hederin, and asiatic acid protease inhibitors may be effective potential antiviral agents against the main viral protease (Mpro) to combat SARS-CoV-2.

Petra/Osiris/Molinspiration and Molecular Docking Analyses of 3-Hydroxy-Indolin-2-one Derivatives as Potential Antiviral Agents

2019 ◽  
Vol 16 ◽  
Author(s):  
Taibi Ben Hadda ◽  
Vesna Rastija ◽  
Faisal AlMalki ◽  
Abderrahim Titi ◽  
Rachid Touzani ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Structural Parameters ◽  
Antiviral Agents ◽  
Chemical Properties ◽  
Docking Study ◽  
Bioactive Molecules ◽  
Geometrical Parameters ◽  
Molecular Docking Study ◽  
Catalytic Core ◽  
Hiv 1

Background: Studies on the interaction between bioactive molecules and HIV-1 virus has been the focus of recent research in the scope of medicinal chemistry and pharmacology. Objective: Investigating the structural parameters and physic-chemical properties of elucidating and identifying of the antiviral pharmacophore sites. Method: A mixed computational Petra/Osiris/Molinspiration/DFT (POM/DFT) based model has been developed for the identification of physico-chemical parameters governing the bioactivity of 22 3-hydroxy-indolin-2-one derivatives of diacetyl-L-tartaric acid and aromatic amines containing combined antiviral/antitumor/antibacterial pharmacophore sites. Molecular docking study was carried out with HIV-1 integrase (pdb ID: 5KGX) in order to provide information about interactions in the binding site of enzyme. Results: The POM analyses of physic-chemical properties and geometrical parameters of compounds 3a-5j, show that they are bearing a two combined (O,O)-pockets leading to a special platform which able to coordinate two transition metals. The increased activity of series 3a-5j, as compared to standard drugs, contains an (Osp2,O sp3,O sp2)-pharmacophore site. The increase of bioactivity from 4b (R1, R2 = H, H) to 3d (R1, R2 = 4-Br, 2-OCH3) could be attributed to the existence of pi-charge transfer from para-bromo-phenyl to its amid group (COδ---NHδ+). Similar to the indole-based reference ligand (pdb: 7SK), compound 3d forms hydrogen bonding interactions between the residues Glu170, Thr174 and His171 of HIV-1 integrase in catalytic core domain of enzyme. Conclusion: Study confirmed the importance of oxygen atoms, especially from the methoxy group of the phenyl ring, and electrophilic amide nitrogen atom for formation of interactions.

scholarly journals Alkyl and Aryl Derivatives Based on p-Coumaric Acid Modification and Inhibitory Action against Leishmania braziliensis and Plasmodium falciparum

Molecules ◽  
2020 ◽  
Vol 25 (14) ◽  
pp. 3178 ◽  
Author(s):  
Susiany P. Lopes ◽  
Lina M. Yepes ◽  
Yunierkis Pérez-Castillo ◽  
Sara M. Robledo ◽  
Damião P. de Sousa
Keyword(s):  
Plasmodium Falciparum ◽  
Low Income ◽  
Hydrophobic Interactions ◽  
Public Health Problem ◽  
Docking Study ◽  
Neglected Diseases ◽  
Leishmania Braziliensis ◽  
Coumaric Acid ◽  
Acid Modification ◽  
Molecular Docking Study

In low-income populations, neglected diseases are the principal cause of mortality. Of these, leishmaniasis and malaria, being parasitic, protozoan infections, affect millions of people worldwide and are creating a public health problem. The present work evaluates the leishmanicidal and antiplasmodial action of a series of twelve p-coumaric acid derivatives. Of the tested derivatives, eight presented antiparasitic activities 1–3, 8–12. The hexyl p-coumarate derivative (9) (4.14 ± 0.55 μg/mL; selectivity index (SI) = 2.72) showed the highest leishmanicidal potency against the Leishmania braziliensis amastigote form. The results of the molecular docking study suggest that this compound inhibits aldehyde dehydrogenase (ALDH), mitogen-activated kinase protein (MPK4), and DNA topoisomerase 2 (TOP2), all of which are key enzymes in the development of Leishmania braziliensis. The data indicate that these enzymes interact via Van der Waals bonds, hydrophobic interactions, and hydrogen bonds with phenolic and aliphatic parts of this same compound. Of the other compounds analyzed, methyl p-coumarate (64.59 ± 2.89 μg/mL; IS = 0.1) demonstrated bioactivity against Plasmodium falciparum. The study reveals that esters presenting a p-coumarate substructure are promising for use in synthesis of derivatives with good antiparasitic profiles.

scholarly journals Selective Targeting of the Interconversion between Glucosylceramide and Ceramide by Scaffold Tailoring of Iminosugar Inhibitors

Molecules ◽  
2019 ◽  
Vol 24 (2) ◽  
pp. 354 ◽  
Author(s):  
Cécile Baudoin-Dehoux ◽  
Tessa Castellan ◽  
Frédéric Rodriguez ◽  
Arnaud Rives ◽  
Fabien Stauffert ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Docking Study ◽  
Ring Expansion ◽  
Membered Ring ◽  
The Other ◽  
Piperidine Ring ◽  
Molecular Docking Study ◽  
Pharmacological Chaperone ◽  
Simple Ring ◽  
Selective Targeting

A series of simple C-alkyl pyrrolidines already known as cytotoxic inhibitors of ceramide glucosylation in melanoma cells can be converted into their corresponding 6-membered analogues by means of a simple ring expansion. This study illustrated how an isomerisation from iminosugar pyrrolidine toward piperidine could invert their targeting from glucosylceramide (GlcCer) formation toward GlcCer hydrolysis. Thus, we found that the 5-membered ring derivatives did not inhibit the hydrolysis reaction of GlcCer catalysed by lysosomal β-glucocerebrosidase (GBA). On the other hand, the ring-expanded C-alkyl piperidine isomers, non-cytotoxic and inactive regarding ceramide glucosylation, revealed to be potent inhibitors of GBA. A molecular docking study showed that the positions of the piperidine ring of the compound 6b and its analogous 2-O-heptyl DIX 8 were similar to that of isofagomine. Furthermore, compound 6b promoted mutant GBA enhancements over 3-fold equivalent to that of the related O-Hept DIX 8 belonging to one of the most potent iminosugar-based pharmacological chaperone series reported to date.

scholarly journals DOCKING STUDIES IN TARGET PROTEINS INVOLVED IN ANTIBACTERIAL ACTION MECHANISMS: ALKALOIDS ISOLATED FROM SCUTELLARIA GENUS

2016 ◽  
Vol 9 (5) ◽  
pp. 121 ◽  
Author(s):  
Sri Dharani R ◽  
Ranjitha R ◽  
Sripathi R ◽  
Ali Muhammad K S ◽  
Ravi S
Keyword(s):  
Cell Wall ◽  
Molecular Docking ◽  
Hydrophobic Interactions ◽  
Docking Study ◽  
Docking Studies ◽  
Cell Wall Synthesis ◽  
Molecular Docking Study ◽  
Bacterial Proteins ◽  
Antimicrobial Studies ◽  
Action Mechanisms

ABSTRACTObjective: In the present work, docking study was performed for 22 selected alkaloids isolated from the genus Scutellaria to evaluate their affinityto bacterial proteins that are known targets for many antibiotics with a different mechanism of action: Inhibitors of cell wall synthesis, inhibitors ofnucleic acids synthesis and antimetabolites.Methods: Molecular docking study was carried out using AutoDock 4.2 version and the visualization result using Chimera 1.10 and DiscoveryStudio 4.5.Result: Among the 22 alkaloids studied, with the DNA gyrase protein 1KZN and a dihydropteroate synthase enzyme 3TYE, the compoundscutebarbatine E showed a docking score of −8.5 and −8.7 Kcal/mol, respectively, involving with hydrophilic and hydrophobic interactions. Withrespect to MurD ligase involved in cell wall synthesis 1UAG and 2X5O, the compound 6,7,nicotinyl scutebarbatine G fared well with a dockingscore of −10.1 and −10.2 Kcal/mol, respectively. Scutebarbatine G performed well with respect to 3UDI with binding scores of −9.3 K cal/mol.Conclusion: Overall, it seems that for the selected alkaloids from the genus Scutellaria, the main mechanism of the action is the inhibition of cell wallsynthesis.Keywords: Scutebarbatine, Alkaloids, Molecular docking, Antimicrobial studies.

scholarly journals Synthesis and Hybrid SAR Property Modeling of Novel Cholinesterase Inhibitors

2021 ◽  
Vol 22 (7) ◽  
pp. 3444
Author(s):  
Jiri Kos ◽  
Violetta Kozik ◽  
Dominika Pindjakova ◽  
Timotej Jankech ◽  
Adam Smolinski ◽  
...  
Keyword(s):  
Hydrophobic Interactions ◽  
Docking Study ◽  
Selectivity Index ◽  
Ache Inhibitor ◽  
Landscape Index ◽  
Molecular Docking Study ◽  
Dynamic Simulations ◽  
Enzymatic Systems ◽  
The Stability

A library of novel 4-{[(benzyloxy)carbonyl]amino}-2-hydroxybenzoic acid amides was designed and synthesized in order to provide potential acetyl- and butyrylcholinesterase (AChE/BChE) inhibitors; the in vitro inhibitory profile and selectivity index were specified. Benzyl (3-hydroxy-4-{[2-(trifluoromethoxy)phenyl]carbamoyl}phenyl)carbamate was the best AChE inhibitor with the inhibitory concentration of IC50 = 36.05 µM in the series, while benzyl {3-hydroxy-4-[(2-methoxyphenyl)carbamoyl]phenyl}-carbamate was the most potent BChE inhibitor (IC50 = 22.23 µM) with the highest selectivity for BChE (SI = 2.26). The cytotoxic effect was evaluated in vitro for promising AChE/BChE inhibitors. The newly synthesized adducts were subjected to the quantitative shape comparison with the generation of an averaged pharmacophore pattern. Noticeably, three pairs of fairly similar fluorine/bromine-containing compounds can potentially form the activity cliff that is manifested formally by high structure–activity landscape index (SALI) numerical values. The molecular docking study was conducted for the most potent AChE/BChE inhibitors, indicating that the hydrophobic interactions were overwhelmingly generated with Gln119, Asp70, Pro285, Thr120, and Trp82 aminoacid residues, while the hydrogen bond (HB)-donor ones were dominated with Thr120. π-stacking interactions were specified with the Trp82 aminoacid residue of chain A as well. Finally, the stability of chosen liganded enzymatic systems was assessed using the molecular dynamic simulations. An attempt was made to explain the noted differences of the selectivity index for the most potent molecules, especially those bearing unsubstituted and fluorinated methoxy group.

scholarly journals Trends in the Binding of Cell Penetrating Peptides to siRNA: A Molecular Docking Study

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
P. V. G. M. Rathnayake ◽  
B. G. C. M. Gunathunge ◽  
P. N. Wimalasiri ◽  
D. N. Karunaratne ◽  
R. J. K. U. Ranatunga
Keyword(s):  
Molecular Docking ◽  
Electrostatic Interactions ◽  
Hydrophobic Interactions ◽  
Docking Study ◽  
Cell Penetrating Peptides ◽  
Molecular Docking Study ◽  
Hydrophobic Peptides ◽  
Cell Penetrating ◽  
Docking Calculations ◽  
Cellular Import

The use of gene therapeutics, including short interfering RNA (siRNA), is limited by the lack of efficient delivery systems. An appealing approach to deliver gene therapeutics involves noncovalent complexation with cell penetrating peptides (CPPs) which are able to penetrate the cell membranes of mammals. Although a number of CPPs have been discovered, our understanding of their complexation and translocation of siRNA is as yet insufficient. Here, we report on computational studies comparing the binding affinities of CPPs with siRNA, considering a variety of CPPs. Specifically, seventeen CPPs from three different categories, cationic, amphipathic, and hydrophobic CPPs, were studied. Molecular mechanics were used to minimize structures, while molecular docking calculations were used to predict the orientation and favorability of sequentially binding multiple peptides to siRNA. Binding scores from docking calculations were highest for amphipathic peptides over cationic and hydrophobic peptides. Results indicate that initial complexation of peptides will likely occur along the major groove of the siRNA, driven by electrostatic interactions. Subsequent binding of CPPs is likely to occur in the minor groove and later on bind randomly, to siRNA or previously bound CPPs, through hydrophobic interactions. However, hydrophobic CPPs do not show this binding pattern. Ultimately binding yields a positively charged nanoparticle capable of noninvasive cellular import of therapeutic molecules.

Evaluation of the Binding Affinity of Anti-Viral Drugs against Main Protease of SARS-CoV-2 through a Molecular Docking Study

2020 ◽  
Vol 20 ◽  
Author(s):  
Milon Mondal ◽  
Chandan Sarkar ◽  
Sarmin Jamaddar ◽  
Abul Bashar Ripon Khalipha ◽  
Muhammad Torequl Islam ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Protease Inhibitors ◽  
Binding Affinity ◽  
Rna Virus ◽  
Antiviral Treatment ◽  
Antiviral Agents ◽  
Docking Study ◽  
Multiple Organ ◽  
Molecular Docking Study ◽  
Viral Protease

Background: Coronavirus disease 2019 (COVID-19) is a life intimidating viral infection caused by a positive sense RNA virus belonging to the Coronaviridae family, named severe acute respiratory distress syndrome coronavirus 2 (SARA-CoV-2). Since its outbreak in December 2019, the pandemic has spread to more than 200 countries, infected more than 26 million, and claimed the lives of more than 800,000 people. As a disease, COVID-19 can lead to severe and occasionally fatal respiratory problems in humans. Infection with this virus is associated with fever, cough, dyspnea, and muscle aches, and it may progress to pneumonia, multiple organ failure, and death. To date, there is no specific antiviral treatment against this virus. However, the main viral protease has been recently discovered and it is regarded as an appropriate target for antiviral agents in the search for treatment of COVID-19, due to its pivotal role in polyproteins processing during viral replication. Aim: Consequently, this study intends to evaluate the effectiveness of FDA-approved anti-viral drugs against SARA-CoV-2 through a molecular docking study. Methods: AutoDock Vina in PyRx platform was used for docking analysis against the main viral protease (Mpro) (PDB ID 6LU7), and Computed Atlas of Surface Topography of proteins (CASTp 3.0) was applied for detecting and characterizing cavities, pockets, and channels of this protein structure. Results: Results revealed that among the conventional antiviral drugs, the protease inhibitors, lopinavir, amprenavir, indinavir, maraviroc, saquinavir, and daclatasvir showed high binding affinity and interacted with amino acid residues of the binding site. Conclusion: In conclusion, protease inhibitors may be effective potential antiviral agents against Mpro to combat SARSCoV-2.

scholarly journals Molecular Docking Study of Astaxanthin Derived from Radio-Resistant Bacterium Deinococcus sp. Strain WMA-LM9 to Matrix Metalloproteinase-1, 3 (MMP-1, MMP-3)

2021 ◽  
Vol 2 (1) ◽  
pp. 6
Author(s):  
Wasim Sajjad ◽  
Sumra Wajid Abbasi ◽  
Liaqat Ali
Keyword(s):  
Matrix Metalloproteinases ◽  
Hydrophobic Interactions ◽  
Data Bank ◽  
Docking Study ◽  
Zinc Ion ◽  
Skin Aging ◽  
Docking Studies ◽  
Molecular Docking Study ◽  
Matrix Metalloproteinase 1 ◽  
National University

Objective: To assess role of astaxanthin in downregulation of matrix metalloproteinases (MMP-1 and MMP-3) as potential mitigator for skin aging and antioxidant for different pathological diseasesStudy Design: Cross sectional.Place and Duration of Study: The study was carried out at Department of Biological Sciences of National University of Medical Sciences, Rawalpindi, Pakistan from June 2019 to March 2020.Materials and Methods: The docking studies of two different matrix metalloproteinases (MMP-1, MMP-3) with astaxanthin were carried out using Autodock/vina. The structural details were obtained from protein data bank and subjected to energy minimization using the UCSF Chimera 1.12.|Results: Out of the two selected targets, we found the highest binding energy (-11.9 kacl/mol) was for stromelysin-1 and astaxanthin docked complex. Astaxanthin was found to bind within the reported, predominantly hydrophobic S1, active site of protein mostly by hydrophobic interactions. The catalytic zinc ion has also shown to establish an electrostatic interaction with histidine residues of the MMPs.Conclusion: The current results suggest that astaxanthin has potential inhibitory activity on MMP-1 and MMP-3 and can be used as treatment to sunburns and skin aging.

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