scholarly journals A Study effect of Substituents X on Methylenecyclopentane and 1- Methylcyclopentene System

2018 ◽  
Vol 1 (1) ◽  
pp. 38-44
Author(s):  
Ghassab Al-Mazaideh
Keyword(s):  
Free Energy ◽  
Dft Calculations ◽  
Gibbs Free Energy ◽  
Free Energy Calculations ◽  
Relative Stabilities ◽  
Energy Calculations ◽  
Effect Of Substituents ◽  
Orbital Energies ◽  
The Stability ◽  
Homo Lumo

In this study, the geometry optimizations, orbital energies (HOMO-LUMO) and relative stabilities of methylene cyclopentane and 1-methylcyclopentene were investigated by DFT calculations. 1-methylcyclopentene was found to be more stable than methylene cyclopentane isomer with enthalpy value H=18.518 kJ/mol. Also, the effect of substituents X (F, OH, CH3, NH2, CN, NO2, CHO and CF3) also studied on the relative stabilities of these two tautomers. The results showed that the stability of both isomers is increased by all substitutes. Gibbs free energy calculations have been used to find the effect of substituents X on the system.

Can the stability of protein mutants be predicted by free energy calculations?

1993 ◽  
Vol 6 (3) ◽  
pp. 289-295 ◽  
Author(s):  
Shi Yun-yu ◽  
Alan E. Mark ◽  
Wang Cun-xin ◽  
Huang Fuhua ◽  
Herman J.C. Berendsen ◽  
...  
Keyword(s):  
Free Energy ◽  
Free Energy Calculations ◽  
Energy Calculations ◽  
Protein Mutants ◽  
The Stability

scholarly journals Free energy calculations on the stability of the 14-3-3ζ protein

2018 ◽  
Vol 1866 (3) ◽  
pp. 442-450 ◽  
Author(s):  
Zuzana Jandova ◽  
Zuzana Trosanova ◽  
Veronika Weisova ◽  
Chris Oostenbrink ◽  
Jozef Hritz
Keyword(s):  
Free Energy ◽  
Free Energy Calculations ◽  
Energy Calculations ◽  
The Stability

scholarly journals C-terminal kink formation is required for lateral gating in BamA

2018 ◽  
Vol 115 (34) ◽  
pp. E7942-E7949 ◽  
Author(s):  
Karl Lundquist ◽  
Jeremy Bakelar ◽  
Nicholas Noinaj ◽  
James C. Gumbart
Keyword(s):  
Free Energy ◽  
Outer Membrane ◽  
Outer Membrane Proteins ◽  
Free Energy Calculations ◽  
Energy Calculations ◽  
Bam Complex ◽  
The Stability ◽  
Lateral Gate ◽  
And Function ◽  
Insertion Process

In Gram-negative bacteria, the outer membrane contains primarily β-barrel transmembrane proteins and lipoproteins. The insertion and assembly of β-barrel outer-membrane proteins (OMPs) is mediated by the β-barrel assembly machinery (BAM) complex, the core component of which is the 16-stranded transmembrane β-barrel BamA. Recent studies have indicated a possible role played by the seam between the first and last β-barrel strands of BamA in the OMP insertion process through lateral gating and a destabilized membrane region. In this study, we have determined the stability and dynamics of the lateral gate through over 12.5 μs of equilibrium simulations and 4 μs of free-energy calculations. From the equilibrium simulations, we have identified a persistent kink in the C-terminal strand and observed spontaneous lateral-gate separation in a mimic of the native bacterial outer membrane. Free-energy calculations of lateral gate opening revealed a significantly lower barrier to opening in the C-terminal kinked conformation; mutagenesis experiments confirm the relevance of C-terminal kinking to BamA structure and function.

Automated Assessment of Binding Affinity via Alchemical Free Energy Calculations

2020 ◽  
Author(s):  
Maximilian Kuhn ◽  
Stuart Firth-Clark ◽  
Paolo Tosco ◽  
Antonia S. J. S. Mey ◽  
Mark Mackey ◽  
...  
Keyword(s):  
Free Energy ◽  
Protein Structures ◽  
Free Energy Calculations ◽  
Distinct Advantage ◽  
Binding Affinities ◽  
Structure Based Drug Design ◽  
Energy Calculations ◽  
Kendall’S Τ ◽  
Experimental Values ◽  
Better Than

Free energy calculations have seen increased usage in structure-based drug design. Despite the rising interest, automation of the complex calculations and subsequent analysis of their results are still hampered by the restricted choice of available tools. In this work, an application for automated setup and processing of free energy calculations is presented. Several sanity checks for assessing the reliability of the calculations were implemented, constituting a distinct advantage over existing open-source tools. The underlying workflow is built on top of the software Sire, SOMD, BioSimSpace and OpenMM and uses the AMBER14SB and GAFF2.1 force fields. It was validated on two datasets originally composed by Schrödinger, consisting of 14 protein structures and 220 ligands. Predicted binding affinities were in good agreement with experimental values. For the larger dataset the average correlation coefficient Rp was 0.70 ± 0.05 and average Kendall’s τ was 0.53 ± 0.05 which is broadly comparable to or better than previously reported results using other methods. <br>

Reaction-based Enumeration, Active Learning, and Free Energy Calculations to Rapidly Explore Synthetically Tractable Chemical Space and Optimize Potency of Cyclin Dependent Kinase 2 Inhibitors

2019 ◽  
Author(s):  
Kyle Konze ◽  
Pieter Bos ◽  
Markus Dahlgren ◽  
Karl Leswing ◽  
Ivan Tubert-Brohman ◽  
...  
Keyword(s):  
Free Energy ◽  
Drug Discovery ◽  
Active Learning ◽  
Large Scale ◽  
Chemical Space ◽  
Population Based ◽  
Free Energy Calculations ◽  
Computational Technique ◽  
Cyclin Dependent Kinase ◽  
Energy Calculations

We report a new computational technique, PathFinder, that uses retrosynthetic analysis followed by combinatorial synthesis to generate novel compounds in synthetically accessible chemical space. Coupling PathFinder with active learning and cloud-based free energy calculations allows for large-scale potency predictions of compounds on a timescale that impacts drug discovery. The process is further accelerated by using a combination of population-based statistics and active learning techniques. Using this approach, we rapidly optimized R-groups and core hops for inhibitors of cyclin-dependent kinase 2. We explored greater than 300 thousand ideas and identified 35 ligands with diverse commercially available R-groups and a predicted IC<sub>50</sub> < 100 nM, and four unique cores with a predicted IC<sub>50</sub> < 100 nM. The rapid turnaround time, and scale of chemical exploration, suggests that this is a useful approach to accelerate the discovery of novel chemical matter in drug discovery campaigns.

Reaction-based Enumeration, Active Learning, and Free Energy Calculations to Rapidly Explore Synthetically Tractable Chemical Space and Optimize Potency of Cyclin Dependent Kinase 2 Inhibitors

2019 ◽  
Author(s):  
Kyle Konze ◽  
Pieter Bos ◽  
Markus Dahlgren ◽  
Karl Leswing ◽  
Ivan Tubert-Brohman ◽  
...  
Keyword(s):  
Free Energy ◽  
Drug Discovery ◽  
Active Learning ◽  
Large Scale ◽  
Chemical Space ◽  
Population Based ◽  
Free Energy Calculations ◽  
Computational Technique ◽  
Cyclin Dependent Kinase ◽  
Energy Calculations

We report a new computational technique, PathFinder, that uses retrosynthetic analysis followed by combinatorial synthesis to generate novel compounds in synthetically accessible chemical space. Coupling PathFinder with active learning and cloud-based free energy calculations allows for large-scale potency predictions of compounds on a timescale that impacts drug discovery. The process is further accelerated by using a combination of population-based statistics and active learning techniques. Using this approach, we rapidly optimized R-groups and core hops for inhibitors of cyclin-dependent kinase 2. We explored greater than 300 thousand ideas and identified 35 ligands with diverse commercially available R-groups and a predicted IC<sub>50</sub> < 100 nM, and four unique cores with a predicted IC<sub>50</sub> < 100 nM. The rapid turnaround time, and scale of chemical exploration, suggests that this is a useful approach to accelerate the discovery of novel chemical matter in drug discovery campaigns.

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