scholarly journals Virtual Screening and Molecular Dynamics Simulation Study of Influenza Polymerase PB2 Inhibitors

Molecules ◽  
2021 ◽  
Vol 26 (22) ◽  
pp. 6944
Author(s):  
Keli Zong ◽  
Lei Xu ◽  
Yuxin Hou ◽  
Qian Zhang ◽  
Jinjing Che ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Virtual Screening ◽  
Influenza A ◽  
Md Simulations ◽  
Biological Evaluation ◽  
Dynamics Simulation ◽  
Binding Modes ◽  
Active Compounds ◽  
Binding Characteristics ◽  
Glide Docking

Influenza A virus is the main cause of worldwide epidemics and annual influenza outbreaks in humans. In this study, a virtual screen was performed to identify compounds that interact with the PB2 cap-binding domain (CBD) of influenza A polymerase. A virtual screening workflow based on Glide docking was used to screen an internal database containing 8417 molecules, and then the output compounds were selected based on solubility, absorbance, and structural fingerprints. Of the 16 compounds selected for biological evaluation, six compounds were identified that rescued cells from H1N1 virus-mediated death at non-cytotoxic concentrations, with EC50 values ranging from 2.5–55.43 μM, and that could bind to the PB2 CBD of H1N1, with Kd values ranging from 0.081–1.53 μM. Molecular dynamics (MD) simulations of the docking complexes of our active compounds revealed that each compound had its own binding characteristics that differed from those of VX-787. Our active compounds have novel structures and unique binding modes with PB2 proteins, and are suitable to serve as lead compounds for the development of PB2 inhibitors. An analysis of the MD simulation also helped us to identify the dominant amino acid residues that play a key role in binding the ligand to PB2, suggesting that we should focus on increasing and enhancing the interaction between inhibitors and these major amino acids during lead compound optimization to obtain more active PB2 inhibitors.

scholarly journals 1,2-Αnnulated Adamantane Heterocyclic Derivatives as Anti-Influenza Α Virus Agents

2019 ◽  
Vol 92 (2) ◽  
pp. 211-228 ◽  
Author(s):  
Vasiliki Pardali ◽  
Erofili Giannakopoulou ◽  
Athina Konstantinidi ◽  
Antonios Kolocouris ◽  
Grigoris Zoidis
Keyword(s):  
Molecular Dynamics ◽  
Influenza A ◽  
Md Simulations ◽  
Biological Evaluation ◽  
Propanoic Acid ◽  
M2 Protein ◽  
Additional Insight ◽  
Structure Activity ◽  
Heterocyclic Derivatives ◽  
Pharmacological Potential

In this report we review our results on the development of 1,2-annulated adamantane heterocyclic derivatives and we discuss the structure-activity relationships obtained from their biological evaluation against influenza A virus. We have designed and synthesized numerous potent 1,2-annulated adamantane analogues of amantadine and rimantadine against influenza A targeting M2 protein the last 20 years. For their synthesis we utilized the key intermediates 2-(2-oxoadamantan-1-yl)acetic acid and 3-(2-oxoadamantan-1-yl)propanoic acid, which were obtained by a simple, fast and efficient synthetic protocol. The latter involved the treatment of protoadamantanone with different electrophiles and a carbon-skeleton rearrangement. These ketoesters offered a new pathway to the synthesis of 1,2-disubstituted adamantanes, which constitute starting materials for many molecules with pharmacological potential, such as the 1,2-annulated adamantane heterocyclic derivatives. To obtain additional insight for their binding to M2 protein three structurally similar 1,2-annulated adamantane piperidines, differing in nitrogen position, were studied using molecular dynamics (MD) simulations in palmitoyl-oleoyl-phosphatidyl-choline (POPC) hydrated bilayers.

scholarly journals Discovery of New Selective Butyrylcholinesterase (BChE) Inhibitors with Anti-Aβ Aggregation Activity: Structure-Based Virtual Screening, Hit Optimization and Biological Evaluation

Molecules ◽  
2019 ◽  
Vol 24 (14) ◽  
pp. 2568 ◽  
Author(s):  
Cheng-Shi Jiang ◽  
Yong-Xi Ge ◽  
Zhi-Qiang Cheng ◽  
Yin-Yin Wang ◽  
Hong-Rui Tao ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Cell Model ◽  
Neuroblastoma Cells ◽  
Biological Evaluation ◽  
Dynamics Simulation ◽  
Dependent Manner ◽  
Binding Modes ◽  
Catalytic Active Site ◽  
Aggregation Activity

In this study, a series of selective butyrylcholinesterase (BChE) inhibitors was designed and synthesized from the structural optimization of hit 1, a 4-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)benzoic acid derivative identified by virtual screening our compound library. The in vitro enzyme assay results showed that compounds 9 ((4-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)phenyl)(pyrrolidin-1-yl)methanone) and 23 (N-(2-bromophenyl)-4-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)benzamide) displayed improved BChE inhibitory activity and good selectivity towards BChE versus AChE. Their binding modes were probed by molecular docking and further validated by molecular dynamics simulation. Kinetic analysis together with molecular modeling studies suggested that these derivatives could target both the catalytic active site (CAS) and peripheral anionic site (PAS) of BChE. In addition, the selected compounds 9 and 23 displayed anti-Aβ1–42 aggregation activity in a dose-dependent manner, and they did not show obvious cytotoxicity towards SH-SY5Y neuroblastoma cells. Also, both compounds showed significantly protective activity against Aβ1-42-induced toxicity in a SH-SY5Y cell model. The present results provided a new valuable chemical template for the development of selective BChE inhibitors.

scholarly journals In Silico Discovery of Potential Azole-Containing mPGES-1 Inhibitors By Virtual Screening, Pharmacophore Modeling and Molecular Dynamics Simulations

2022 ◽  
Author(s):  
Lalehan Özalp ◽  
İlkay Küçükgüzel ◽  
Ayşe Ogan
Keyword(s):  
Molecular Dynamics ◽  
Side Effects ◽  
Virtual Screening ◽  
Correlation Coefficients ◽  
Pharmacokinetic Profile ◽  
Pharmacophore Modeling ◽  
Dynamics Simulation ◽  
Prostaglandin E ◽  
Binding Modes ◽  
Design Strategies

Abstract Inhibition of microsomal prostaglandin E2 synthase-1 (mPGES-1) is promising for designing novel nonsteroidal anti-inflammatory drugs, as they lack side-effects associated with inhibition of cyclooxygenase enzymes. Azole compounds are nitrogen-containing heterocycles and have a wide use in medicine and are considered as promising compounds in medicinal chemistry. Various computer-aided drug design strategies are incorporated in this study. Structure-based virtual screening was performed employing various docking programs. Receiver Operator Characteristic (ROC) curves were used to evaluate the selectivity of each program. Furthermore, scoring power of Autodock4 and Autodock Vina was assessed by Pearson’s correlation coefficients. Pharmacophore models were generated and Güner-Henry score of the best model was calculated as 0.89. Binding modes of the final 10 azole compounds were analyzed and further investigation of the best binding (-8.38 kcal/mol) compound was performed using molecular dynamics simulation, revealing that furazan1224 (ZINC001142847306) occupied the binding site of the substrate, prostaglandin H2 (PGH2) and remained stable for 100 ns. Continuous hydrogen bonds with amino acids in the active site supported the stability of furazan1224 throughout the trajectory. Pharmacokinetic profile showed that furazan1224 lacks the risks of inhibiting cytochrome P450 3A4 enzyme and central nervous system-related side-effects.

Identification of New Hsp90 Inhibitors: Structure Based Virtual Screening, Molecular Dynamic Simulation, Synthesis and Biological Evaluation

2021 ◽  
Vol 21 ◽  
Author(s):  
Maryam Abbasi ◽  
Massoud Amanlou ◽  
Mahmoud Aghaei ◽  
Farshid Hassanzadeh ◽  
Hojjat Sadeghi-Aliabadi
Keyword(s):  
Virtual Screening ◽  
Molecular Dynamic Simulation ◽  
Molecular Dynamic ◽  
Dynamic Simulation ◽  
Md Simulations ◽  
Biological Evaluation ◽  
Dynamics Simulation ◽  
Hsp70 Expression ◽  
Hsp90 Inhibitors ◽  
Screening Study

Background: Heat shock protein90 (Hsp90) is overexpressed in tumor cells, thus the inhibition of the Hsp90 ATPase activity would be a meaningfully an effective strategy in cancer therapy. Objective: The present work was aimed at four steps: designing new Hsp90 inhibitors as anti-cancer by a virtual screening study; synthesize designed compounds; biological evaluation of them and finally molecular dynamic (MD) simulations of best compounds. Methods: A virtual screening study was performed on a library (100 compounds) of the ZINC database with benzimidazole scaffold; then an extracted compound and two derivatives were synthesized. The anti-proliferative and ATPase inhibitory activities of these compounds were evaluated by MTT and ATPase inhibition assays, respectively. The western blot analysis was performed to the evaluation of the expression level of Hsp70 and Her2 proteins. Finally, 200 ns molecular dynamic simulation was carried out to confirm stability the strongest synthesized compound in Hsp90 active site. Results: ZINC00173501 compound with an aminobenzimidazole scaffold was chosen by the virtual screening study. ZINC00173501 compound and two of its derivatives were synthesized. ATPase inhibitory activity of three synthesized compounds shown that ZINC00173501 compound was the most potent inhibitor (IC50= 8.6 μM) with the anti-proliferative activity 14.41 μM, 19.07 μM and more than 100 μM against MCF-7, HeLa and HUVEC cell lines, respectively. The high level of Hsp70 expression and low level of Her2 expression confirmed ZINC00173501 as an Hsp90 inhibitor. Finally, molecular dynamics simulation showed that ZINC00173501 was stable in Hsp90 active cite during 200 ns simulation. Conclusion: The biological evaluation results show that 2-aminobenzimidazole scaffold could be suggested as a lead for inhibition of Hsp90.

Identification of Antimycobacterial Agent Using In-silico Virtual Screening, ADME Prediction, Docking, and Molecular Dynamics Simulations Approach

2020 ◽  
Vol 16 ◽  
Author(s):  
Swayansiddha Tripathy ◽  
Susanta Kumar Sahu ◽  
Mohammed Afzal Azam ◽  
Srikanth Jupudi ◽  
Vivek Kumar Gupta ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Virtual Screening ◽  
Minimal Inhibitory Concentration ◽  
Inhibitory Concentration ◽  
Colorimetric Method ◽  
Dynamics Simulation ◽  
Antibiotics Resistance ◽  
Antibacterial Drug ◽  
Microtiter Plate Assay ◽  
Glide Docking

Background: The widespread hazardous issue of antibiotics resistance can be overcome by the development of target based potent antibacterial agents. Filamentous temperature-sensitive mutant Z (FtsZ), a simpler structural prokaryotic homolog of eukaryotic cytoskeletal tubulin, was considered as a competent target in antibacterial drug discovery. Objective: The purpose of present work is to evaluate the antitubercular activity of virtual hits by funnel-shaped filtering with glide docking followed by MM-GBSA binding energy and molecular dynamics simulation. Pharmacokinetics and biochemical activity of the computationally screened virtual hits have been studied to focus their potential to inhibit the bacterial cell division. Method: The docking study was performed against the crystal structure of Staphylococcus aureus and Mycobacterium tuberculosis FtsZ protein with the hits obtained from High Throughput Virtual Screening using Glide module in Schrodinger. ADME profile and 50 ns molecular dynamics simulationstudies were performed using the Schrödinger suite. The minimal inhibitory concentration of the test compounds were determined bythe colorimetric method by Resazurin Microtiter plate Assay. Results: The binding of hit molecules T5427054 and 6M356S were mainly supported by van der Waals interaction and an electrostatic component of solvation energycomputed by MM-GBSA method. 50 ns MD simulation built stability and dynamic property of the best-docked complex T5427054/2Q1Y. Both the hit molecules displayed antimycobacterial activity with minimal inhibitory concentration 500 μg/mL. Conclusion: In this study, it is found that new screened hit molecules with better theoretical results could be preferred to use as antimycobacterial agents and further their structural modification might be improved antimycobacterial properties of hit molecules.

Identification of fosaprepitant as a novel GSTP1 inhibitor through structure-based virtual screening, molecular dynamics simulation, and biological evaluation

2021 ◽  
Author(s):  
Hao Lin ◽  
Wenxiu Sun ◽  
Tao Zeng ◽  
Hengda Li ◽  
Chenming Xu ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
Virtual Screening ◽  
Biological Evaluation ◽  
Therapeutic Agents ◽  
Dynamics Simulation ◽  
Glutathione S Transferase ◽  
Promising Target ◽  
Cancer Cell Survival ◽  
Prevention And Therapy

Glutathione S-transferase P1 (GSTP1) is a promising target for cancer prevention and therapy, particularly because of its involvement in promoting cancer cell survival and resistance of tumors to therapeutic agents....

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