In Vitro, In Vivo, and In Silico Methods for Assessment of Muscle Size and Muscle Growth Regulation

Phosphine-borane complexes are novel chemical entities with preclinical efficacy in neuronal and ophthalmic disease models. In vitro and in vivo studies showed that the metabolites of these compounds are capable of cleaving disulfide bonds implicated in the downstream effects of axonal injury. A difficulty in using standard in silico methods for studying these drugs is that most computational tools are not designed for borane-containing compounds. Using in silico and machine learning methodologies, the absorption-distribution properties of these unique compounds were assessed. Features examined with in silico methods included cellular permeability, octanol-water partition coefficient, blood-brain barrier permeability, oral absorption and serum protein binding. The resultant neural networks demonstrated an appropriate level of accuracy and were comparable to existing in silico methodologies. Specifically, they were able to reliably predict pharmacokinetic features of known boron-containing compounds. These methods predicted that phosphine-borane compounds and their metabolites meet the necessary pharmacokinetic features for orally active drug candidates. This study showed that the combination of standard in silico predictive and machine learning models with neural networks is effective in predicting pharmacokinetic features of novel boron-containing compounds as neuroprotective drugs.

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Bioassays and In Silico Methods in the Identification of Human DNA Topoisomerase IIα Inhibitors

Current Medicinal Chemistry ◽

10.2174/0929867325666180306165725 ◽

2018 ◽

Vol 25 (28) ◽

pp. 3286-3318 ◽

Cited By ~ 7

Author(s):

Kaja Bergant ◽

Matej Janezic ◽

Andrej Perdih

Keyword(s):

In Silico ◽

In Vivo Studies ◽

Topoisomerase Iiα ◽

Dna Topoisomerase ◽

Human Dna ◽

Practical Guidelines ◽

In Silico Methods ◽

Dna Topoisomerase Iiα

Background: The family of DNA topoisomerases comprises a group of enzymes that catalyse the induction of topological changes to DNA. These enzymes play a role in the cell replication machinery and are, therefore, important targets for anticancer drugs - with human DNA topoisomerase IIα being one of the most prominent. Active compounds targeting this enzyme are classified into two groups with diverse mechanisms of action: DNA poisons act by stabilizing a covalent cleavage complex between DNA and the topoisomerase enzyme, transforming it into a cellular toxin, while the second diverse group of catalytic inhibitors, provides novel inhibition avenues for tackling this enzyme due to frequent occurrence of side effects observed during the DNA poison therapy. Methods: Based on a comprehensive literature search we present an overview of available bioassays and in silico methods in the identification of human DNA topoisomerase IIα inhibitors. Results and Conclusion: A comprehensive outline of the available methods and approaches that explore in detail the in vitro mechanistic and functional aspects of the topoisomerase IIα inhibition of both topo IIα inhibitor groups is presented. The utilized in vitro cell-based assays and in vivo studies to further explore the validated topo IIα inhibitors in subsequent preclinical stages of the drug discovery are discussed. The potential of in silico methods in topoisomerase IIα inhibitor discovery is outlined. A list of practical guidelines was compiled to aid new as well experienced researchers in how to optimally approach the design of targeted inhibitors and validation in the preclinical drug development stages.

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Differential regulation of actin and myosin isoenzyme synthesis in functionally overloaded skeletal muscle

Biochemical Journal ◽

10.1042/bj2650525 ◽

1990 ◽

Vol 265 (2) ◽

pp. 525-532 ◽

Cited By ~ 24

Author(s):

P Gregory ◽

J Gagnon ◽

D A Essig ◽

S K Reid ◽

G Prior ◽

...

Keyword(s):

Total Protein ◽

Molecular Mechanisms ◽

Muscle Growth ◽

Muscle Size ◽

Slow Myosin ◽

Myosin Isoenzyme ◽

Anterior Latissimus Dorsi ◽

Fractional Synthesis

Overload hypertrophy of the chicken anterior latissimus dorsi muscle is accompanied by a replacement of one myosin isoenzyme (slow myosin-1, SM1) by another (slow myosin-2, SM2). To investigate the molecular mechanisms by which these changes occur, we measured the fractional synthesis rates (ks) in vivo of individual myosin-heavy-chain isoenzymes, total actin and total protein during the first 72 h of muscle growth. Although the ks of total protein and actin were doubled at 24 h, the ks for SM1 and SM2 were depressed. However, the ks of both isomyosins were nearly tripled by 72 h. Despite the increase in muscle size observed at 72 h, the amount of SM1 was reduced by half, indicating increased degradation of SM1. Results of translation of polyribosomes in vitro paralleled the results obtained in vivo. The proportion of total polyadenylylated mRNA in total RNA was increased at 48 and 72 h, but unchanged at 24 h despite the increase in protein synthesis at 24 h. Nuclease-protection analyses indicate that the level of specific SM1 and SM2 mRNAs change in a reciprocal fashion during overload. We conclude that gene-specific and temporal differences exist in the regulatory mechanisms that control overload-induced muscle growth.

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A Review: In – Silico Approaches in Predictive Toxicology

International Journal of Pharmaceutical Sciences Review and Research ◽

10.47583/ijpsrr.2021.v70i02.012 ◽

2021 ◽

Vol 70 (2) ◽

Author(s):

Sachin M. Mendhi ◽

Manoj S. Ghoti ◽

Mandar A. Thool ◽

Rinkesh M. Tekade

Keyword(s):

In Silico ◽

Predictive Toxicology ◽

New Drug ◽

Virtual Ligand Screening ◽

Preclinical Trials ◽

Living Organisms ◽

Toxicity Of Drugs ◽

In Silico Methods

This article deals with the in – silico techniques for predicting the toxicity of chemical compounds. Toxicology is the branch of biology that deals with the study of adverse effect of chemical substances on the living organisms and the practice of treating and preventing such adverse effects. Predicting toxicity of a new drug to be produced is the first aim of preclinical trials. It is achieved by in-silico methods. There are several in - silico technique softwares which are used for the prediction of ADME and hence toxicity of drugs. In – silico methods involves the use of various softwares to calculate and then predict the toxicity of a compound by first determining its structural and pharmacokinetic and pharmacodynamic properties and then it correlates this information with already existing drugs and molecules and thus gives us conclusion. The article focuses on QSAR and its techniques, HQSAR, several other methods like structural alerts and rule-based models, chemical category and read across model, dose and time response model, virtual ligand screening, docking, 3D pharmacophore mapping, simulation approaches, PKPD models and several other approaches like bioinformatics. After reviewing and studying various in silico techniques the conclusion comes out to be that, in-silico methods of predictive toxicology are more better than in-vitro and in-vivo methods since they are much more safe (as animals are not harmed), economic, fast and accurate w.r.to, results/output in predicting toxicity of compounds by computational methods and hence are widely used in the production of new drug for accessing its toxicity

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Protective Effect of A2B Receptor Antagonist (TRP 1) on Acetic Acid Induced Ulcerative Colitis in Rats: in vitro, in vivo and in silico Methods

Indian Journal of Pharmaceutical Education and Research ◽

10.5530/ijper.52.1.12 ◽

2018 ◽

Vol 52 (1) ◽

pp. 101-109 ◽

Cited By ~ 1

Author(s):

Praveen Kumar Pasala ◽

Ramesh Alluri ◽

Sri Chandana Mavulati ◽

Raghu Prasad Mailavaram ◽

Khasim Shaik ◽

...

Keyword(s):

Ulcerative Colitis ◽

Acetic Acid ◽

Protective Effect ◽

Receptor Antagonist ◽

In Silico ◽

A2b Receptor ◽

In Silico Methods

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Discovery and characterization of nutritionally regulated genes associated with muscle growth in Atlantic salmon

Physiological Genomics ◽

10.1152/physiolgenomics.00065.2010 ◽

2010 ◽

Vol 42A (2) ◽

pp. 114-130 ◽

Cited By ~ 41

Author(s):

Neil I. Bower ◽

Ian A. Johnston

Keyword(s):

Skeletal Muscle ◽

Atlantic Salmon ◽

Growth Regulation ◽

Expression Profiles ◽

Muscle Growth ◽

Cdna Libraries ◽

In Vitro Expression ◽

Novel Transcript

A genomics approach was used to identify nutritionally regulated genes involved in growth of fast skeletal muscle in Atlantic salmon ( Salmo salar L. ). Forward and reverse subtractive cDNA libraries were prepared comparing fish with zero growth rates to fish growing rapidly. We produced 7,420 ESTs and assembled them into nonredundant clusters prior to annotation. Contigs representing 40 potentially unrecognized nutritionally responsive candidate genes were identified. Twenty-three of the subtractive library candidates were also differentially regulated by nutritional state in an independent fasting-refeeding experiment and their expression placed in the context of 26 genes with established roles in muscle growth regulation. The expression of these genes was also determined during the maturation of a primary myocyte culture, identifying 13 candidates from the subtractive cDNA libraries with putative roles in the myogenic program. During early stages of refeeding DNAJA4, HSPA1B, HSP90A, and CHAC1 expression increased, indicating activation of unfolded protein response pathways. Four genes were considered inhibitory to myogenesis based on their in vivo and in vitro expression profiles ( CEBPD, ASB2, HSP30, novel transcript GE623928). Other genes showed increased expression with feeding and highest in vitro expression during the proliferative phase of the culture ( FOXD1, DRG1) or as cells differentiated ( SMYD1, RTN1, MID1IP1, HSP90A, novel transcript GE617747). The genes identified were associated with chromatin modification ( SMYD1, RTN1), microtubule stabilization ( MID1IP1), cell cycle regulation ( FOXD1, CEBPD, DRG1), and negative regulation of signaling ( ASB2) and may play a role in the stimulation of myogenesis during the transition from a catabolic to anabolic state in skeletal muscle.

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