scholarly journals Synthesis, Spectral Characterization and Molecular Docking Studies of Novel Benzidin-bis-tetrahydroacridine Analogues

2020 ◽  
Vol 71 (5) ◽  
pp. 163-181
Author(s):  
Madalina Marina Hrubaru ◽  
Carmellina Daniela Badiceanu ◽  
Anthony Chinonso Ekennia ◽  
Sunday N. Okafor ◽  
Cristian Enache ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Binding Sites ◽  
Docking Studies ◽  
Binding Affinities ◽  
Binding Modes ◽  
Docking Simulations ◽  
Ft Ir ◽  
Dynamics Simulations ◽  
And Behavior ◽  
Human Butyrylcholinesterase

Alzheimer�s is a progresive neurodegenerative disease that interferes with human cognitive ability, memory and behavior. The inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes are major therapeutic routes for the treatment of Alzheimer disease. In the study, nevel bis-polymethylenquinoline-bis-carboxamides (3a-f) and bis-polymethylenquinoline-bis-carboxylic acids (5a-b) having as precursor benzidine, were obtained in good yields by Pfitzinger condensation reactions of bis-isatines with corresponding cyclanones. The compounds were characterized by elemental analysis, FT-IR, NMR and mass spectrometry. Furthermore, the compounds were subjected to molecular docking dynamics simulations to ascertain their potentials as inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Molecular docking simulations showed varied binding activities towards the two binding sites of acetylcholinesterase: 4EY7 and 1OCD, and human butyrylcholinesterase: 1P0I. Compounds 3e and 5b demostrated strong binding affinities with 1P0I, 1OCD and 4EY7 biotargets similar to the binding modes of donepezil and tacrine (co-crystallized inhibitors of acetylcholinesterase) and butyrate (co-crystallized inhibitors of butyrylcholinesterase).

In Silico Prediction of P-glycoprotein Binding: Insights from Molecular Docking Studies

2019 ◽  
Vol 26 (10) ◽  
pp. 1746-1760 ◽  
Author(s):  
Santiago Vilar ◽  
Eduardo Sobarzo-Sánchez ◽  
Eugenio Uriarte
Keyword(s):  
Molecular Docking ◽  
Binding Sites ◽  
Docking Studies ◽  
Efflux Transporter ◽  
Molecular Docking Studies ◽  
Docking Simulations ◽  
Central Nervous System Drugs ◽  
P Glycoprotein ◽  
Molecular Mechanism Of Action ◽  
Key Residues

The P-glycoprotein is an efflux transporter that expels substances out of the cells and has an important impact on the pharmacokinetic and pharmacodynamic properties of drugs. The study of the interactions between ligands and the P-glycoprotein has implications in the design of Central Nervous System drugs and their transport across the blood-brain barrier. Moreover, since the P-glycoprotein is overexpressed in some types of cancers, the protein is responsible for expelling the drug therapies from the cells, and hence, for drug resistance. In this review, we describe different P-glycoprotein binding sites reported for substrates, inhibitors and modulators, and focus on molecular docking studies that provide useful information about drugs and P-glycoprotein interactions. Docking in crystallized structures and homology models showed potential in the detection of the binding site and key residues responsible for ligand recognition. Moreover, virtual screening through molecular docking discriminates P-glycoprotein ligands from decoys. We also discuss challenges and limitations of molecular docking simulations applied to this particular protein. Computational structure-based approaches are very helpful in the study of novel ligands that interact with the P-glycoprotein and provide insights to understand the P-glycoprotein molecular mechanism of action.

A New Series Of 1,3-Dimethylxanthine Based Adenosine A2a Receptor Antagonists As A Non-Dopaminergic Treatment Of Parkinson’s Disease

2020 ◽  
Vol 17 ◽  
Author(s):  
Suman Rohilla ◽  
Ranju Bansal ◽  
Puneet Chauhan ◽  
Sonja Kachler ◽  
Karl-Norbert Klotz
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Molecular Docking ◽  
Binding Affinity ◽  
Docking Studies ◽  
Binding Modes ◽  
Molecular Docking Studies ◽  
In Silico Docking ◽  
Adenosine A2a Receptor Antagonists ◽  
The Impact

Background: Adenosine receptors (AR) have emerged as competent and innovative nondopaminergic targets for the development of potential drug candidates and thus constitute an effective and safer treatment approach for Parkinson’s disease (PD). Xanthine derivatives are considered as potential candidates for the treatment Parkinson’s disease due to their potent A2A AR antagonistic properties. Objective: The objectives of the work are to study the impact of substituting N7-position of 8-m/pchloropropoxyphenylxanthine structure on in vitro binding affinity of compounds with various AR subtypes, in vivo antiparkinsonian activity and binding modes of newly synthesized xanthines with A2A AR in molecular docking studies. Methods: Several new 7-substituted 8-m/p-chloropropoxyphenylxanthine analogues have been prepared. Adenosine receptor binding assays were performed to study the binding interactions with various subtypes and perphenazine induced rat catatonia model was used for antiparkinsonian activity. Molecular docking studies were performed using Schrödinger molecular modeling interface. Results: 8-para-substituted xanthine 9b bearing an N7-propyl substituent displayed the highest affinity towards A2A AR (Ki = 0.75 µM) with moderate selectivity versus other AR subtypes. 7-Propargyl analogue 9d produced significantly longlasting antiparkinsonian effects and also produced potent and selective binding affinity towards A2A AR. In silico docking studies further highlighted the crucial structural components required to develop xanthine derived potential A2A AR ligands as antiparkinsonian agents. Conclusion: A new series of 7-substituted 8-m/p-chloropropoxyphenylxanthines having good affinity for A2A AR and potent antiparkinsonian activity has been developed.

IDENTIFICATION OF SELETIVE CLAUDIN CATION CHANNEL BLOCKERS

2021 ◽  
Vol 27 (Supplement_1) ◽  
pp. S25-S26
Author(s):  
Jingjing Ma ◽  
Emma Wu ◽  
Ye Li ◽  
William Seibel ◽  
Le Shen ◽  
...  
Keyword(s):  
Small Molecules ◽  
Homology Model ◽  
Docking Studies ◽  
Channel Blockers ◽  
Binding Modes ◽  
Barrier Dysfunction ◽  
Epithelial Barrier Function ◽  
Dynamics Simulations ◽  
In Silico Models

Abstract Compromised epithelial barrier function is known to be associated with inflammatory bowel disease (IBD) and may contribute to disease development. One mechanism of barrier dysfunction is increased expression of paracellular tight junction ion and water channels formed by claudins. Claudin-2 and -15 are two such channels. We hypothesize that blocking these channels could be a viable therapeutic approach to treat diarrhea. In an effort to develop blockers of these channels, we turn to our previously developed and validated in silico models of claudin-15 (Samanta et al. 2018). We reasoned that compounds that can bind with the interior of claudin pores can limit paracellular water and ion flux. Thus, we used docking algorithms to search for putative small molecules that bind in the claudin-15 pore. AutoDock Vina was initially used to assess rigid docking using small compound databases. The small molecules were analyzed based on binding affinity to the pore and visualized using VMD for their potential blockage of the channel. Clusters of binding modes were identified based on the prominent interacting residues of the protein with the small molecules. We initially screened 10,500 compounds from within the UIC Centre for Drug Discovery and a cross-section of 10,000 compounds from the NCI open compound repository. This initial screen allowed us to identify 2 first-in-class selective claudin-15 blockers with efficacy in MDCK monolayers induced to express claudin-15 and in wildtype duodenum. Next, we screened the entire NCI open compound repository for additional molecules structurally related to our best initially identified molecule and this has allowed us to identify 13 additional molecules that increase TER of claudin-15 expressing MDCK monolayers by 90–160%. Additionally, these molecules possess similar structural components that will be collected in a fragment library and explored through molecular dynamics simulations. We also developed a claudin-2 homology model on which we are performing docking studies and in vitro measurements, which we expect will result in similar candidate ligands for blocking claudin-2. Our study will provide important insight into the role of claudin-dependent cation permeability in fundamental physiology, which we believe will lead to the utility of claudin blockers as a novel and much needed approach to treat diseases such as IBD.

scholarly journals Interaction between DNA, Albumin and Apo-Transferrin and Iridium(III) Complexes with Phosphines Derived from Fluoroquinolones as a Potent Anticancer Drug

2021 ◽  
Vol 14 (7) ◽  
pp. 685
Author(s):  
Sandra Amanda Kozieł ◽  
Monika Katarzyna Lesiów ◽  
Daria Wojtala ◽  
Edyta Dyguda-Kazimierowicz ◽  
Dariusz Bieńko ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Serum Proteins ◽  
Docking Study ◽  
Minor Groove ◽  
Docking Studies ◽  
Minor Groove Binding ◽  
Binding Modes ◽  
Groove Binding ◽  
Molecular Docking Study ◽  
Threading Intercalation

A group of cytotoxic half-sandwich iridium(III) complexes with aminomethyl(diphenyl)phosphine derived from fluoroquinolone antibiotics exhibit the ability to (i) accumulate in the nucleus, (ii) induce apoptosis, (iii) activate caspase-3/7 activity, (iv) induce the changes in cell cycle leading to G2/M phase arrest, and (v) radicals generation. Herein, to elucidate the cytotoxic effects, we investigated the interaction of these complexes with DNA and serum proteins by gel electrophoresis, fluorescence spectroscopy, circular dichroism, and molecular docking studies. DNA binding experiments established that the complexes interact with DNA by moderate intercalation and predominance of minor groove binding without the capability to cause a double-strand cleavage. The molecular docking study confirmed two binding modes: minor groove binding and threading intercalation with the fluoroquinolone part of the molecule involved in pi stacking interactions and the Ir(III)-containing region positioned within the major or minor groove. Fluorescence spectroscopic data (HSA and apo-Tf titration), together with molecular docking, provided evidence that Ir(III) complexes can bind to the proteins in order to be transferred. All the compounds considered herein were found to bind to the tryptophan residues of HSA within site I (subdomain II A). Furthermore, Ir(III) complexes were found to dock within the apo-Tf binding site, including nearby tyrosine residues.

scholarly journals Anti-Methanogenic Effect of Phytochemicals on Methyl-Coenzyme M Reductase—Potential: In Silico and Molecular Docking Studies for Environmental Protection

Micromachines ◽  
2021 ◽  
Vol 12 (11) ◽  
pp. 1425
Author(s):  
Yuvaraj Dinakarkumar ◽  
Jothi Ramalingam Rajabathar ◽  
Selvaraj Arokiyaraj ◽  
Iyyappan Jeyaraj ◽  
Sai Ramesh Anjaneyulu ◽  
...  
Keyword(s):  
Molecular Docking ◽  
In Silico ◽  
Rosmarinic Acid ◽  
Docking Studies ◽  
Thymus Vulgaris ◽  
Piper Betle ◽  
Coenzyme M ◽  
Dynamics Simulations ◽  
Autodock 4.0 ◽  
Methyl Coenzyme M Reductase

Methane is a greenhouse gas which poses a great threat to life on earth as its emissions directly contribute to global warming and methane has a 28-fold higher warming potential over that of carbon dioxide. Ruminants have been identified as a major source of methane emission as a result of methanogenesis by their respective gut microbiomes. Various plants produce highly bioactive compounds which can be investigated to find a potential inhibitor of methyl-coenzyme M reductase (the target protein for methanogenesis). To speed up the process and to limit the use of laboratory resources, the present study uses an in-silico molecular docking approach to explore the anti-methanogenic properties of phytochemicals from Cymbopogon citratus, Origanum vulgare, Lavandula officinalis, Cinnamomum zeylanicum, Piper betle, Cuminum cyminum, Ocimum gratissimum, Salvia sclarea, Allium sativum, Rosmarinus officinalis and Thymus vulgaris. A total of 168 compounds from 11 plants were virtually screened. Finally, 25 scrutinized compounds were evaluated against methyl-coenzyme M reductase (MCR) protein using the AutoDock 4.0 program. In conclusion, the study identified 21 out of 25 compounds against inhibition of the MCR protein. Particularly, five compounds: rosmarinic acid (−10.71 kcal/mol), biotin (−9.38 kcal/mol), α-cadinol (−8.16 kcal/mol), (3R,3aS,6R,6aR)-3-(2H-1,3-benzodioxol-4-yl)-6-(2H-1,3-benzodioxol-5-yl)-hexahydrofuro[3,4-c]furan-1-one (−12.21 kcal/mol), and 2,4,7,9-tetramethyl-5decyn4,7diol (−9.02 kcal/mol) showed higher binding energy towards the MCR protein. In turn, these compounds have potential utility as rumen methanogenic inhibitors in the proposed methane inhibitor program. Ultimately, molecular dynamics simulations of rosmarinic acid and (3R,3aS,6R,6aR) -3-(2H-1,3-benzodioxol-4-yl)-6-(2H-1,3-benzodioxol-5-yl)-hexahydrofuro[3,4-c]furan-1-one yielded the best possible interaction and stability with the active site of 5A8K protein for 20 ns.

Protein-Ligand Docking Methodologies and Its Application in Drug Discovery

2016 ◽  
pp. 196-219
Author(s):  
Sanchaita Rajkhowa ◽  
Ramesh C. Deka
Keyword(s):  
Molecular Docking ◽  
Drug Discovery ◽  
Drug Design ◽  
High Throughput Screening ◽  
Docking Studies ◽  
Stable Complex ◽  
Scoring Functions ◽  
Binding Modes ◽  
Structure Based Drug Design ◽  
Modern Drug

Molecular docking is a key tool in structural biology and computer-assisted drug design. Molecular docking is a method which predicts the preferred orientation of a ligand when bound in an active site to form a stable complex. It is the most common method used as a structure-based drug design. Here, the authors intend to discuss the various types of docking methods and their development and applications in modern drug discovery. The important basic theories such as sampling algorithm and scoring functions have been discussed briefly. The performances of the different available docking software have also been discussed. This chapter also includes some application examples of docking studies in modern drug discovery such as targeted drug delivery using carbon nanotubes, docking of nucleic acids to find the binding modes and a comparative study between high-throughput screening and structure-based virtual screening.

scholarly journals Synthesis, Antiproliferative Activity and Molecular Docking Studies of Novel Doubly Modified Colchicine Amides and Sulfonamides as Anticancer Agents

Molecules ◽  
2020 ◽  
Vol 25 (8) ◽  
pp. 1789 ◽  
Author(s):  
Julia Krzywik ◽  
Witold Mozga ◽  
Maral Aminpour ◽  
Jan Janczak ◽  
Ewa Maj ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Cell Lines ◽  
Anticancer Agents ◽  
Antiproliferative Activity ◽  
Docking Studies ◽  
Binding Modes ◽  
Colchicine Binding Site ◽  
3T3 Cell Lines ◽  
Colchicine Derivatives

Colchicine is a well-known compound with strong antiproliferative activity that has had limited use in chemotherapy because of its toxicity. In order to create more potent anticancer agents, a series of novel colchicine derivatives have been obtained by simultaneous modification at C7 (amides and sulfonamides) and at C10 (methylamino group) positions and characterized by spectroscopic methods. All the synthesized compounds have been tested in vitro to evaluate their cytotoxicity toward A549, MCF-7, LoVo, LoVo/DX and BALB/3T3 cell lines. Additionally, the activity of the studied compounds was investigated using computational methods involving molecular docking of the colchicine derivatives to β-tubulin. The majority of the obtained derivatives exhibited higher cytotoxicity than colchicine, doxorubicin or cisplatin against tested cancer cell lines. Furthermore, molecular modeling studies of the obtained compounds revealed their possible binding modes into the colchicine binding site of tubulin.

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