scholarly journals Encapsulation of the vitamins D3 and E in cucurbit[7]uril: A computational investigation

2020 ◽  
Author(s):  
Osmair Vital de Oliveira ◽  
Isabella Barros de Oliveira ◽  
Felipe Edilino de Lima ◽  
Rafael Giordano Viegas
Keyword(s):  
Aqueous Solution ◽  
Binding Free Energy ◽  
Solvation Shell ◽  
Dynamics Simulation ◽  
Stable Complex ◽  
Computational Investigation ◽  
Release Agent ◽  
New Host ◽  
Fat Soluble Vitamins ◽  
Macrocyclic Molecules

In this work, molecular dynamics simulation (MD) was used to study the encapsulation of fat-soluble vitamins D3 (vD3) and E (a-TOC) into cucubit[7]uril (CB[7]) in an aqueous solution. Cucurbiturils is a class of macrocyclic molecules largely used as carrier and controlled release agent in order to improve the solubility and chemoprotective of drugs. Along 50 ns of MD trajectory, the vitamins formed a stable complex with CB[7] without significantly altering its structure. Moreover, the second solvation shell of the CB[7] was not disrupted by the inclusion of the vitamins. The solvation enthalpy was ~ –173.0 kcal/mol for both complexes and –177.6 kcal/mol for the isolated CB[7], suggesting that the vitamin@CB[7] complexes are soluble in water. The binding free energy indicates that CB[7] can act as carrier agent for these vitamins, with values of –17.54 and –23.76 kcal/mol for vD3@CB[7] and a-TOC@CB[7], respectively. Finally, herein we highlight that CB[7] can be a new host to be used for vitamin delivery in biological systems.

scholarly journals De novo ssRNA Aptamers against the SARS-CoV-2 Main Protease: In Silico Design and Molecular Dynamics Simulation

2021 ◽  
Vol 22 (13) ◽  
pp. 6874
Author(s):  
Francesco Morena ◽  
Chiara Argentati ◽  
Ilaria Tortorella ◽  
Carla Emiliani ◽  
Sabata Martino
Keyword(s):  
De Novo ◽  
Binding Free Energy ◽  
3D Structure ◽  
Dynamics Simulation ◽  
Stable Complex ◽  
Therapeutic Drug ◽  
Energy Calculation ◽  
Potential Candidate ◽  
Initial Sequence ◽  
Main Protease

Herein, we have generated ssRNA aptamers to inhibit SARS-CoV-2 Mpro, a protease necessary for the SARS-CoV-2 coronavirus replication. Because there is no aptamer 3D structure currently available in the databanks for this protein, first, we modeled an ssRNA aptamer using an entropic fragment-based strategy. We refined the initial sequence and 3D structure by using two sequential approaches, consisting of an elitist genetic algorithm and an RNA inverse process. We identified three specific aptamers against SARS-CoV-2 Mpro, called MAptapro, MAptapro-IR1, and MAptapro-IR2, with similar 3D conformations and that fall in the dimerization region of the SARS-CoV-2 Mpro necessary for the enzymatic activity. Through the molecular dynamic simulation and binding free energy calculation, the interaction between the MAptapro-IR1 aptamer and the SARS-CoV-2 Mpro enzyme resulted in the strongest and the highest stable complex; therefore, the ssRNA MAptapro-IR1 aptamer was selected as the best potential candidate for the inhibition of SARS-CoV-2 Mpro and a perspective therapeutic drug for the COVID-19 disease.

scholarly journals Stability, Hydrogen Bond Occupancy Analysis and Binding Free Energy Calculation from Flavonol Docked in DAPK1 Active Site Using Molecular Dynamic Simulation Approaches

2020 ◽  
Author(s):  
Adi Tiara Zikri ◽  
Harno Dwi Pranowo ◽  
Winarto Haryadi
Keyword(s):  
Molecular Dynamics ◽  
Hydrogen Bond ◽  
Free Energy ◽  
Molecular Dynamics Simulation ◽  
Binding Free Energy ◽  
Dynamics Simulation ◽  
Stable Complex ◽  
Energy Calculation ◽  
Compound C ◽  
C Complex

Stability and hydrogen bond occupancy analysis of flavonol derivative docked in DAPK1 have been carried out using molecular dynamics simulation approach. Six flavonol derivatives were docked in DAPK1 as protein target, then continued with molecular dynamics simulation. NVT and NPT ensembles were used to equilibrate the system, followed by 20 ns sampling time for each system. Structural stability and hydrogen bond occupancy analyses were carried out at the NVT ensemble, while free binding energy analysis was done at NPT ensemble. From all compounds used in this work, compound B (5,7-dihydroxy-2-(4-hydroxyphenyl)-6-methoxy-4H-chromen-4-one) has a similar interaction with reference ligands (quercetin, kaempferol, and fisetin), and the most stable complex system has the maximum RMSD around 2 Å. Compound C complex has -48.06 kJ/mol binding free energy score, and it was slightly different from quercetin, kaempferol, and fisetin complexes. Even though complex C has similar binding free energy with the reference compound, complex B shows more stable interactions due to their hydrogen bond and occupancy.

Gingerol Derivatives as 14α-demethylase Inhibitors: Design and Development of Natural, Safe Antifungals for Immune-compromised Patients

2020 ◽  
Vol 17 (7) ◽  
pp. 918-928
Author(s):  
Sweta Sharma ◽  
Arpita Yadav
Keyword(s):  
Cell Membranes ◽  
Fungal Infections ◽  
Dynamics Simulation ◽  
Stable Complex ◽  
Active Site Residues ◽  
Design And Development ◽  
Triazole Derivative ◽  
Fungal Cell ◽  
Term Administration ◽  
Compromised Patients

Background: : Currently, clinically used drugs for internal fungal infections have severe side effects. Patients suffering from severe fungal infections and those at a constant risk of developing such infections require long-term administration of safe antifungals. Objective: : This work deals with the design and development of safe, non-toxic antifungals derived from natural compounds for immune-compromised patients, such as HIV patients, who are at a constant risk of developing internal fungal infections. Methods: : Molecular modeling, docking and molecular dynamics simulation studies were performed on the main constituents of ginger and their derivatives to study their capability to inhibit 14α- demethylase enzyme. Results: : Ergosterol is the key component of the fungal cell membrane for its integrity and rigidity, synthesized from lanosterol catalyzed by 14α-demethylase enzyme. In our studies, it is determined that 6-gingerol, 6-paradol, 6-shogaol and their imidazole and triazole derivatives can inhibit the synthesis of ergosterol thus weakening the fungal cell membranes. The triazole derivative of 6-gingerol forms enhanced binding interactions with the active site residues of 14α-demethylase, carries an affinity for catalytically required cofactor heme and forms a stable complex with time without the probability of premature expulsion. Thus, this compound inhibits the formation of ergosterol leading to weakened fungal cell membranes and eventually death of fungal cells. Conclusion: : The triazole derivative of 6-gingerol is recommended as a lead compound for the development of non-toxic antifungals.

scholarly journals The effect of protein mutations on drug binding suggests ensuing personalised drug selection

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Shunzhou Wan ◽  
Deepak Kumar ◽  
Valentin Ilyin ◽  
Ussama Al Homsi ◽  
Gulab Sher ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Ligand Binding ◽  
Binding Free Energy ◽  
Personalised Medicine ◽  
Clinical Decision ◽  
Drug Binding ◽  
Dynamics Simulation ◽  
Breast Cancer Patients ◽  
Natural Ligand ◽  
Affinity Interaction

AbstractThe advent of personalised medicine promises a deeper understanding of mechanisms and therefore therapies. However, the connection between genomic sequences and clinical treatments is often unclear. We studied 50 breast cancer patients belonging to a population-cohort in the state of Qatar. From Sanger sequencing, we identified several new deleterious mutations in the estrogen receptor 1 gene (ESR1). The effect of these mutations on drug treatment in the protein target encoded by ESR1, namely the estrogen receptor, was achieved via rapid and accurate protein–ligand binding affinity interaction studies which were performed for the selected drugs and the natural ligand estrogen. Four nonsynonymous mutations in the ligand-binding domain were subjected to molecular dynamics simulation using absolute and relative binding free energy methods, leading to the ranking of the efficacy of six selected drugs for patients with the mutations. Our study shows that a personalised clinical decision system can be created by integrating an individual patient’s genomic data at the molecular level within a computational pipeline which ranks the efficacy of binding of particular drugs to variant proteins.

scholarly journals Testing automatic methods to predict free binding energy of host–guest complexes in SAMPL7 challenge

2021 ◽  
Vol 35 (2) ◽  
pp. 209-222
Author(s):  
Dylan Serillon ◽  
Carles Bo ◽  
Xavier Barril
Keyword(s):  
Degrees Of Freedom ◽  
Binding Free Energy ◽  
Binding Mode ◽  
Specific System ◽  
New Host ◽  
Guest Molecules ◽  
Host Guest Complex ◽  
Automatic Methods ◽  
Material Sciences ◽  
Fundamental Direction

AbstractThe design of new host–guest complexes represents a fundamental challenge in supramolecular chemistry. At the same time, it opens new opportunities in material sciences or biotechnological applications. A computational tool capable of automatically predicting the binding free energy of any host–guest complex would be a great aid in the design of new host systems, or to identify new guest molecules for a given host. We aim to build such a platform and have used the SAMPL7 challenge to test several methods and design a specific computational pipeline. Predictions will be based on machine learning (when previous knowledge is available) or a physics-based method (otherwise). The formerly delivered predictions with an RMSE of 1.67 kcal/mol but will require further work to identify when a specific system is outside of the scope of the model. The latter is combines the semiempirical GFN2B functional, with docking, molecular mechanics, and molecular dynamics. Correct predictions (RMSE of 1.45 kcal/mol) are contingent on the identification of the correct binding mode, which can be very challenging for host–guest systems with a large number of degrees of freedom. Participation in the blind SAMPL7 challenge provided fundamental direction to the project. More advanced versions of the pipeline will be tested against future SAMPL challenges.

scholarly journals Toward the Identification of Potential α-Ketoamide Covalent Inhibitors for SARS-CoV-2 Main Protease: Fragment-Based Drug Design and MM-PBSA Calculations

Processes ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 1004
Author(s):  
Mahmoud A. El Hassab ◽  
Mohamed Fares ◽  
Mohammed K. Abdel-Hamid Amin ◽  
Sara T. Al-Rashood ◽  
Amal Alharbi ◽  
...  
Keyword(s):  
Drug Design ◽  
Active Site ◽  
Binding Free Energy ◽  
Stable Complex ◽  
Active Site Residues ◽  
Structure Based Drug Design ◽  
Enzyme Active Site ◽  
Potential Inhibitor ◽  
Main Protease ◽  
Covalent Docking

Since December 2019, the world has been facing the outbreak of the SARS-CoV-2 pandemic that has infected more than 149 million and killed 3.1 million people by 27 April 2021, according to WHO statistics. Safety measures and precautions taken by many countries seem insufficient, especially with no specific approved drugs against the virus. This has created an urgent need to fast track the development of new medication against the virus in order to alleviate the problem and meet public expectations. The SARS-CoV-2 3CL main protease (Mpro) is one of the most attractive targets in the virus life cycle, which is responsible for the processing of the viral polyprotein and is a key for the ribosomal translation of the SARS-CoV-2 genome. In this work, we targeted this enzyme through a structure-based drug design (SBDD) protocol, which aimed at the design of a new potential inhibitor for Mpro. The protocol involves three major steps: fragment-based drug design (FBDD), covalent docking and molecular dynamics (MD) simulation with the calculation of the designed molecule binding free energy at a high level of theory. The FBDD step identified five molecular fragments, which were linked via a suitable carbon linker, to construct our designed compound RMH148. The mode of binding and initial interactions between RMH148 and the enzyme active site was established in the second step of our protocol via covalent docking. The final step involved the use of MD simulations to test for the stability of the docked RMH148 into the Mpro active site and included precise calculations for potential interactions with active site residues and binding free energies. The results introduced RMH148 as a potential inhibitor for the SARS-CoV-2 Mpro enzyme, which was able to achieve various interactions with the enzyme and forms a highly stable complex at the active site even better than the co-crystalized reference.

scholarly journals Scaffold Hopping of α-Rubromycin Enables Direct Access to FDA-Approved Cromoglicic Acid as a SARS-CoV-2 MPro Inhibitor

2021 ◽  
Vol 14 (6) ◽  
pp. 541
Author(s):  
Hani A. Alhadrami ◽  
Ahmed M. Sayed ◽  
Heba Al-Khatabi ◽  
Nabil A. Alhakamy ◽  
Mostafa E. Rateb
Keyword(s):  
Binding Free Energy ◽  
Human Fibroblasts ◽  
Critical Time ◽  
Dynamics Simulation ◽  
Direct Access ◽  
Energy Calculation ◽  
Wide Range ◽  
Normal Human ◽  
Novel Scaffold

The COVID-19 pandemic is still active around the globe despite the newly introduced vaccines. Hence, finding effective medications or repurposing available ones could offer great help during this serious situation. During our anti-COVID-19 investigation of microbial natural products (MNPs), we came across α-rubromycin, an antibiotic derived from Streptomyces collinus ATCC19743, which was able to suppress the catalytic activity (IC50 = 5.4 µM and Ki = 3.22 µM) of one of the viral key enzymes (i.e., MPro). However, it showed high cytotoxicity toward normal human fibroblasts (CC50 = 16.7 µM). To reduce the cytotoxicity of this microbial metabolite, we utilized a number of in silico tools (ensemble docking, molecular dynamics simulation, binding free energy calculation) to propose a novel scaffold having the main pharmacophoric features to inhibit MPro with better drug-like properties and reduced/minimal toxicity. Nevertheless, reaching this novel scaffold synthetically is a time-consuming process, particularly at this critical time. Instead, this scaffold was used as a template to explore similar molecules among the FDA-approved medications that share its main pharmacophoric features with the aid of pharmacophore-based virtual screening software. As a result, cromoglicic acid (aka cromolyn) was found to be the best hit, which, upon in vitro MPro testing, was 4.5 times more potent (IC50 = 1.1 µM and Ki = 0.68 µM) than α-rubromycin, with minimal cytotoxicity toward normal human fibroblasts (CC50 > 100 µM). This report highlights the potential of MNPs in providing unprecedented scaffolds with a wide range of therapeutic efficacy. It also revealed the importance of cheminformatics tools in speeding up the drug discovery process, which is extremely important in such a critical situation.

Assessing the ligand selectivity of sphingosine kinases using molecular dynamics and MM-PBSA binding free energy calculations

2016 ◽  
Vol 12 (4) ◽  
pp. 1174-1182 ◽  
Author(s):  
Liang Fang ◽  
Xiaojian Wang ◽  
Meiyang Xi ◽  
Tianqi Liu ◽  
Dali Yin
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Model Building ◽  
Binding Free Energy ◽  
Homology Model ◽  
Free Energy Calculations ◽  
Dynamics Simulation ◽  
Ligand Selectivity ◽  
Sphingosine Kinases ◽  
Binding Free Energy Calculations

Three residues of SK1 were identified important for selective SK1 inhibitory activity via SK2 homology model building, molecular dynamics simulation, and MM-PBSA studies.

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