scholarly journals Semi-automated workflow for molecular pair analysis and QSAR-assisted transformation space expansion

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Zi-Yi Yang ◽  
Li Fu ◽  
Ai-Ping Lu ◽  
Shao Liu ◽  
Ting-Jun Hou ◽  
...  
Keyword(s):  
Qsar Model ◽  
Small Scale ◽  
Qsar Modeling ◽  
Lead Compounds ◽  
Molecular Pair ◽  
Promising Tool ◽  
Space Expansion ◽  
The Relationship ◽  
Transformation Space ◽  
Pair Analysis

AbstractIn the process of drug discovery, the optimization of lead compounds has always been a challenge faced by pharmaceutical chemists. Matched molecular pair analysis (MMPA), a promising tool to efficiently extract and summarize the relationship between structural transformation and property change, is suitable for local structural optimization tasks. Especially, the integration of MMPA with QSAR modeling can further strengthen the utility of MMPA in molecular optimization navigation. In this study, a new semi-automated procedure based on KNIME was developed to support MMPA on both large- and small-scale datasets, including molecular preparation, QSAR model construction, applicability domain evaluation, and MMP calculation and application. Two examples covering regression and classification tasks were provided to gain a better understanding of the importance of MMPA, which has also shown the reliability and utility of this MMPA-by-QSAR pipeline.

Identification of Main Protease of Coronavirus SARS-CoV-2 (Mpro)Inhibitors from Melissa officinalis

2020 ◽  
Vol 17 ◽  
Author(s):  
Olusola O. Elekofehinti ◽  
Opeyemi Iwaloye ◽  
Courage D. Famusiwa ◽  
Olanrewaju Akinseye ◽  
Joao B. T. Rocha
Keyword(s):  
Qsar Model ◽  
Computational Approach ◽  
Melissa Officinalis ◽  
Lead Compounds ◽  
Main Protease ◽  
The World ◽  
Recent Outbreak ◽  
Global Concern ◽  
Catalytic Dyad ◽  
Potential Therapeutic Intervention

Background: he recent outbreak of Coronavirus SARS-CoV-2 (Covid-19) which has rapidly spread around the world in about three months with tens of thousands of deaths recorded so far is a global concern. An urgent need for potential therapeutic intervention is of necessity. Mpro is an attractive druggable target for the development of anti-COVID-19 drug development. Compounds previously characterized from Melissa officinalis were queried against main protease of coronavirus SARS-CoV-2 using computational approach. Results: Melitric acid A and salvanolic acid A had higher affinity than lopinavir and ivermectin using both AutodockVina and XP docking algorithms. The computational approach was employed in the generation of QSAR model using automated QSAR, and in the docking of ligands from Melissa officinalis with SARS-CoV-2 Mpro inhibitors. The best model obtained was KPLS_Radial_28 (R2 = 0.8548 and Q2=0.6474, and was used in predicting the bioactivity of the lead compounds. Molecular mechanics based MM-GBSA confirmed salvanolic acid A as the compound with the highest free energy and predicted bioactivity of 4.777; it interacted with His-41 of the catalytic dyad (Cys145-His41) of SARS-CoV-2 main protease (Mpro), as this may hinder the cutting of inactive viral protein into active ones capable of replication. Conclusion: Salvanolic acid A can be further evaluated as potential Mpro inhibitor.

Elaboration of Novel TTK1 Inhibitory Leads via QSAR-Guided Selection of Crystallographic Pharmacophores Followed By In vitro Assay

2020 ◽  
Vol 16 ◽  
Author(s):  
Mahmoud A. Al-Sha'er ◽  
Mutasem O. Taha
Keyword(s):  
Standard Error ◽  
Qsar Model ◽  
Qsar Modeling ◽  
Vitro Assay ◽  
Physicochemical Descriptors ◽  
Qsar Models ◽  
Ic50 Values ◽  
Pharmacophore Hypotheses ◽  
Selection Of

Introduction: Tyrosine threonine kinase (TTK1) is a key regulator of chromosome segregation. TTK targeting received recent concern for the enhancement of possible anticancer therapies. Objective: In this regard we employed our well-known method of QSAR-guided selection of best crystallographic pharmacophore(s) to discover considerable binding interactions that anchore inhibitors into TTK1 binding site. Method:Sixtyone TTK1 crystallographic complexes were used to extract 315 pharmacophore hypotheses. QSAR modeling was subsequently used to choose a single crystallographic pharmacophore that when combined with other physicochemical descriptors elucidates bioactivity discrepancy within a list of 55 miscellaneous inhibitors. Results: The best QSAR model was robust and predictive (r2(55) = 0.75, r2LOO = 0.72 , r2press against external testing list of 12 compounds = 0.67), Standard error of estimate (training set) (S)= 0.63 , Standard error of estimate (testing set)(Stest) = 0.62. The resulting pharmacophore and QSAR models were used to scan the National Cancer Institute (NCI) database for new TTK1 inhibitors. Conclusion: Five hits confirmed significant TTK1 inhibitory profiles with IC50 values ranging between 11.7 and 76.6 micM.

scholarly journals Maternal toxoplasmosis and the risk of childhood autism: serological and molecular small-scale studies

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Jamila S. Al Malki ◽  
Nahed Ahmed Hussien ◽  
Fuad Al Malki
Keyword(s):  
Neurodevelopmental Disorders ◽  
Repetitive Behavior ◽  
Saudi Arabian ◽  
Childhood Autism ◽  
Small Scale ◽  
Autistic Children ◽  
High Prevalence ◽  
Life Threatening ◽  
The Relationship ◽  
Delayed Language Development

Abstract Background Toxoplasmosis resulting from infection with the Toxoplasma parasite has become an endemic disease worldwide. Recently, a few studies have reported a high prevalence of Toxoplasmosis infections among Saudi Arabian women. This disease could become life threatening for pregnant women and for immunodeficient people. There is evidence that infections during pregnancy, especially in the early stages, are associated with neurodevelopmental disorders. Autism disorder represents one of the most common neurodevelopmental disorders worldwide; it is associated with delayed language development, weak communication interaction, and repetitive behavior. The relationship between prenatal toxoplasmosis and autism in childhood remains unclear. The present study aims to report a link between maternal toxoplasmosis and autistic offspring among Saudi Arabian women. Method Blood samples (36 maternal, 36 from their non-autistic children, and 36 from their autistic children) were collected for serological and molecular evaluation. Results A toxoplasmosis infection was reported for 33.34% of participants using an ELISA assay (5.56% IgG+/IgM+, 11.11% IgG−/IgM+, and 16.67% IgG+/IgM-); however, a nested PCR assay targeting B1 toxoplasmosis specific genes recorded positive tests for 80.56% of the samples. In addition, the present study detected several points of mutation of mtDNA including NADH dehydrogenase (ND1, ND4) and Cyt B genes and the nDNA pyruvate kinase (PK) gene for autistic children infected with toxoplasmosis. Conclusion Considering previous assumptions, we suggest that a maternal toxoplasmosis infection could have a role in the development of childhood autism linked to mtDNA and nDNA impairment.

scholarly journals A yeast metabolome-based model for an ecotoxicological approach in the management of lignocellulosic ethanol stillage

2019 ◽  
Vol 6 (1) ◽  
pp. 180718 ◽  
Author(s):  
Luca Roscini ◽  
Lorenzo Favaro ◽  
Laura Corte ◽  
Lorenzo Cagnin ◽  
Claudia Colabella ◽  
...  
Keyword(s):  
Heavy Metals ◽  
Saccharomyces Cerevisiae ◽  
Predictive Model ◽  
Lignocellulosic Ethanol ◽  
Bioethanol Production ◽  
Inhibitor Concentration ◽  
Promising Tool ◽  
Different Types ◽  
The Relationship ◽  
Ecotoxicological Bioassay

Lignocellulosic bioethanol production results in huge amounts of stillage, a potentially polluting by-product. Stillage, rich in heavy metals and, mainly, inhibitors, requires specific toxicity studies to be adequately managed. To this purpose, we applied an FTIR ecotoxicological bioassay to evaluate the toxicity of lignocellulosic stillage. Two weak acids and furans, most frequently found in lignocellulosic stillage, have been tested in different mixtures against three Saccharomyces cerevisiae strains. The metabolomic reaction of the test microbes and the mortality induced at various levels of inhibitor concentration showed that the strains are representative of three different types of response. Furthermore, the relationship between concentrations and FTIR synthetic stress indexes has been studied, with the aim of defining a model able to predict the concentrations of inhibitors in stillage, resulting in an optimized predictive model for all the strains. This approach represents a promising tool to support the ecotoxicological management of lignocellulosic stillage.

Birthweight and Adult Health in a Population-Based Sample of Norwegian Twins

2005 ◽  
Vol 8 (2) ◽  
pp. 148-155 ◽  
Author(s):  
Andrej M. Grjibovski ◽  
Jennifer R. Harris ◽  
Per Magnus
Keyword(s):  
Health Outcomes ◽  
Population Based ◽  
Adult Health ◽  
Brain Disorder ◽  
Full Sample ◽  
Intraclass Correlations ◽  
Opposite Sex ◽  
Lower Birthweight ◽  
The Relationship ◽  
Pair Analysis

AbstractPopulation-based twin data were used to test (a) whether lower birthweight confers a greater risk of adult health disorders, and (b) whether within-pair birthweight differences in twins explain discordance for health outcomes. The sample consisted of 1201 monozygotic (MZ) male twins, 1048 dizygotic (DZ) male twins, 1679 MZ female twins, 1489 DZ female twins, and 2423 opposite-sex DZ twins, born in Norway between 1967 and 1979. The relationship between birthweight and self-reported health outcomes were studied using multivariable logistic regression. In the full sample (n= 7840), birthweight was negatively associated with risk for nearsightedness (odds ratio OR = 0.76, 95% CI: 0.65 – 0.92) and minimal brain disorder (OR = 0.27, 95% CI: 0.16–0.44) when adjusted for gestational age, sex, zygosity, age, education and body mass index after correction for intraclass correlations and multiple comparisons. Within-pair analysis of 159 MZ and 224 DZ pairs revealed that myopic twins were on average 2 g (p= .966) and 64 g (p= .040) lighter than nonmyopic twins in MZ and DZ pairs respectively, suggesting that genetic factors may play an important role in the associations between birthweight and nearsightedness. Within-pair analysis of twins discordant for a minimal brain disorder indicated that affected twins were 80 g (p= .655) and 85 g (p= .655) lighter than their healthy co-twins in MZ and DZ pairs respectively, although there were only 2 MZ and 2 DZ discordant pairs.

Hydrostatic Collapse Pressure and Radial Collapse Force Comparisons for Ultra-Deepwater Pipelines

2014 ◽  
Author(s):  
Marco A. P. Rosas ◽  
Ana Paula F. Souza ◽  
Marcos V. Rodrigues ◽  
Danilo Machado L. da Silva
Keyword(s):  
Numerical Models ◽  
Research Work ◽  
Compressive Force ◽  
Quadratic Function ◽  
Radial Force ◽  
Small Scale ◽  
Collapse Pressure ◽  
First Results ◽  
Specimen Test ◽  
The Relationship

In this paper the behavior and the relationship between hydrostatic collapse pressure and diametrically opposed radial compressive force for pipelines were analyzed. This study presents an introduction of a research work aimed to assess the pipeline collapse pressure based on the radial collapse force. Initially the hydrostatic collapse pressure is analyzed, for pipes with different diameter to wall thickness ratio (D/t) and ovalities, using classical assessment (DNV method) and numerical models (FE). Then, the compressive radial force is also analyzed using numerical models validated by a small-scale ring specimen test. After that, the relationship between hydrostatic collapse pressure and compressive radial force is discussed. These first results show that the radial force is a quadratic function of the collapse pressure.

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