scholarly journals Combination of consensus and ensemble docking strategies for the discovery of human dihydroorotate dehydrogenase inhibitors

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Garri Chilingaryan ◽  
Narek Abelyan ◽  
Arsen Sargsyan ◽  
Karen Nazaryan ◽  
Andre Serobian ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Early Recognition ◽  
Biosynthesis Pathway ◽  
Dihydroorotate Dehydrogenase ◽  
Benchmark Study ◽  
Ensemble Docking ◽  
Whole Process ◽  
Structural Conformation ◽  
Key Enzyme ◽  
Consensus Scoring

AbstractThe inconsistencies in the performance of the virtual screening (VS) process, depending on the used software and structural conformation of the protein, is a challenging issue in the drug design and discovery field. Varying performance, especially in terms of early recognition of the potential hit compounds, negatively affects the whole process and leads to unnecessary waste of the time and resources. Appropriate application of the ensemble docking and consensus-scoring approaches can significantly increase reliability of the VS results. Dihydroorotate dehydrogenase (DHODH) is a key enzyme in the pyrimidine biosynthesis pathway. It is considered as a valuable therapeutic target in cancer, autoimmune and viral diseases. Based on the conducted benchmark study and analysis of the effect of different combinations of the applied methods and approaches, here we suggested a structure-based virtual screening (SBVS) workflow that can be used to increase the reliability of VS.

scholarly journals Improving Reliability of the Virtual Screening Process for Human Dihydroorotate Dehydrogenase Enzyme by Combination of the Ensemble and Consensus Docking Approaches

2021 ◽  
Author(s):  
Garri Chilingaryan ◽  
Narek Abelyan ◽  
Arsen Sargsyan ◽  
Karen Nazaryan ◽  
Andre Serobian ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Early Recognition ◽  
Dihydroorotate Dehydrogenase ◽  
Screening Process ◽  
Benchmark Study ◽  
Whole Process ◽  
Structural Conformation ◽  
Dehydrogenase Enzyme ◽  
Key Enzyme ◽  
Consensus Scoring

Abstract The inconsistencies in the performance of the virtual screening (VS) process, depending on the used software and structural conformation of the protein, is a challenging issue in the drug design and discovery field. Varying performance, especially in terms of early recognition of the potential hit compounds, negatively affects the whole process and leads to unnecessary waste of the time and resources. Appropriate application of the ensemble docking and consensus-scoring approaches can significantly increase reliability of the VS results. Dihydroorotate dehydrogenase (DHODH) is a key enzyme in the pyrimidine biosynthesis pathway. It is considered as a valuable therapeutic target in cancer, autoimmune and viral diseases. Based on the conducted benchmark study and analysis of the effect of different combinations of the applied methods and approaches, here we suggested a structure-based virtual screening (SBVS) workflow that can be used to increase the reliability of VS.

Improving Structure-Based Virtual Screening with Ensemble Docking and Machine Learning

2021 ◽  
Author(s):  
Joel Ricci-Lopez ◽  
Sergio A. Aguila ◽  
Michael K. Gilson ◽  
Carlos A. Brizuela
Keyword(s):  
Machine Learning ◽  
Virtual Screening ◽  
Ensemble Docking

scholarly journals In silicoidentification of putativeTrypanosoma cruzienolase inhibitors

2019 ◽  
Author(s):  
Edward A. Valera-Vera ◽  
Melisa Sayé ◽  
Chantal Reigada ◽  
Mariana R. Miranda ◽  
Claudio A. Pereira
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Virtual Screening ◽  
Active Site ◽  
Screening Strategy ◽  
Glycolytic Enzyme ◽  
Docking Simulations ◽  
Enzyme Active Site ◽  
Key Enzyme

AbstractEnolase is a glycolytic enzyme that catalyzes the interconversion between 2-phosphoglycerate and phosphoenolpyruvate. In trypanosomatids enolase was proposed as a key enzyme afterin silicoandin vivoanalysis and it was validated as a protein essential for the survival of the parasite. Therefore, enolase constitutes an interesting enzyme target for the identification of drugs against Chagas disease. In this work, a combined virtual screening strategy was implemented, employing similarity virtual screening, molecular docking and molecular dynamics. First, two known enolase inhibitors and the enzyme substrates were used as queries for the similarity screening on the Sweetlead database using five different algorithms. Compounds retrieved in the top 10 of at least three search algorithms were selected for further analysis, resulting in six compounds of medical use (etidronate, pamidronate, fosfomycin, acetohydroximate, triclofos, and aminohydroxybutyrate). Molecular docking simulations predicted acetohydroxamate and triclofos would not bind to the active site of the enzyme, and a re-scoring of the obtained poses signaled fosfomycin and aminohydroxybutyrate as bad enzyme binders. Docking poses obtained for etidronate, pamidronate, and PEP, were used for molecular dynamics calculations to describe their mode of binding. From the obtained results, we propose etidronate as a possibleTcENO inhibitor, and describe desirable and undesirable molecular motifs to be taken into account in the repurposing or design of drugs aiming this enzyme active site.

scholarly journals Bornyl Diphosphate Synthase From Cinnamomum burmanni and Its Application for (+)-Borneol Biosynthesis in Yeast

2021 ◽  
Vol 9 ◽  
Author(s):  
Rui Ma ◽  
Ping Su ◽  
Juan Guo ◽  
Baolong Jin ◽  
Qing Ma ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Biosynthetic Pathway ◽  
Main Product ◽  
Microbial Fermentation ◽  
Biosynthesis Pathway ◽  
Analgesic Effects ◽  
Pathway Reconstruction ◽  
Key Enzyme ◽  
Shake Flasks

(+)-Borneol is a desirable monoterpenoid with effective anti-inflammatory and analgesic effects that is known as soft gold. (+)-bornyl diphosphate synthase is the key enzyme in the (+)-borneol biosynthesis pathway. Despite several reported (+)-bornyl diphosphate synthase genes, relatively low (+)-borneol production hinders the attempts to synthesize it using microbial fermentation. Here, we identified the highly specific (+)-bornyl diphosphate synthase CbTPS1 from Cinnamomum burmanni. An in vitro assay showed that (+)-borneol was the main product of CbTPS1 (88.70% of the total products), and the Km value was 5.11 ± 1.70 μM with a kcat value of 0.01 s–1. Further, we reconstituted the (+)-borneol biosynthetic pathway in Saccharomyces cerevisiae. After tailored truncation and adding Kozak sequences, the (+)-borneol yield was improved by 96.33-fold to 2.89 mg⋅L–1 compared with the initial strain in shake flasks. This work is the first reported attempt to produce (+)-borneol by microbial fermentation. It lays a foundation for further pathway reconstruction and metabolic engineering production of this valuable natural monoterpenoid.

Cryptochrome 2 is involved in betacyanin decomposition induced by blue light in Suaeda salsa

2006 ◽  
Vol 33 (7) ◽  
pp. 697 ◽  
Author(s):  
Wang Chang-Quan ◽  
Liu Tao
Keyword(s):  
Western Blot ◽  
Blue Light ◽  
Hypocotyl Elongation ◽  
Suaeda Salsa ◽  
Biosynthesis Pathway ◽  
Tyrosine Hydroxylation ◽  
Key Enzyme ◽  
Cryptochrome 2 ◽  
Hydroxylation Activity

Seeds of the halophyte Suaeda salsa (L.) Pall. were cultured in 24 h dark and 14 h blue light / 10 h dark to examine the role of blue light and the blue-light-absorbing photoreceptor cryptochrome 2 (CRY2) in betacyanin accumulation, hypocotyl elongation and cotyledon opening in S. salsa seedlings. Darkness significantly promoted betacyanin accumulation and hypocotyl elongation but inhibited cotyledon opening. Blue light suppressed betacyanin accumulation and hypocotyl elongation but stimulated cotyledon opening. Betacyanin in S. salsa seedlings decomposed with time in blue light. Western blot analysis showed that CRY2 protein accumulated both in hypocotyls and cotyledons of S. salsa seedlings grown in dark, but degraded with time in blue light, which was paralleled by a decrease of tyrosine hydroxylation activity of tyrosinase, a key enzyme involved in the betalain biosynthesis pathway. These results suggest that CRY2 protein mediates betacyanin decomposition via inactivation of tyrosinase in S. salsa seedlings, and the blue-light-dependent degradation of CRY2 protein is crucial to its function.

scholarly journals CompScore: Boosting Structure-Based Virtual Screening Performance by Incorporating Docking Scoring Function Components into Consensus Scoring

2019 ◽  
Vol 59 (9) ◽  
pp. 3655-3666 ◽  
Author(s):  
Yunierkis Perez-Castillo ◽  
Stellamaris Sotomayor-Burneo ◽  
Karina Jimenes-Vargas ◽  
Mario Gonzalez-Rodriguez ◽  
Maykel Cruz-Monteagudo ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Scoring Function ◽  
Screening Performance ◽  
Consensus Scoring ◽  
Virtual Screening Performance

scholarly journals Ensemble Docking Coupled to Linear Interaction Energy Calculations for Identification of Coronavirus Main Protease (3CLpro) Non-Covalent Small-Molecule Inhibitors

Molecules ◽  
2020 ◽  
Vol 25 (24) ◽  
pp. 5808
Author(s):  
Marko Jukič ◽  
Dušanka Janežič ◽  
Urban Bren
Keyword(s):  
Virtual Screening ◽  
Interaction Energy ◽  
Binding Free Energy ◽  
Conformational Space ◽  
Binding Modes ◽  
Linear Interaction ◽  
Linear Interaction Energy ◽  
Ensemble Docking ◽  
Novel Approach ◽  
Screening Study

SARS-CoV-2, or severe acute respiratory syndrome coronavirus 2, represents a new strain of Coronaviridae. In the closing 2019 to early 2020 months, the virus caused a global pandemic of COVID-19 disease. We performed a virtual screening study in order to identify potential inhibitors of the SARS-CoV-2 main viral protease (3CLpro or Mpro). For this purpose, we developed a novel approach using ensemble docking high-throughput virtual screening directly coupled with subsequent Linear Interaction Energy (LIE) calculations to maximize the conformational space sampling and to assess the binding affinity of identified inhibitors. A large database of small commercial compounds was prepared, and top-scoring hits were identified with two compounds singled out, namely 1-[(R)-2-(1,3-benzimidazol-2-yl)-1-pyrrolidinyl]-2-(4-methyl-1,4-diazepan-1-yl)-1-ethanone and [({(S)-1-[(1H-indol-2-yl)methyl]-3-pyrrolidinyl}methyl)amino](5-methyl-2H-pyrazol-3-yl)formaldehyde. Moreover, we obtained a favorable binding free energy of the identified compounds, and using contact analysis we confirmed their stable binding modes in the 3CLpro active site. These compounds will facilitate further 3CLpro inhibitor design.

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