In silico approaches using pharmacophore model combined with molecular docking for discovery of novel ULK1 inhibitors

2021 ◽  
Author(s):  
Siyu He ◽  
Yang Liu ◽  
Qihang Li ◽  
Weiping Lyu ◽  
Feng Feng ◽  
...  
Keyword(s):  
Pharmacophore Model ◽  
Docking Studies ◽  
Dynamics Simulation ◽  
Autophagic Flux ◽  
The Novel ◽  
Starting Point ◽  
Docking Approach ◽  
Good Starting Point

Background: Discovery of effective autophagy-initiating kinase ULK1 inhibitors has attracted more and more attention in cancer treatment. Methodology & results: The present study describes the application of a pharmacophore-based virtual screening and structure-based docking approach guided drug design. Compound U-2 exhibited a nanomolar range of IC50 against the ULK1 target. Molecular dynamics simulation was used to assess the quality of docking studies. The determinants of binding affinity were investigated, and a different binding pattern was observed. Subsequently, prediction properties of ADMET (absorption, distribution, metabolism, excretion and toxicity) and hepatotoxicity in vitro studies indicated that U-2 possessed good drug-like properties. Moreover, western blot analysis indicated that the compound inhibited autophagic flux in cells. Conclusion: The present study provides an appropriate guideline for discovering novel ULK1 inhibitors. The novel compound may serve as a good starting point for further development and optimizations.

Pharmacophore Modeling and Docking Studies to Investigate Potential Leads for the Development of β -Secretase APP Cleavage Enzyme-1 (BACE-1) Inhibitors

2019 ◽  
Vol 16 (7) ◽  
pp. 775-784
Author(s):  
Richa Arya ◽  
Satya Prakash Gupta ◽  
Sarvesh Paliwal ◽  
Swapnil Sharma ◽  
Kirtika Madan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Medical Condition ◽  
Pharmacophore Model ◽  
Pharmacophore Modeling ◽  
Docking Studies ◽  
Pyridine Derivative ◽  
Cleavage Enzyme ◽  
Bace 1

Background: Alzheimer’s disease is a medical condition with detrimental brain health. It is majorly diagnosed in aging individuals plaque in β) characterized by accumulated Amyloidal beta (A 1 BACE) 1 secretase APP cleavage enzyme βneurological areas. The ) is the target of choice that can be exploited to find drugs against Alzheimer’s disease. Methods: A series of BACE-1 inhibitors with reported binding constant were considered for the development of a feature based pharmacophore model. Results: The good correlation coefficient (r=0.91) and RMSD of 0.93 was observed with 30 compounds in training set. The model was validated internally (r2test=0.76) as well as externally by Fischer validation. The pharmacophore based virtual screening retrieved compounds that were docked and biologically evaluated. Conclusion: The three structurally diverse molecules were tested by in-vitro method. The pyridine derivative with highest fit value (6.9) exhibited IC50 value of 2.70 µM and thus was found to be the most promising lead molecule as BACE-1 inhibitor.

scholarly journals Molecular Docking and Molecular Dynamics Simulation Studies of Triterpenes from Vernonia patula with the Cannabinoid Type 1 Receptor

2021 ◽  
Vol 22 (7) ◽  
pp. 3595
Author(s):  
Md Afjalus Afjalus Siraj ◽  
Md. Sajjadur Rahman ◽  
Ghee T. Tan ◽  
Veronique Seidel
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Molecular Dynamics Simulation ◽  
Binding Affinity ◽  
Docking Studies ◽  
Dynamics Simulation ◽  
Simulation Studies ◽  
Cannabinoid Type 1 Receptor ◽  
Docking Approach

A molecular docking approach was employed to evaluate the binding affinity of six triterpenes, namely epifriedelanol, friedelin, α-amyrin, α-amyrin acetate, β-amyrin acetate, and bauerenyl acetate, towards the cannabinoid type 1 receptor (CB1). Molecular docking studies showed that friedelin, α-amyrin, and epifriedelanol had the strongest binding affinity towards CB1. Molecular dynamics simulation studies revealed that friedelin and α-amyrin engaged in stable non-bonding interactions by binding to a pocket close to the active site on the surface of the CB1 target protein. The studied triterpenes showed a good capacity to penetrate the blood–brain barrier. These results help to provide some evidence to justify, at least in part, the previously reported antinociceptive and sedative properties of Vernonia patula.

scholarly journals Identification of potential TNF-α inhibitors: from in silico to in vitro studies

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Komal Zia ◽  
Sajda Ashraf ◽  
Almas Jabeen ◽  
Maria Saeed ◽  
Mohammad Nur-e-Alam ◽  
...  
Keyword(s):  
Small Molecule ◽  
Therapeutic Potential ◽  
Pharmacophore Model ◽  
Docking Studies ◽  
Immune Functions ◽  
Binding Interaction ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Potential Inhibitors

AbstractTumor Necrosis Factor Alpha (TNF-α) is a pleiotropic pro-inflammatory cytokine. It act as central biological regulator in critical immune functions, but its dysregulation has been linked with a number of diseases. Inhibition of TNF-α has considerable therapeutic potential for diseases such as cancer, diabetes, and especially autoimmune diseases. Despite the fact that many small molecule inhibitors have been identified against TNF-α, no orally active drug has been reported yet which demand an urgent need of a small molecule drug against TNF-α. This study focuses on the development of ligand-based selective pharmacophore model to perform virtual screening of plant origin natural product database for the identification of potential inhibitors against TNF-α. The resultant hits, identified as actives were evaluated by molecular docking studies to get insight into their potential binding interaction with the target protein. Based on pharmacophore matching, interacting residues, docking score, more affinity towards TNF-α with diverse scaffolds five compounds were selected for in vitro activity study. Experimental validation led to the identification of three chemically diverse potential compounds with the IC50 32.5 ± 4.5 µM, 6.5 ± 0.8 µM and 27.4 ± 1.7 µM, respectively.

scholarly journals Preparation of Innovative Skin Compatible Films to Release Polysaccharides for Biobased Beauty Masks

Cosmetics ◽  
2018 ◽  
Vol 5 (4) ◽  
pp. 70 ◽  
Author(s):  
Maria-Beatrice Coltelli ◽  
Serena Danti ◽  
Luisa Trombi ◽  
Pierfrancesco Morganti ◽  
Giovanna Donnarumma ◽  
...  
Keyword(s):  
Immune Modulation ◽  
Human Keratinocytes ◽  
In Vitro Tests ◽  
Biobased Materials ◽  
Starting Point ◽  
Good Starting Point ◽  
Skin Compatibility ◽  
The Impact ◽  
Fast Release

The preparation and selection of biobased materials compatible with skin is essential for producing innovative and highly eco-friendly beauty masks. The use of a commercial elastomeric poly(hydroxyalkanoate) and starch was fundamental to select materials for bioplastic films with the necessary resistance in wet conditions, skin compatibility and capacity for a fast release of polysaccharides and similar active and functional molecules. Micrometric calcium carbonate was also used to control the stickiness of film during moulding. Starch release in water was investigated by gravimetric and infrared analyses. The compatibility with skin was investigated via two different in vitro tests based on human keratinocytes and human mesenchymal stromal cells. The materials were highly cytocompatible with skin, enabled immune modulation by keratinocytes and starch release in water up to 49% by weight in 30 min. These outcomes are a good starting point for boosting the production of biobased and biodegradable beauty masks, thus decreasing the impact onto environment of cosmetic products that are currently still mainly produced using petrol-based substrates.

scholarly journals Ligand-based pharmacophore model for the discovery of novel CXCR2 antagonists as anti-cancer metastatic agents

2018 ◽  
Vol 5 (7) ◽  
pp. 180176 ◽  
Author(s):  
Jinxin Che ◽  
Zhilong Wang ◽  
Haichao Sheng ◽  
Feng Huang ◽  
Xiaowu Dong ◽  
...  
Keyword(s):  
Metastatic Cancer ◽  
Pharmacophore Model ◽  
The Novel ◽  
Antagonist Activity ◽  
H1299 Cell ◽  
Anti Cancer ◽  
Cxcr2 Antagonists ◽  
H1299 Cell Line ◽  
Cxcr2 Antagonist

Metastatic cancer is considered a fatal progression of cancer worldwide. It has been shown that a key player in this scenario is the CXC chemokine receptor 2 (CXCR2). To identify novel CXCR2 antagonists, a pharmacophore model was built with the H ip H op program by screening a database containing compounds which were designed based on the known structure–activity relationship (SAR) of the diarylurea series CXCR2 antagonists. Compound 1a bearing the novel skeleton was selected from database screening and subjected to the in vitro biological test which showed a moderate CXCR2 antagonist potential. With further modification and exploration of SAR, compound 1e demonstrated improved CXCR2 antagonist activity with an IC 50 value of 14.8 µM. Furthermore, wound healing assay using the NCI-H1299 cell line indicated that 1e showed an excellent anti-cancer metastatic effect (72% inhibition in cell migration at 50 µg ml −1 ).

scholarly journals Phloroglucinol as a Potential Candidate against Trypanosoma congolense Infection: Insights from In Vivo, In Vitro, Molecular Docking and Molecular Dynamic Simulation Analyses

Molecules ◽  
2022 ◽  
Vol 27 (2) ◽  
pp. 469
Author(s):  
Nasirudeen Idowu Abdulrashid ◽  
Suleiman Aminu ◽  
Rahma Muhammad Adamu ◽  
Nasir Tajuddeen ◽  
Murtala Bindawa Isah ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Docking Studies ◽  
Binding Energies ◽  
Sub Saharan Africa ◽  
Dynamics Simulation ◽  
Potential Candidate ◽  
Inhibitory Effects ◽  
Hydrogen Bond Interaction

Sub-Saharan Africa is profoundly challenged with African Animal Trypanosomiasis and the available trypanocides are faced with drawbacks, necessitating the search for novel agents. Herein, the chemotherapeutic potential of phloroglucinol on T. congolense infection and its inhibitory effects on the partially purified T. congolense sialidase and phospholipase A2 (PLA2) were investigated. Treatment with phloroglucinol for 14 days significantly (p < 0.05) suppressed T. congolense proliferation, increased animal survival and ameliorated anemia induced by the parasite. Using biochemical and histopathological analyses, phloroglucinol was found to prevent renal damages and splenomegaly, besides its protection against T. congolense-associated increase in free serum sialic acids in infected animals. Moreover, the compound inhibited bloodstream T. congolense sialidase via mixed inhibition pattern with inhibition binding constant (Ki) of 0.181 µM, but a very low uncompetitive inhibitory effects against PLA2 (Ki > 9000 µM) was recorded. Molecular docking studies revealed binding energies of −4.9 and −5.3 kcal/mol between phloroglucinol with modeled sialidase and PLA2 respectively, while a 50 ns molecular dynamics simulation using GROMACS revealed the sialidase-phloroglucinol complex to be more compact and stable with higher free binding energy (−67.84 ± 0.50 kJ/mol) than PLA2-phloroglucinol complex (−77.17 ± 0.52 kJ/mol), based on MM-PBSA analysis. The sialidase-phloroglucinol complex had a single hydrogen bond interaction with Ser453 while none was observed for the PLA2-phloroglucinol complex. In conclusion, phloroglucinol showed moderate trypanostatic activity with great potential in ameliorating some of the parasite-induced pathologies and its anti-anemic effects might be linked to inhibition of sialidase rather than PLA2.

scholarly journals Astaxanthin-Mediated Bacterial Lethality: Evidence from Oxidative Stress Contribution and Molecular Dynamics Simulation

2021 ◽  
Vol 2021 ◽  
pp. 1-24
Author(s):  
Jamiu Olaseni Aribisala ◽  
Sonto Nkosi ◽  
Kehinde Idowu ◽  
Ismaila Olanrewaju Nurain ◽  
Gaositwe Melvin Makolomakwa ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
In Silico ◽  
Current Knowledge ◽  
Dynamics Simulation ◽  
The Novel ◽  
Topoisomerase Iv ◽  
Test Organisms ◽  
Gyrase A ◽  
Vitro Analysis

The involvement of cellular oxidative stress in antibacterial therapy has remained a topical issue over the years. In this study, the contribution of oxidative stress to astaxanthin-mediated bacterial lethality was evaluated in silico and in vitro. For the in vitro analysis, the minimum inhibitory concentration (MIC) of astaxanthin was lower than that of novobiocin against Staphylococcus aureus but generally higher than those of the reference antibiotics against other test organisms. The level of superoxide anion of the tested organisms increased significantly following treatment with astaxanthin when compared with DMSO-treated cells. This increase compared favorably with those observed with the reference antibiotics and was consistent with a decrease in the concentration of glutathione (GSH) and corresponding significant increase in ADP/ATP ratio. These observations are suggestive of probable involvement of oxidative stress in antibacterial capability of astaxanthin and in agreement with the results of the in silico evaluations, where the free energy scores of astaxanthins’ complexes with topoisomerase IV ParC and ParE were higher than those of the reference antibiotics. These observations were consistent with the structural stability and compactness of the complexes as astaxanthin was observed to be more stable against topoisomerase IV ParC and ParE than DNA Gyrase A and B. Put together, findings from this study underscored the nature and mechanism of antibacterial action of astaxanthin that could suggest practical approaches in enhancing our current knowledge of antibacterial arsenal and aid in the novel development of alternative natural topo2A inhibitor.

scholarly journals Molecular docking and molecular dynamics simulation study of inositol phosphorylceramide synthase – inhibitor complex in leishmaniasis: Insight into the structure based drug design

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 1610 ◽  
Author(s):  
Vineetha Mandlik ◽  
Shailza Singh
Keyword(s):  
Molecular Dynamics ◽  
Dynamics Simulation ◽  
Sphingolipid Metabolism ◽  
Drug Candidate ◽  
Binding Modes ◽  
Structure Based Drug Design ◽  
Starting Point ◽  
Synthase Inhibitor

Inositol phosphorylceramide synthase (IPCS) has emerged as an important, interesting and attractive target in the sphingolipid metabolism of Leishmania. IPCS catalyzes the conversion of ceramide to IPC which forms the most predominant sphingolipid in Leishmania. IPCS has no mammalian equivalent and also plays an important role in maintaining the infectivity and viability of the parasite. The present study explores the possibility of targeting IPCS; development of suitable inhibitors for the same would serve as a treatment strategy for the infectious disease leishmaniasis. Five coumarin derivatives were developed as inhibitors of IPCS protein. Molecular dynamics simulations of the complexes of IPCS with these inhibitors were performed which provided insights into the binding modes of the inhibitors. In vitro screening of the top three compounds has resulted in the identification of one of the compounds (compound 3) which shows little cytotoxic effects. This compound therefore represents a good starting point for further in vivo experimentation and could possibly serve as an important drug candidate for the treatment of leishmaniasis.

scholarly journals Fragment-Based Virtual Screening to Discover Potential Plasmodium PI4KIIIβ Ligands

2021 ◽  
Author(s):  
Akachukwu Ibezim ◽  
Mbanefo S. Madukaife ◽  
Sochi C Osigwe ◽  
Nadja Engel ◽  
Ramanathan Karuppasamy ◽  
...  
Keyword(s):  
Antimalarial Activity ◽  
Plasmodium Species ◽  
Homology Model ◽  
Binding Energies ◽  
Dynamics Simulation ◽  
Active Site Residues ◽  
Starting Point ◽  
Binding Cavity

Plasmodium species that cause malaria, a disease responsible for about half a million deaths per annum despite concerted efforts to combat it. The causative agent depends on type III beta phosphatidylinositol 4-kinase (PPI4K) during the development of merozoite. PPI4K is the only clinically validated Plasmodium kinase so far and its inhibitors are effective both in vitro and in vivo. In this work, a small library of ~22 000 fragments was virtually screened using PPI4K homology model to discover potential ligands of the enzyme. 16 virtual hits were selected based on &le; -9.0 kcal/mol binding energy cut off and were subjected to similarity and substructure searching after they had passed PAINS screening. The derivatives obtained showed improved binding energies, which ranged from -10.00 to -13.80 kcal/mol. Moreover, the topmost ranking compound 31, with interesting drug-like quality was stable within the protein&rsquo;s binding cavity during the 10 ns molecular dynamics simulation period. In addition, analysis of its binding pose revealed some unique binding interactions with PPI4K active site residues as the basis for the observed improved binding affinity. Overall, compound 31 appears to be a viable starting point for the development of PPI4K inhibitors with antimalarial activity.

scholarly journals Newly Synthesized Fluorinated Cinnamylpiperazines Possessing Low In Vitro MAO-B Binding

Molecules ◽  
2020 ◽  
Vol 25 (21) ◽  
pp. 4941
Author(s):  
Ivana I. Jevtić ◽  
Thu Hang Lai ◽  
Jelena Z. Penjišević ◽  
Sladjana Dukić-Stefanović ◽  
Deana B. Andrić ◽  
...  
Keyword(s):  
Binding Assay ◽  
Docking Studies ◽  
Emission Tomography ◽  
Binding Affinities ◽  
The Novel ◽  
Competitive Binding Assay ◽  
Mao B ◽  
Positron Emission ◽  
Further Development

Herein, we report on the synthesis and pharmacological evaluation of ten novel fluorinated cinnamylpiperazines as potential monoamine oxidase B (MAO-B) ligands. The designed derivatives consist of either cinnamyl or 2-fluorocinnamyl moieties connected to 2-fluoropyridylpiperazines. The three-step synthesis starting from commercially available piperazine afforded the final products in overall yields between 9% and 29%. An in vitro competitive binding assay using l-[3H]Deprenyl as radioligand was developed and the MAO-B binding affinities of the synthesized derivatives were assessed. Docking studies revealed that the compounds 8–17 were stabilized in both MAO-B entrance and substrate cavities, thus resembling the binding pose of l-Deprenyl. Although our results revealed that the novel fluorinated cinnamylpiperazines 8–17 do not possess sufficient MAO-B binding affinity to be eligible as positron emission tomography (PET) agents, the herein developed binding assay and the insights gained within our docking studies will certainly pave the way for further development of MAO-B ligands.

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