scholarly journals rRNA Platform Technology for Drug Discovery Methods for Identifying Ligands That Target Plasmodium RNA Structural Motifs

2021 ◽  
Author(s):  
Harrison Ndung’u Mwangi ◽  
Francis Jackim Mulaa
Keyword(s):  
In Silico ◽  
Structure Prediction ◽  
Sequence Data ◽  
Target Identification ◽  
Three Dimensional ◽  
Physical Models ◽  
Structural Basis ◽  
Modeling Software ◽  
Rna Structural Motifs

Determining the structure of the P. falciparum40s leads to better understanding of the structural basis for its protein-synthesizing roles in the cell. This enables researchers in the field of drug development to run in silico ligand screening experiments using the solved P. falciparum 40S structure as a target against a library of potential anti-malarial compounds. Drug leads identified through this method can lead to further biochemical and In vitro binding studies with the ultimate goal of developing new class of anti-malarial drugs. The use of structure prediction and modeling technologies in this study dramatically reduces the time it takes from target identification to drug lead determination. Furthermore, very many compounds that were previously incapable of being experimentally tested can now be tested in silico against the generated structure. Owing to the increasing utility of bioinformatics and three dimensional structural modeling software, one can accurately build physical models solely from sequence data by unwrapping the information therein on probable motif sites capable of being anchored onto available compounds or aptamers.

In Silico Study of Potential Cross-Kingdom Plant MicroRNA Based Regulation in Chronic Myeloid Leukemia

2020 ◽  
Vol 17 (2) ◽  
pp. 125-132
Author(s):  
Marjanu Hikmah Elias ◽  
Noraziah Nordin ◽  
Nazefah Abdul Hamid
Keyword(s):  
Targeted Therapy ◽  
In Silico ◽  
Structure Prediction ◽  
Tertiary Structure ◽  
Target Prediction ◽  
In Silico Analysis ◽  
Microrna Target ◽  
Good Target

Background: Chronic Myeloid Leukaemia (CML) is associated with the BCRABL1 gene, which plays a central role in the pathogenesis of CML. Thus, it is crucial to suppress the expression of BCR-ABL1 in the treatment of CML. MicroRNA is known to be a gene expression regulator and is thus a good candidate for molecularly targeted therapy for CML. Objective: This study aims to identify the microRNAs from edible plants targeting the 3’ Untranslated Region (3’UTR) of BCR-ABL1. Methods: In this in silico analysis, the sequence of 3’UTR of BCR-ABL1 was obtained from Ensembl Genome Browser. PsRNATarget Analysis Server and MicroRNA Target Prediction (miRTar) Server were used to identify miRNAs that have binding conformity with 3’UTR of BCR-ABL1. The MiRBase database was used to validate the species of plants expressing the miRNAs. The RNAfold web server and RNA COMPOSER were used for secondary and tertiary structure prediction, respectively. Results: In silico analyses revealed that cpa-miR8154, csi-miR3952, gma-miR4414-5p, mdm-miR482c, osa-miR1858a and osa-miR1858b show binding conformity with strong molecular interaction towards 3’UTR region of BCR-ABL1. However, only cpa-miR- 8154, osa-miR-1858a and osa-miR-1858b showed good target site accessibility. Conclusion: It is predicted that these microRNAs post-transcriptionally inhibit the BCRABL1 gene and thus could be a potential molecular targeted therapy for CML. However, further studies involving in vitro, in vivo and functional analyses need to be carried out to determine the ability of these miRNAs to form the basis for targeted therapy for CML.

scholarly journals Protein Folding: Search for Basic Physical Models

2003 ◽  
Vol 3 ◽  
pp. 623-635 ◽  
Author(s):  
Ivan Y. Torshin ◽  
Robert W. Harrison
Keyword(s):  
Protein Folding ◽  
Tertiary Structure ◽  
Three Dimensional ◽  
Physical Models ◽  
Dimensional Structure ◽  
Computational Techniques ◽  
Linear Sequence ◽  
Physical Forces

How a unique three-dimensional structure is rapidly formed from the linear sequence of a polypeptide is one of the important questions in contemporary science. Apart from biological context ofin vivoprotein folding (which has been studied only for a few proteins), the roles of the fundamental physical forces in thein vitrofolding remain largely unstudied. Despite a degree of success in using descriptions based on statistical and/or thermodynamic approaches, few of the current models explicitly include more basic physical forces (such as electrostatics and Van Der Waals forces). Moreover, the present-day models rarely take into account that the protein folding is, essentially, a rapid process that produces a highly specific architecture. This review considers several physical models that may provide more direct links between sequence and tertiary structure in terms of the physical forces. In particular, elaboration of such simple models is likely to produce extremely effective computational techniques with value for modern genomics.

scholarly journals Rational Design of a Triple-Layered Coaxial Extruder System: in silico and in vitro Evaluations Directed Towards Optimizing Cell Viability

2020 ◽  
Vol 6 (4) ◽  
Author(s):  
Christian Augusto Silva ◽  
Carlos J Cortés-Rodriguez ◽  
Jonas Hazur ◽  
Supachai Reakasame ◽  
Aldo R. Boccaccini
Keyword(s):  
Cell Viability ◽  
In Silico ◽  
Rational Design ◽  
Three Dimensional ◽  
Complex Structures ◽  
Vascular Networks ◽  
Coaxial Nozzle ◽  
Wide Availability ◽  
Cell Functionality

Biofabrication is a rapidly evolving field whose main goal is the manufacturing of three-dimensional (3D) cell-laden constructs that closely mimic tissues and organs. Despite recent advances on materials and techniques directed toward the achievement of this goal, several aspects such as tissue vascularization and prolonged cell functionality are limiting bench-to-bedside translation. Extrusion-based 3D bioprinting has been devised as a promising biofabrication technology to overcome these limitations, due to its versatility and wide availability. Here, we report the development of a triple-layered coaxial nozzle for use in the biomanufacturing of vascular networks and vessels. The design of the coaxial nozzle was first optimized toward guaranteeing high cell viability upon extrusion. This was done with the aid of in silico evaluations and their subsequent experimental validation by investigating the bioprinting of an alginate-based bioink. Results confirmed that the values for pressure distribution predicted by in silico experiments resulted in cell viabilities above 70% and further demonstrated the effect of layer thickness and extrusion pressure on cell viability. Our work paves the way for the rational design of multi-layered coaxial extrusion systems to be used in biofabrication approaches to replicate the very complex structures found in native organs and tissues.

scholarly journals Role of cellulose family in fibril organization of collagen for forming 3D cancer spheroids: In vitro and in silico approach

Bioimpacts ◽  
2020 ◽  
Vol 11 (2) ◽  
pp. 111-117
Author(s):  
Elaheh Dalir Abdolahinia ◽  
Behzad Jafari ◽  
Sepideh Parvizpour ◽  
Jaleh Barar ◽  
Samad Nadri ◽  
...  
Keyword(s):  
In Silico ◽  
Carboxymethyl Cellulose ◽  
Three Dimensional ◽  
3D Culture ◽  
Cell Aggregation ◽  
Cellulose Derivatives ◽  
Solid Media ◽  
Semi Solid

Introduction: Cell aggregation of three-dimensional (3D) culture systems (the so-called spheroids) are designed as in vitro platform to represent more accurately the in vivo environment for drug discovery by using semi-solid media. The uniform multicellular tumor spheroids can be generated based on the interaction of cells with extracellular matrix (ECM) macromolecules such as collagen and integrin. This study aimed to investigate the possible interactions between the cellulose family and collagen using both in vitro and in silico approaches. Methods: The 3D microtissue of JIMT-1 cells was generated using hanging drop method to study the effects of charge and viscosity of the medium containing cellulose family. To determine the mode of interaction between cellulose derivatives (CDs) and collagen-integrin, docking analysis and molecular simulation were further performed using open source web servers and chemical simulations (GROMACS), respectively. Results: The results confirmed that the addition of CDs into the 3D medium can promote the formation of solid spheroids, where methylcellulose (MC) yielded uniform spheroids compared to carboxymethyl cellulose (CMC). Moreover, the computational analysis showed that MC interacted with both integrin and collagen, while sodium carboxymethyl cellulose (NaCMC) only interacted with collagen residues. The stated different behaviors in the 3D culture formation and collagen interaction were found in the physicochemical properties of CDs. Conclusion: Based on in vitro and in silico findings, MC is suggested as an important ECM-mimicking entity that can support the semi-solid medium and promote the formation of the uniform spheroid in the 3D culture.

scholarly journals Scaling of joint mass and metabolism fluctuations in in silico cell-laden spheroids

2021 ◽  
Vol 118 (38) ◽  
pp. e2025211118
Author(s):  
Ermes Botte ◽  
Francesco Biagini ◽  
Chiara Magliaro ◽  
Andrea Rinaldo ◽  
Amos Maritan ◽  
...  
Keyword(s):  
Metabolic Rate ◽  
In Silico ◽  
Probability Distributions ◽  
Three Dimensional ◽  
Joint Probability ◽  
Consistent Estimate ◽  
Metabolic Rates ◽  
Scaling Exponents

Variations and fluctuations are characteristic features of biological systems and are also manifested in cell cultures. Here, we describe a computational pipeline for identifying the range of three-dimensional (3D) cell-aggregate sizes in which nonisometric scaling emerges in the presence of joint mass and metabolic rate fluctuations. The 3D cell-laden spheroids with size and single-cell metabolic rates described by probability density functions were randomly generated in silico. The distributions of the resulting metabolic rates of the spheroids were computed by modeling oxygen diffusion and reaction. Then, a method for estimating scaling exponents of correlated variables through statistically significant data collapse of joint probability distributions was developed. The method was used to identify a physiologically relevant range of spheroid sizes, where both nonisometric scaling and a minimum oxygen concentration (0.04 mol⋅m−3) is maintained. The in silico pipeline described enables the prediction of the number of experiments needed for an acceptable collapse and, thus, a consistent estimate of scaling parameters. Using the pipeline, we also show that scaling exponents may be significantly different in the presence of joint mass and metabolic-rate variations typically found in cells. Our study highlights the importance of incorporating fluctuations and variability in size and metabolic rates when estimating scaling exponents. It also suggests the need for taking into account their covariations for better understanding and interpreting experimental observations both in vitro and in vivo and brings insights for the design of more predictive and physiologically relevant in vitro models.

Synthesis, In silico and Biological Studies of Thiazolyl-2h-chromen-2-one Derivatives as Potent Antitubercular Agents

2020 ◽  
Vol 16 (5) ◽  
pp. 511-522 ◽  
Author(s):  
Bhagwat S. Jadhav ◽  
Ramesh S. Yamgar ◽  
Rajesh S. Kenny ◽  
Suraj N. Mali ◽  
Hemchandra K. Chaudhari ◽  
...  
Keyword(s):  
Schiff Base ◽  
In Silico ◽  
Antitubercular Activity ◽  
Inhibition Mechanism ◽  
Mycobacterium Tuberculosis H37rv ◽  
Schiff Base Derivatives ◽  
Biological Studies ◽  
H37rv Strain ◽  
Modeling Software

Background: A series of new six thiazolyl-2-amine-based Schiff base derivatives (4a-4f) were synthesized by a sequential multistep reaction starting with Salicylaldehyde. Methods: All the Schiff base derivatives were screened in-vitro for their antibacterial activity against Mycobacterium tuberculosis (H37RV strain) ATCC No-27294. The synthesized compounds were characterized by FTIR, 1H-NMR, 13C-NMR and Mass spectrometry. Results: Among the compounds tested, 4c and 4f derivatives exhibited potent antitubercular activity against M. tuberculosis at MIC 6.25 μg/mL. Conclusion: We extended our study to explore the inhibition mechanism by conducting molecular docking analysis by using Schrodinger’s molecular modeling software. All the newly synthesized compounds were found to be in-silico AMES test non-toxic and non-carcinogens. The good Qikprop’s Absorption, Distribution, Metabolism and Excretion (ADMET) would definitely help the researchers in order to make more potent Anti-TB agents.

Understanding the highly efficient catalysis of prokaryotic peptide deformylases by shedding light on the determinants specifying the low activity of the human counterpart

2014 ◽  
Vol 70 (2) ◽  
pp. 242-252 ◽  
Author(s):  
Sonia Fieulaine ◽  
Michel Desmadril ◽  
Thierry Meinnel ◽  
Carmela Giglione
Keyword(s):  
Sequence Similarity ◽  
Three Dimensional ◽  
Binding Pocket ◽  
Dimensional Structure ◽  
Structural Basis ◽  
Human Counterpart ◽  
Low Activity

Peptide deformylases (PDFs), which are essential and ubiquitous enzymes involved in the removal of theN-formyl group from nascent chains, are classified into four subtypes based on the structural and sequence similarity of specific conserved domains. All PDFs share a similar three-dimensional structure, are functionally interchangeablein vivoand display similar propertiesin vitro, indicating that their molecular mechanism has been conserved during evolution. The human mitochondrial PDF is the only exception as despite its conserved fold it reveals a unique substrate-binding pocket together with an unusual kinetic behaviour. Unlike human PDF, the closely related mitochondrial PDF1As from plants have catalytic efficiencies and enzymatic parameters that are similar to those of other classes of PDFs. Here, the aim was to identify the structural basis underlying the properties of human PDF compared with all other PDFs by focusing on plant mitochondrial PDF1A. The construction of a chimaera composed of plant PDF1A with the nonrandom substitutions found in a conserved motif of its human homologue converted it into an enzyme with properties similar to the human enzyme, indicating the crucial role of these positions. The crystal structure of this human-like plant PDF revealed that substitution of two residues leads to a reduction in the volume of the ligand-binding site together with the introduction of negative charges, unravelling the origin of the weak affinity of human PDF for its substrate. In addition, the substitution of the two residues of human PDF modifies the transition state of the reaction through alteration of the network of interactions between the catalytic residues and the substrate, leading to an overall reduced reaction rate.

scholarly journals Simulation of lung alveolar epithelial wound healing in vitro

2010 ◽  
Vol 7 (49) ◽  
pp. 1157-1170 ◽  
Author(s):  
Sean H. J. Kim ◽  
Michael A. Matthay ◽  
Keith Mostov ◽  
C. Anthony Hunt
Keyword(s):  
Wound Healing ◽  
In Silico ◽  
Wound Repair ◽  
Three Dimensional ◽  
Alveolar Type ◽  
Alveolar Epithelial ◽  
Epithelial Wound Healing ◽  
Additional Cell

The mechanisms that enable and regulate alveolar type II (AT II) epithelial cell wound healing in vitro and in vivo remain largely unknown and need further elucidation. We used an in silico AT II cell-mimetic analogue to explore and better understand plausible wound healing mechanisms for two conditions: cyst repair in three-dimensional cultures and monolayer wound healing. Starting with the analogue that validated for key features of AT II cystogenesis in vitro , we devised an additional cell rearrangement action enabling cyst repair. Monolayer repair was enabled by providing ‘cells’ a control mechanism to switch automatically to a repair mode in the presence of a distress signal. In cyst wound simulations, the revised analogue closed wounds by adhering to essentially the same axioms available for alveolar-like cystogenesis. In silico cell proliferation was not needed. The analogue recovered within a few simulation cycles but required a longer recovery time for larger or multiple wounds. In simulated monolayer wound repair, diffusive factor-mediated ‘cell’ migration led to repair patterns comparable to those of in vitro cultures exposed to different growth factors. Simulations predicted directional cell locomotion to be critical for successful in vitro wound repair. We anticipate that with further use and refinement, the methods used will develop as a rigorous, extensible means of unravelling mechanisms of lung alveolar repair and regeneration.

scholarly journals Development and In Vitro Evaluation of Controlled Release Viagra® Containing Poloxamer-188 Using Gastroplus™ PBPK Modeling Software for In Vivo Predictions and Pharmacokinetic Assessments

2021 ◽  
Vol 14 (5) ◽  
pp. 479
Author(s):  
Mosab Arafat ◽  
Muhammad Sarfraz ◽  
Salahdein AbuRuz
Keyword(s):  
Controlled Release ◽  
Drug Release ◽  
In Silico ◽  
Hydroxypropyl Methylcellulose ◽  
Pbpk Modeling ◽  
Matrix System ◽  
Substantial Impact ◽  
Poloxamer 188 ◽  
Modeling Software

Sildenafil is the active substance in Viagra® tablets, which is approved by the FDA to treat sexual dysfunction in men. Poor solubility and short half-life, however, can limit the span of its effectiveness. Therefore, this study focused on an oral controlled release matrix system with the aim to improve solubility, control the drug release, and sustain the duration of drug activity. The controlled release matrices were prepared with poloxamer-188, hydroxypropyl methylcellulose, and magnesium stearate. Various formulations of different ratios were developed, evaluated in vitro, and assessed in silico. Poloxamer-188 appeared to have a remarkable influence on the release profile of sildenafil citrate. In general, the rate of drug release decreased as the amount of polymer was gradually increased in the matrix system, achieving a maximum release period over 12 h. The in silico assessment by using the GastroPlus™ PBPK modeling software predicted a significant variation in Cmax, tmax, t½, and AUC0-t among the formulations. In conclusion, the combination of polymers in matrix systems can have substantial impact on controlling and modifying the drug release pattern.

scholarly journals Fungal Genomic Resources for Strain Identification and Diversity Analysis of 1900 Fungal Species

2021 ◽  
Vol 7 (4) ◽  
pp. 288
Author(s):  
Mir Asif Iquebal ◽  
Sarika Jaiswal ◽  
Vineet Kumar Mishra ◽  
Rahul Singh Jasrotia ◽  
Ulavappa B. Angadi ◽  
...  
Keyword(s):  
Genome Sequence ◽  
In Silico ◽  
Sequence Data ◽  
Fungal Species ◽  
Genomic Research ◽  
Whole Genome Sequence ◽  
Strain Identification ◽  
Diversity Analysis ◽  
Whole Genome

Identification and diversity analysis of fungi is greatly challenging. Though internal transcribed spacer (ITS), region-based DNA fingerprinting works as a “gold standard” for most of the fungal species group, it cannot differentiate between all the groups and cryptic species. Therefore, it is of paramount importance to find an alternative approach for strain differentiation. Availability of whole genome sequence data of nearly 2000 fungal species are a promising solution to such requirement. We present whole genome sequence-based world’s largest microsatellite database, FungSatDB having >19M loci obtained from >1900 fungal species/strains using >4000 assemblies across globe. Genotyping efficacy of FungSatDB has been evaluated by both in-silico and in-vitro PCR. By in silico PCR, 66 strains of 8 countries representing four continents were successfully differentiated. Genotyping efficacy was also evaluated by in vitro PCR in four fungal species. This approach overcomes limitation of ITS in species, strain signature, and diversity analysis. It can accelerate fungal genomic research endeavors in agriculture, industrial, and environmental management.

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