scholarly journals Heterocyclic Substitutions Greatly Improve Affinity and Stability of Folic Acid towards FRα. an In Silico Insight

Molecules ◽  
2021 ◽  
Vol 26 (4) ◽  
pp. 1079
Author(s):  
Mohammad G. Al-Thiabat ◽  
Fadi G. Saqallah ◽  
Amirah Mohd Gazzali ◽  
Noratiqah Mohtar ◽  
Beow Keat Yap ◽  
...  
Keyword(s):  
Folic Acid ◽  
Binding Affinity ◽  
Root Mean Square ◽  
Active Site ◽  
Hydrophobic Interactions ◽  
Md Simulations ◽  
The Body ◽  
Electrostatic Energy ◽  
Epithelial Tissue ◽  
Mean Square

Folate receptor alpha (FRα) is known as a biological marker for many cancers due to its overexpression in cancerous epithelial tissue. The folic acid (FA) binding affinity to the FRα active site provides a basis for designing more specific targets for FRα. Heterocyclic rings have been shown to interact with many receptors and are important to the metabolism and biological processes within the body. Nineteen FA analogs with substitution with various heterocyclic rings were designed to have higher affinity toward FRα. Molecular docking was used to study the binding affinity of designed analogs compared to FA, methotrexate (MTX), and pemetrexed (PTX). Out of 19 FA analogs, analogs with a tetrazole ring (FOL03) and benzothiophene ring (FOL08) showed the most negative binding energy and were able to interact with ASP81 and SER174 through hydrogen bonds and hydrophobic interactions with amino acids of the active site. Hence, 100 ns molecular dynamics (MD) simulations were carried out for FOL03, FOL08 compared to FA, MTX, and PTX. The root mean square deviation (RMSD) and root mean square fluctuation (RMSF) of FOL03 and FOL08 showed an apparent convergence similar to that of FA, and both of them entered the binding pocket (active site) from the pteridine part, while the glutamic part was stuck at the FRα pocket entrance during the MD simulations. Molecular mechanics Poisson-Boltzmann surface accessible (MM-PBSA) and H-bond analysis revealed that FOL03 and FOL08 created more negative free binding and electrostatic energy compared to FA and PTX, and both formed stronger H-bond interactions with ASP81 than FA with excellent H-bond profiles that led them to become bound tightly in the pocket. In addition, pocket volume calculations showed that the volumes of active site for FOL03 and FOL08 inside the FRα pocket were smaller than the FA–FRα system, indicating strong interactions between the protein active site residues with these new FA analogs compared to FA during the MD simulations.

scholarly journals Conjugated β-Cyclodextrin Enhances the Affinity of Folic Acid towards FRα: Molecular Dynamics Study

Molecules ◽  
2021 ◽  
Vol 26 (17) ◽  
pp. 5304
Author(s):  
Mohammad G. Al-Thiabat ◽  
Amirah Mohd Gazzali ◽  
Noratiqah Mohtar ◽  
Vikneswaran Murugaiyah ◽  
Ezatul Ezleen Kamarulzaman ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Folic Acid ◽  
Root Mean Square ◽  
Active Site ◽  
Md Simulation ◽  
Binding Free Energy ◽  
Cancer Drug ◽  
Radius Of Gyration ◽  
Mean Square ◽  
The Stability

Drug targeting is a progressive area of research with folate receptor alpha (FRα) receiving significant attention as a biological marker in cancer drug delivery. The binding affinity of folic acid (FA) to the FRα active site provides a basis for recognition of FRα. In this study, FA was conjugated to beta-cyclodextrin (βCD) and subjected to in silico analysis (molecular docking and molecular dynamics (MD) simulation (100 ns)) to investigate the affinity and stability for the conjugated system compared to unconjugated and apo systems (ligand free). Docking studies revealed that the conjugated FA bound into the active site of FRα with a docking score (free binding energy < −15 kcal/mol), with a similar binding pose to that of unconjugated FA. Subsequent analyses from molecular dynamics (MD) simulations, root mean square deviation (RMSD), root mean square fluctuation (RMSF), and radius of gyration (Rg) demonstrated that FA and FA–βCDs created more dynamically stable systems with FRα than the apo-FRα system. All systems reached equilibrium with stable RMSD values ranging from 1.9–2.4 Å and the average residual fluctuation values of the FRα backbone atoms for all residues (except for terminal residues ARG8, THR9, THR214, and LEU215) were less than 2.1 Å with a consistent Rg value of around 16.8 Å throughout the MD simulation time (0–100 ns). The conjugation with βCD improved the stability and decreased the mobility of all the residues (except residues 149–151) compared to FA–FRα and apo-FRα systems. Further analysis of H-bonds, binding free energy (MM-PBSA), and per residue decomposition energy revealed that besides APS81, residues HIS20, TRP102, HIS135, TRP138, TRP140, and TRP171 were shown to have more favourable energy contributions in the holo systems than in the apo-FRα system, and these residues might have a direct role in increasing the stability of holo systems.

Molecular docking and molecular dynamics simulations of fumarate hydratase and its mutant H235N complexed with pyromellitic acid and citrate

2017 ◽  
Vol 15 (06) ◽  
pp. 1750026 ◽  
Author(s):  
S. Subasri ◽  
Santosh Kumar Chaudhary ◽  
K. Sekar ◽  
Manish Kesherwani ◽  
D. Velmurugan
Keyword(s):  
Molecular Dynamics ◽  
Active Site ◽  
Model Building ◽  
Hydrophobic Interactions ◽  
Conformational Stability ◽  
Fumarate Hydratase ◽  
Md Simulations ◽  
Major Effect ◽  
Active Site Residues ◽  
Pyromellitic Acid

Fumarase catalyzes the reversible, stereospecific hydration/dehydration of fumarate to L-malate during the Kreb’s cycle. In the crystal structure of the tetrameric fumarase, it was found that some of the active site residues S145, T147, N188 G364 and H235 had water-mediated hydrogen bonding interactions with pyromellitic acid and citrate which help to the protonation state for the conversion of fumarate to malate. When His 235 is mutated with Asn (H235N), water-mediated interactions were lost due to the shifting of active site water molecule by 0.7 Å away. Molecular dynamics (MD) simulations were also carried out by NAMD and analyzed using Assisted Model Building with Energy Refinement (AMBER) program to better understand the conformational stability and other aspects during the binding of pyromellitic acid and citrate with native and mutant FH. The role of hydrogen bonds and hydrophobic interactions was also analyzed. The present study confirms that the H235N mutation has a major effect on the catalytic activity of fumarase which is evident from the biochemical studies.

scholarly journals Fruit Bromelain-Derived Peptide Potentially Restrains the Attachment of SARS-CoV-2 Variants to hACE2: A Pharmacoinformatics Approach

Molecules ◽  
2022 ◽  
Vol 27 (1) ◽  
pp. 260
Author(s):  
Trina Ekawati Tallei ◽  
Fatimawali ◽  
Ahmad Akroman Adam ◽  
Mona M. Elseehy ◽  
Ahmed M. El-Shehawi ◽  
...  
Keyword(s):  
Root Mean Square ◽  
Antiviral Agents ◽  
Md Simulations ◽  
Radius Of Gyration ◽  
Mean Square ◽  
Angiotensin Converting Enzyme 2 ◽  
In Silico Study ◽  
Mean Square Fluctuation ◽  
Binding Residues ◽  
Binding Energy Calculations

Before entering the cell, the SARS-CoV-2 spike glycoprotein receptor-binding domain (RBD) binds to the human angiotensin-converting enzyme 2 (hACE2) receptor. Hence, this RBD is a critical target for the development of antiviral agents. Recent studies have discovered that SARS-CoV-2 variants with mutations in the RBD have spread globally. The purpose of this in silico study was to determine the potential of a fruit bromelain-derived peptide. DYGAVNEVK. to inhibit the entry of various SARS-CoV-2 variants into human cells by targeting the hACE binding site within the RBD. Molecular docking analysis revealed that DYGAVNEVK interacts with several critical RBD binding residues responsible for the adhesion of the RBD to hACE2. Moreover, 100 ns MD simulations revealed stable interactions between DYGAVNEVK and RBD variants derived from the trajectory of root-mean-square deviation (RMSD), radius of gyration (Rg), and root-mean-square fluctuation (RMSF) analysis, as well as free binding energy calculations. Overall, our computational results indicate that DYGAVNEVK warrants further investigation as a candidate for preventing SARS-CoV-2 due to its interaction with the RBD of SARS-CoV-2 variants.

scholarly journals An EMG Patch for the Real-Time Monitoring of Muscle-Fatigue Conditions During Exercise

Sensors ◽  
2019 ◽  
Vol 19 (14) ◽  
pp. 3108 ◽  
Author(s):  
Shing-Hong Liu ◽  
Chuan-Bi Lin ◽  
Ying Chen ◽  
Wenxi Chen ◽  
Tai-Shen Huang ◽  
...  
Keyword(s):  
Muscle Fatigue ◽  
Real Time ◽  
Root Mean Square ◽  
The Body ◽  
Median Frequency ◽  
Mean Square ◽  
Sport Injuries ◽  
Physiological Measurement ◽  
The Real ◽  
Emg Signal

In recent years, wearable monitoring devices have been very popular in the health care field and are being used to avoid sport injuries during exercise. They are usually worn on the wrist, the same as sport watches, or on the chest, like an electrocardiogram patch. Common functions of these wearable devices are that they use real time to display the state of health of the body, and they are all small sized. The electromyogram (EMG) signal is usually used to show muscle activity. Thus, the EMG signal could be used to determine the muscle-fatigue conditions. In this study, the goal is to develop an EMG patch which could be worn on the lower leg, the gastrocnemius muscle, to detect real-time muscle fatigue while exercising. A micro controller unit (MCU) in the EMG patch is part of an ARM Cortex-M4 processor, which is used to measure the median frequency (MF) of an EMG signal in real time. When the muscle starts showing tiredness, the median frequency will shift to a low frequency. In order to delete the noise of the isotonic EMG signal, the EMG patch has to run the empirical mode decomposition algorithm. A two-electrode circuit was designed to measure the EMG signal. The maximum power consumption of the EMG patch was about 39.5 mAh. In order to verify that the real-time MF values measured by the EMG patch were close to the off-line MF values measured by the computer system, we used the root-mean-square value to estimate the difference in the real-time MF values and the off-line MF values. There were 20 participants that rode an exercise bicycle at different speeds. Their EMG signals were recorded with an EMG patch and a physiological measurement system at the same time. Every participant rode the exercise bicycle twice. The averaged root-mean-square values were 2.86 ± 0.86 Hz and 2.56 ± 0.47 Hz for the first and second time, respectively. Moreover, we also developed an application program implemented on a smart phone to display the participants’ muscle-fatigue conditions and information while exercising. Therefore, the EMG patch designed in this study could monitor the muscle-fatigue conditions to avoid sport injuries while exercising.

The 2.8 Å resolution structure of Streptomyces griseus protease B and its homology with α-chymotrypsin and Streptomyces griseus protease A

1979 ◽  
Vol 57 (2) ◽  
pp. 135-144 ◽  
Author(s):  
Louis T. J. Delbaere ◽  
Gary D. Brayer ◽  
Michael N. G. James
Keyword(s):  
Root Mean Square ◽  
Root Mean Square Deviation ◽  
Active Site ◽  
Heavy Atom ◽  
Streptomyces Griseus ◽  
Mean Square ◽  
Mean Square Deviation ◽  
Tertiary Structures ◽  
Protease B ◽  
Resolution Structure

The 2.8 Å (1 Å = 0.1 nm) resolution structure of the crystalline orthorhombic form of the microbial serine protease Streptomyces griseus protease B (SGPB) has been solved by the method of multiple isomorphous replacement using five heavy-atom derivatives. The geometrical arrangement of the active site quartet, Ser-214, Asp-102, His-57, and Ser-195, is similar to that found for pancreatic α-chymotrypsin. SGPB and α-chymotrypsin have only 18% identity of primary structure but their tertiary structures are 63% topologically equivalent within a root mean square deviation of 2.07 Å. The major tertiary structural differences between the bacterial enzyme SGPB and the pancreatic enzymes is due to the zymogen requirement of the multicellular organisms in order to protect themselves against autolytic degradation. The two pronase enzymes, SGPB and Streptomyces griseus protease A (SGPA), have 61% identity of sequence and their tertiary structures are 85% topologically equivalent within a root mean square deviation of 1.46 Å. The active site regions of SGPA and SGPB are similar and their tertiary structures differ only in three minor regions of surface loops.

Study on Intelligent Control Strategy for Semi-Active Suspension System of Tracked Vehicle

2011 ◽  
Vol 48-49 ◽  
pp. 1162-1171 ◽  
Author(s):  
Yi Hui Zeng ◽  
Shao Jun Liu ◽  
Wei Cheng
Keyword(s):  
Root Mean Square ◽  
Intelligent Control ◽  
Pitch Angle ◽  
Control Method ◽  
Active Suspension ◽  
Suspension System ◽  
The Body ◽  
Mean Square ◽  
Tracked Vehicle ◽  
Magneto Rheological

Considering the multiple and complicated driving conditions for tracked vehicles and their structural features, a comprehensive intelligent control method to deal with semi-active suspension was proposed based on the principle of magneto rheological damper. One half of the tracked vehicle suspension system is taken as the research object, where analysis is directed to the vertical amplitude, pitch angle and vertical body acceleration response. And the magneto rheological damper was taken as an actuator, the fuzzy control was taken as feedforward and PID control was taken as feedback. The control system model has been established by using of the complex random road output to simulink due to the condition of MATLAB/Simulink. The simulation results show that it is of good real-time control competence, good robustness and high accuracy, etc. Contrasting to passive suspension, some capability parameters such as the body vertical amplitude, pitch angle and the body vertical acceleration of the semi-active suspension system can had been well controlled by using of the intelligent hybrid control method, for exmple, the root mean square value of vertical amplitude decreased by 37.2%，the root mean square value of pitch angle decreased by 45.2% and root mean square value of the vertical vibration acceleration decreased by 38.6%.

scholarly journals Decoding the Molecular Effects of Atovaquone Linked Resistant Mutations on Plasmodium falciparum Cytb-ISP Complex in the Phospholipid Bilayer Membrane

2021 ◽  
Vol 22 (4) ◽  
pp. 2138
Author(s):  
Lorna Chebon-Bore ◽  
Taremekedzwa Allan Sanyanga ◽  
Colleen Varaidzo Manyumwa ◽  
Afrah Khairallah ◽  
Özlem Tastan Bishop
Keyword(s):  
Plasmodium Falciparum ◽  
Active Site ◽  
Protein Function ◽  
Hydrophobic Interactions ◽  
Point Mutations ◽  
Md Simulations ◽  
Resistance Mechanisms ◽  
Phospholipid Bilayer ◽  
Active Site Residues ◽  
Presence And Absence

Atovaquone (ATQ) is a drug used to prevent and treat malaria that functions by targeting the Plasmodium falciparum cytochrome b (PfCytb) protein. PfCytb catalyzes the transmembrane electron transfer (ET) pathway which maintains the mitochondrial membrane potential. The ubiquinol substrate binding site of the protein has heme bL, heme bH and iron-sulphur [2FE-2S] cluster cofactors that act as redox centers to aid in ET. Recent studies investigating ATQ resistance mechanisms have shown that point mutations of PfCytb confer resistance. Thus, understanding the resistance mechanisms at the molecular level via computational approaches incorporating phospholipid bilayer would help in the design of new efficacious drugs that are also capable of bypassing parasite resistance. With this knowledge gap, this article seeks to explore the effect of three drug resistant mutations Y268C, Y268N and Y268S on the PfCytb structure and function in the presence and absence of ATQ. To draw reliable conclusions, 350 ns all-atom membrane (POPC:POPE phospholipid bilayer) molecular dynamics (MD) simulations with derived metal parameters for the holo and ATQ-bound -proteins were performed. Thereafter, simulation outputs were analyzed using dynamic residue network (DRN) analysis. Across the triplicate MD runs, hydrophobic interactions, reported to be crucial in protein function were assessed. In both, the presence and absence of ATQ and a loss of key active site residue interactions were observed as a result of mutations. These active site residues included: Met 133, Trp136, Val140, Thr142, Ile258, Val259, Pro260 and Phe264. These changes to residue interactions are likely to destabilize the overall intra-protein residue communication network where the proteins’ function could be implicated. Protein dynamics of the ATQ-bound mutant complexes showed that they assumed a different pose to the wild-type, resulting in diminished residue interactions in the mutant proteins. In summary, this study presents insights on the possible effect of the mutations on ATQ drug activity causing resistance and describes accurate MD simulations in the presence of the lipid bilayer prior to conducting inhibitory drug discovery for the PfCytb-iron sulphur protein (Cytb-ISP) complex.

scholarly journals Targeting SARS-CoV-2 Main Protease by Teicoplanin: A Mechanistic Insight by in Silico Studies

2020 ◽  
Author(s):  
Faizul Azam
Keyword(s):  
Root Mean Square ◽  
Bacterial Infections ◽  
Rational Design ◽  
Hydrophobic Interactions ◽  
Mean Square ◽  
Molecular Docking Study ◽  
Mechanistic Insight ◽  
Main Protease ◽  
In Silico Studies

<p>First emerged in late December 2019, the outbreak of novel severe acute respiratory syndrome corona virus-2 (SARS-CoV-2) pandemic has instigated public-health emergency around the globe. Although available medications can only alleviate few symptoms like difficulty in breathing, the world is craving to identify specific antiviral agents or vaccines against SARS-CoV-2. Teicoplanin is a glycopeptide class of antibiotic which is regularly used for treating Gram-positive bacterial infections, has shown potential therapeutic efficacy against SARS-CoV-2 <i>in vitro</i>. Therefore, in this study, a mechanistic insight of intermolecular interactions between teicoplanin and SARS-CoV-2 main protease has been scrutinized by employing molecular modelling approaches. Molecular docking study was carried out by three different docking programs including AutoDock4, AutoDock Vina and Dock6. The dynamic and thermodynamics constraints of docked drug in complex with target protein under specific physiological conditions was ascertained by all-atom molecular dynamics (MD) simulation study. Root mean square deviation of carbon α chain exhibited uniform value in the range of 1-1.7 Å while root mean square fluctuations were also recorded below 1.72 Å, justifying the stability of the bound complex in biological environments. Key interacting residues involved in hydrogen bonds include Thr26, His41, Asn142, Ser144, Glu166, and Gln189. Several water bridges and hydrophobic interactions also anchored docked teicoplanin in the inhibitor binding site. These outcomes are supposed to be fruitful in rational design of antiviral drugs against SARS-CoV-2.</p>

scholarly journals Investigating the role of N-terminal domain in phosphodiesterase 4B-inhibition by molecular dynamics simulation

2020 ◽  
Author(s):  
Vidushi Sharma ◽  
Sharad Wakode
Keyword(s):  
Ligand Binding ◽  
Root Mean Square ◽  
Active Site ◽  
Binding Pocket ◽  
Dynamics Simulation ◽  
Radius Of Gyration ◽  
Mean Square ◽  
Sequence Identity ◽  
Terminal Domain ◽  
Phosphodiesterase 4B

AbstractPhosphodiesterase 4B (PDE4B) is a potential therapeutic target for the inflammatory respiratory diseases such as congestive obstructive pulmonary disease (COPD) and asthma. The sequence identity of ∼88% with its isoform PDE4D is the key barrier in developing selective PDE4B inhibitors which may help to overcome associated side effects. Despite high sequence identity, both isoforms differ in few residues present in N-terminal (UCR2) and C-terminal (CR3) involved in catalytic site formation. Previously, we designed and tested specific PDE4B inhibitors considering N-terminal residues as a part of the catalytic cavity. In continuation, current work thoroughly presents an MD simulation-based analysis of N-terminal residues and their role in ligand binding. The various parameters viz. root mean square deviation (RMSD), radius of gyration (Rg), root mean square fluctuation (RMSF), principal component analysis (PCA), dynamical cross-correlation matrix (DCCM) analysis, secondary structure analysis, and residue interaction mapping were investigated to establish rational. Results showed that UCR2 reduced RMSF values for the metal binding pocket (31.5±11 to 13.12±6 Å2) and the substrate-binding pocket (38.8±32 to 17.3±11 Å2). UCR2 enhanced anti-correlated motion at the active site region that led to the improved ligand-binding affinity of PDE4B from −24.57±3 to −35.54±2 kcal/mol. Further, the atomic-level analysis indicated that T-pi and π-π interactions between inhibitors and residues are vital forces that regulate inhibitor association to PDE4B with high affinity. In conclusion, UCR2, the N-terminal domain, embraces the dynamics of PDE4B active site and stabilizes PDE4B inhibitor interactions. Therefore the N-terminal domain needs to be included by designing next-generation, selective PDE4B-inhibitors as potential anti-inflammatory drugs.

scholarly journals Investigating Fungi-Derived Bioactive Molecules as Inhibitor of the SARS Coronavirus Papain Like Protease: Computational Based Study

2021 ◽  
Vol 8 ◽  
Author(s):  
Aweke Mulu Belachew ◽  
Asheber Feyisa ◽  
Seid Belay Mohamed ◽  
Jerusalem Fekadu W/Mariam
Keyword(s):  
Binding Affinity ◽  
Root Mean Square ◽  
Bioactive Compounds ◽  
Bioactive Molecules ◽  
World Health ◽  
Solvent Accessible Surface Area ◽  
Mean Square ◽  
Sars Coronavirus ◽  
Reference Drug ◽  
Wet Lab

Due to the rapid growth of the COVID-19 pandemic and its outcomes, developing a remedy to fight the predicament is critical. So far, it has infected more than 214,468,601 million people and caused the death of 4,470,969 million people according to the August 27, 2021, World Health Organization's (WHO) report. Several studies have been published on both computational and wet-lab approaches to develop antivirals for COVID-19, although there has been no success yet. However, the wet-lab approach is laborious, expensive, and time-consuming, and computational techniques have screened the activity of bioactive compounds from different sources with less effort and cost. For this investigation, we screened the binding affinity of fungi-derived bioactive molecules toward the SARS coronavirus papain-like protease (PLpro) by using computational approaches. Studies showed that protease inhibitors can be very effective in controlling virus-induced infections. Additionally, fungi represent a vast source of bioactive molecules, which could be potentially used for antiviral therapy. Fifty fungi-derived bioactive compounds were investigated concerning SARS-CoV-2 PLpro by using Auto Dock 4.2.1, Gromacs 2018. 2, ADMET, Swiss-ADME, FAF-Drugs 4.023, pKCSM, and UCLA-DOE server. From the list of the screened bioactive compounds, Dihydroaltersolanol C, Anthraquinone, Nigbeauvin A, and Catechin were selected with the Auto-Dock results of −8.68, −7.52, −10.46, and −10.58 Kcal/mol, respectively, based on their binding affinity compared to the reference drug. We presented the drug likeliness, toxicity, carcinogenicity, and mutagenicity of all compounds using ADMET analysis. They interacted with the amino acid residues, Gly163, Trp106, Ser111, Asp164, and Cys270, through hydrogen bonds. The root-mean-square deviation (RMSD), root-mean-square fluctuations (RMSF), solvent-accessible surface area (SASA), and radius of gyration (Rg) values revealed a stable interaction. From the overall analyses, we can conclude that Dihydroaltersolanol C, Anthraquinone, Nigbeauvin A, and Catechin are classified as promising candidates for PLpro, thus potentially useful in developing a medicine for COVID-19.

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