Biomolecular Entropy Estimation

The concepts of entropy and mutual information (MI) are fundamental aspects of statistical mechanics. However, whilst entropy is a key driver in chemical and biological processes, it remains difficult to model and is consequently ill understood. Various entropy estimation techniques have been developed, with the most direct being based on information theoretic approaches.

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Molecular Design For Drug Discovery

Computational molecular design is a useful tool in modern drug discovery. Virtual screening is an approach that evaluates individual members of compound libraries. In contrast, design approaches construct compounds by combining scaffolds and sidegroups to optimise the calculated binding affinity.

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Modelling Solvation Thermodynamics

Inhomogeneous fluid solvation theory (IFST) is a statistical mechanical framework for calculating the effect of a solute on the free energy of the surrounding solvent relative to its bulk state. The solute can be a protein, peptide, or small molecule and the solvent is commonly water. One of the useful features of IFST is that the free energy changes are calculated for small subvolumes surrounding the solute and this allows the contribution of different regions of space to be calculated and visualized.

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Visualizations of the relative free energy density for regions surrounding acetamide

Ligandability And Target Selection

The druggability of a protein target is defined as the relative ease or difficulty of developing a small molecule that can effectively modulate the protein’s activity in vivo. The ligandability of a protein is defined as the relative ease or difficulty of developing a small molecule that can inhibit the protein in vitro. This is an important difference, as there are complex pharmacodynamic and pharmacokinetic factors that influence druggability but not ligandability.

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Testing Water Models

Water is one of the simplest molecules in existence, but also one of the most important in biological and engineered systems. However, understanding the structure and dynamics of liquid water remains a major scientific challenge. Molecular dynamics simulations of liquid water can be used to calculate the radial distribution functions (RDFs), the relative angular distributions, and the excess enthalpies,entropies, and free energies.

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The TIP3P-Ewald, TIP4P-2005,TIP5P-Ewald, and SWM4-NDP water models

Designing Effective Screening Libraries

Shrewd selection of screening compounds is one of the most vital enabling steps in the drug discovery process. A screening library must have the correct balance of properties such as molecular weight and lipophilicity. An ideal hit molecule must also be amenable to chemical elaboration, show reasonable levels of cell permeability, and have a range of commercially available analogues, some of which have also been tested in the same assay.

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Computer-Aided Chemical Biology

The development of publically-available chemical probes for the purpose of target exploration is a new paradigm in drug discovery. This shift has been pioneered by non-profit and open-source ventures such as the SGC and NIH chemical probes. Having publically available chemical probes for potential drug targets facilitates an open assessment of target viability, paving the way for commercial ventures to develop effective treatments at a lower societal cost.

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The Virtual Bond Algorithm used in the alchemical free-energy calculations

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