Binding free energy decomposition and multiple unbinding paths of buried ligands in a PreQ1 riboswitch

Riboswitches are naturally occurring RNA elements that control bacterial gene expression by binding to specific small molecules. They serve as important models for RNA-small molecule recognition and have also become a novel class of targets for developing antibiotics. Here, we carried out conventional and enhanced-sampling molecular dynamics (MD) simulations, totaling 153.5 μs, to characterize the determinants of binding free energies and unbinding paths for the cognate and synthetic ligands of a PreQ1 riboswitch. Binding free energy analysis showed that two triplets of nucleotides U6-C15-A29 and G5-G11-C16, contribute the most to the binding of the cognate ligands, by hydrogen bonding and by base stacking, respectively. Mg2+ ions are essential in stabilizing the binding pocket. For the synthetic ligands, the hydrogen-bonding contributions of the U6-C15-A29 triplet are significantly compromised, and the bound state resembles the apo state in several respects, including the disengagement of the C15-A14-A13 and A32-G33 base stacks. The bulkier synthetic ligands lead to significantly loosening of the binding pocket, including extrusion of the C15 nucleobase and a widening of the C15-C30 groove. Enhanced-sampling simulations further revealed that the cognate and synthetic ligands unbind in almost opposite directions. Our work offers new insight for designing riboswitch ligands.

Binding Affinities of Sanggenon Derivatives as PTP1B Inhibitors; Using Molecular Dynamics and Free Energy Calculations

Recently, protein tyrosine phosphatase 1B (PTP1B) inhibitors have become the frontier as possible targeting for anti-cancer and antidiabetic drugs. The contemporary observe represents a pc assisted version to investigate the importance of precise residues within the binding web site of PTP1B with numerous Sanggenon derivatives remoted from nature. Molecular dynamics (MD) simulations were performed to estimate the dynamics of the complexes, and absolute binding unfastened energies have been calculated with exclusive additives, and carried out through the usage of the Molecular Mechanics-Poisson-Boltzmann floor region (MM-PB/SA) and Generalized Born surface vicinity (MM-GB/SA) strategies. The effects show that the expected free energies of the complexes are normally constant with the available experimental statistics. MM/GBSA free energy decomposition analysis shows that the residues Asp29, Arg24, Met258, and , Arg254 in the second active site in PTP1B are crucial for the excessive selectivity of the inhibitors.

In silico investigation of critical binding pattern in SARS-CoV-2 spike protein with angiotensin-converting enzyme 2

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a newly-discovered coronavirus and responsible for the spread of coronavirus disease 2019 (COVID-19). SARS-CoV-2 infected millions of people in the world and immediately became a pandemic in March 2020. SARS-CoV-2 belongs to the beta-coronavirus genus of the large family of Coronaviridae. It is now known that its surface spike glycoprotein binds to the angiotensin-converting enzyme-2 (ACE2), which is expressed on the lung epithelial cells, mediates the fusion of the cellular and viral membranes, and facilitates the entry of viral genome to the host cell. Therefore, blocking the virus-cell interaction could be a potential target for the prevention of viral infection. The binding of SARS-CoV-2 to ACE2 is a protein–protein interaction, and so, analyzing the structure of the spike glycoprotein of SARS-CoV-2 and its underlying mechanism to bind the host cell receptor would be useful for the management and treatment of COVID-19. In this study, we performed comparative in silico studies to deeply understand the structural and functional details of the interaction between the spike glycoprotein of SARS-CoV-2 and its cognate cellular receptor ACE2. According to our results, the affinity of the ACE2 receptor for SARS-CoV-2 was higher than SARS-CoV. According to the free energy decomposition of the spike glycoprotein-ACE2 complex, we found critical points in three areas which are responsible for the increased binding affinity of SARS-CoV-2 compared with SARS-CoV. These mutations occurred at the receptor-binding domain of the spike glycoprotein that play an essential role in the increasing the affinity of coronavirus to ACE2. For instance, mutations Pro462Ala and Leu472Phe resulted in the altered binding energy from − 2 kcal mol−1 in SARS-COV to − 6 kcal mol−1 in SARS-COV-2. The results demonstrated that some mutations in the receptor-binding motif could be considered as a hot-point for designing potential drugs to inhibit the interaction between the spike glycoprotein and ACE2.

Insight Into the Binding Mode Knowledge of New Possible Anti-Hypertensive Compounds Designed in Silico Using Neutral Endopeptidase (NEP) As A Target.

Arterial hypertension is a health problem that affects millions of people around the world. Particularly in Chile, according to the last health survey in 2019, 28.7% of the population had this condition, and arterial hypertension complications cause one in three deaths per year. In this work, we have used molecular simulation tools to evaluate new compounds designed in silico by our group as possible anti-hypertensive agents, taking Neutral Endopeptidase (NEP) as a target, a key enzyme in the arterial hypertension regulation at the level kidney. We use docking experiments, molecular dynamics simulation, free energy decomposition calculations means of Molecular Mechanics Poisson–Boltzmann (MM-PBSA) method and ligand efficiency analysis. To identify the best anti-hypertensive agent we realized pharmacokinetic and toxicological predictions (ADME-Tox). The principal results obtained shown the ligands designed in silico were adequately oriented in the thermolysin active centre. The Lig783, Lig2177, and Lig3444 compounds were those with better dynamic behaviour. The energetic components that contribute to the complexes stability are the electrostatic and Van der Waals components; however, when the ADME-Tox properties were analyzed, we conclude that the best anti-hypertensive candidate agents are Lig783 and Lig3444, taking Neutra Endopeptidase as a target.

Insights into structure and dynamics of extracellular domain of Toll-like receptor 5 in Cirrhinus mrigala (mrigala): A molecular dynamics simulation approach

The toll-like receptor 5 (TLR5) is the most conserved important pattern recognition receptors (PRRs) often stimulated by bacterial flagellins and plays a major role in the first-line defense against invading pathogenic bacteria and in immune homeostasis. Experimental crystallographic studies have shown that the extracellular domain (ECD) of TLR5 recognizes flagellin of bacteria and functions as a homodimer in model organism zebrafish. However, no structural information is available on TLR5 functionality in the major carp Cirrhinus mrigala (mrigala) and its interaction with bacterial flagellins. Therefore, the present study was undertaken to unravel the structural basis of TLR5-flagellin recognition in mrigala using structural homodimeric TLR5-flagellin complex of zebrafish as reference. Integrative structural modeling and molecular dynamics simulations were employed to explore the structural and mechanistic details of TLR5 recognition. Results from structural snapshots of MD simulation revealed that TLR5 consistently formed close interactions with the three helices of the D1 domain in flagellin on its lateral side mediated by several conserved amino acids. Results from the intermolecular contact analysis perfectly substantiate with the findings of per residue-free energy decomposition analysis. The differential recognition mediated by flagellin to TLR5 in mrigala involves charged residues at the interface of binding as compared to the zebrafish complex. Overall our results shows TLR5 of mrigala involved in innate immunity specifically recognized a conserved site on flagellin which advocates the scientific community to explore host-specific differences in receptor activation.

Investigation of Critical Binding Pattern in SARS-CoV-2 Spike Glycoprotein with Angiotensin-Converting Enzyme 2: An in Silico Analysis

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a newly-discovered coronavirus and responsible for the spread of coronavirus disease 2019 (COVID-19). SARS-CoV-2 infected millions of people in the world and immediately became a pandemic in March 2020. SARS-CoV-2 belongs to the beta-coronavirus genus of the large family of Coronaviridae. It is now known that its surface spike glycoprotein binds to the angiotensin-converting enzyme-2 (ACE2), which is expressed on the lung epithelial cells, mediates the fusion of the cellular and viral membranes, and facilitates the entry of viral genome to the host cell. Therefore, blocking the virus-cell interaction could be a potential target for the prevention of viral infection. The binding of SARS-CoV-2 to ACE2 is a protein-protein interaction, and so, analyzing the structure of the spike glycoprotein of SARS-CoV-2 and its underlying mechanism to bind the host cell receptor would be useful for the management and treatment of COVID-19. In this study, we performed comparative in silico studies to deeply understand the structural and functional details of the interaction between the spike glycoprotein of SARS-CoV-2 and its cognate cellular receptor ACE2. According to our results, the affinity of the ACE2 receptor for SARS-CoV-2 was higher than SARS-CoV. According to the free energy decomposition of the spike glycoprotein-ACE2 complex, we found critical points in three areas which are responsible for the increased binding affinity of SARS-CoV-2 compared with SARS-CoV. These mutations occurred at the receptor-binding domain of the spike glycoprotein that play an essential role in the increasing the affinity of coronavirus to ACE2. For instance, mutations Pro462Ala and Leu472Phe resulted in the altered binding energy from -2 kcal·mol−1 in SARS-COV to -6 kcal·mol−1 in SARS-COV-2. The results demonstrated that some mutations in the receptor-binding motif could be considered as a hot-point for designing potential drugs to inhibit the interaction between the spike glycoprotein and ACE2.

Binding Mode Knowledge of New Possible Anti-Hypertensive Compounds Designed In Silico Using Neutral Endopeptidase (NEP) as a Target

Arterial hypertension is a health problem that affects millions of people around the world. Particularly in Chile, according to the last health survey in 2019, 28.7% of the population had this condition, and arterial hypertension complications cause one in three deaths per year. In this work, we have used molecular simulation tools to evaluate new compounds designed in silico by our group as possible anti-hypertensive agents, taking Neutral Endopeptidase (NEP) as a target, a key enzyme in the arterial hypertension regulation at the level kidney. We use docking experiments, molecular dynamics simulation, free energy decomposition calculations (by MM-PBSA method), and ligand efficiency analysis to identify the best anti-hypertensive agent pharmacokinetic and toxicological predictions (ADME-Tox). The energetic components that contribute to the complexes stability are the electrostatic and Van der Waals components; however, when the ADME-Tox properties were analyzed, we conclude that the best anti-hypertensive candidate agents are Lig783 and Lig3444, taking Neutra Endopeptidase as a target.

A molecular dynamics simulation study of interactions between aprotinin and transmembrane serine proteases TMPRSS2 and prostasin

Aprotinin is a small protein, which inhibits trypsin and related proteolytic enzymes, it has been shown experimentally that it can inhibit SARS-CoV-2 replication.However, the molecular mechanisms relate to it are not totally known. TMPRSS2 is a human transmembrane serine protease which is important for viral spread and pathogenesis. In the current study, we use homology modeling for obtaining an initial structure of the complex between aprotinin and TMPRSS2, having as template the crystallographic structure of the complex between aprotinin and prostasin, other transmembrane serine protease which is related to other processes such as the regulation of hypertension. The binding modes of both complexes were predicted based on initial geometry optimization, and molecular dynamic simulations, calculating MM/PBSA and MM/GBSA free-energy calculations after the simulations. The calculated binding free energies suggested a better affinity of TMPRSS2 to aprotinin than prostasin. Moreover, hydrogen bond analyses along the trajectory simulation showed that the hydrogen-bond networks between TMPRSS2 and aprotinin are more stable than the corresponding to prostasin and aprotinin which explain their higher binding free energies. Additionally, in order to elucidate the different contributions of KLK14 residues to the free energy of binding, MM/GBSA free-energy decomposition analyses were performed. Based on their results, Glu97, Glu144H, Asp189 and Ser190 residues have been postulated as TMPRSS2 potential hotspots for its binding to aprotinin and by extension to other possible inhibitors.

Virtual Compound Screening and Molecular Dynamics to Identify New Inhibitors for Human Glutathione Reductase

Background: Oxidative stress is a defense mechanism against malarial intracellular parasite infection. On the other hand, the Human glutathione reductase enzyme reduces oxidative stress in the cells, making the inhibitors of this enzyme a promising candidate for malaria treatment. Objective: Rational drug design was used in this work to plan new human glutathione reductase inhibitors. Methods: Virtual screening was performed using the ZINC database and molecular docking was used to detect appropriate human glutathione reductase inhibitors. Based on the docking scores obtained, the top three highest-ranked ligands were selected for the molecular dynamics simulation study. The MD simulation was performed for each complex in a length of 100 ns. Results: RMSD, RMSF and hydrogen bond analyzes were performed on the derived trajectories. Molecular mechanics generalized born surface area (MM-GBSA) and pairwise per-residue free energy decomposition analyzes were performed for the determination of binding free energy and the determination of dominant residues involved in the binding process, respectively. The binding free energy analysis showed that the molecule of 3-((7-(furan-2-ylmethyl)-5,6-diphenyl-7H-pyrrolo[2,3- d] pyrimidin-4-yl) amino) propan-1-ol is the most potent inhibitor among the molecules considered against human glutathione reductase enzyme. Conclusion: This molecule can be considered a novel candidate for antimalarial treatments.