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Download our presentation and posters from the 253rd ACS National Meeting. Also available is the presentation, and poster, by the University of Bristol which features Flare, our new structure-based design application.
Tim Cheeseright, Director of Products, Cresset
Electrostatics are critical to ligand binding and yet largely overlooked in new molecule design due to the difficulty in calculation and visualization of meaningful potentials. We have previously shown how electrostatics can be used effectively for scaffold hopping, virtual screening, ligand alignment and SAR interpretation. In this poster we will focus on ligand and protein electrostatics. We will show how considering the changes in ligand electrostatics improves the outcome for new molecule design. Going beyond traditional H-bonding based pharmacophore descriptors enables designers to map the effect of molecular changes on the full electrostatic potential of their molecules. Full exploitation of aromatic dipole moments, C-H hydrogen bonding, halogen bonds, and pi-pi interactions is only possible by understanding the electrostatic basis of these effects. Consideration of the protein electrostatics can inform ligand design to generate complementary patterns of electron rich and electron poor regions.
Tim Cheeseright, Director of Products, Cresset
The electrostatics of protein active sites can inform ligand design and SAR. However, no calculation of electrostatic potentials in the active site can be complete without also considering whether water molecules are tightly bound and contributing to the potentials and ligand binding. In this poster we will explore the effect of including water molecules shown to be energetically favorable on the electrostatic potential of individual proteins. We will present a new application to enable rapid and accurate calculation of water stability and protein interaction potentials. Combining these analyses with the popular Waterswap technique results in an in-depth knowledge of protein targets and ligand protein binding.
Tim Cheeseright, Director of Products, Cresset
The XED molecular mechanics force field is unique in providing off-atom centered charges that enable studying complex charge distributions in ligands and proteins alike. We have previously described the use of the molecular interaction potentials derived from the XED force field for ligand similarity calculations which have, in turn, enabled virtual screening, scaffold hopping and SAR analysis to be performed using these effective and meaningful descriptors. In this talk we will describe in detail our application of the XED force field to proteins. We will focus on the calculation of protein interaction potentials showing how protein electrostatics provide deep insights into ligand binding that would otherwise be missed. In parallel to the calculation of the protein interaction potentials we describe using XED to minimize protein-ligand complexes and demonstrate the synergy between these methods.
Christopher Woods, University of Bristol
Binding free energy methods allow computational chemists to predict whether or not changes to a ligand increase or decrease its binding affinity to a medicinally important protein. While these methods can reveal whether or not a change to the ligand increases its binding affinity, they provide little information as to how this change affects individual molecular interactions. Such information would be extremely useful, as it could provide feedback to a drug designer that could inspire the next series of ligand modifications. For example, it would be valuable for the free energy calculation to reveal that addition of a hydroxyl group to a ligand strengthens its interaction with an active site aspartate residue, but simultaneously destabilises a water molecule that bridges between it and the protein. This feedback could inspire a drug designer to investigate ligand modifications that combine addition of the hydroxyl group with the addition of moeities that displace the bridging water molecule. We have developed a range of binding free energy methods, based on WaterSwap. These swap-based methods allow calculation of absolute and relative protein-ligand binding free energies using a single simulation over a single λ-coordinate. Use of a single coordinate allows components of the binding free energy (i.e. specific interactions between the ligand and individual active-site residues, or between the ligand and neighbouring water molecules) to be integrated across λ during the simulation. The resulting components are used to colour-code 3D views of the proteinligand system. This allows drug designers to easily visualise the affect of ligand modifications on the interactions between the ligand and individual residues in the protein, and individual water molecules in the binding site. These components are not true free energies. However, what they reveal is chemically intuitive, and provide a level of insight that allows drug designers to suggest modifications that lead to improved binding affinity. The components show cooperative affects, and also reveal how increasing the strength of interaction
Christopher Woods, University of Bristol
The huge expense of developing a new drug can be wasted if natural mutations of amino acid residues in the targetted protein lead to a loss of drug binding affinity. Rational drug design is a continual struggle, with evolution driving mutations that develop emerging drug resistance into widespread drug inefficacy. We have developed a new free energy method, based on WaterSwap, that can provide drug designers with the insight needed to understand how protein mutations affect drug binding. This method allows the change in binding free energy of the drug associated with the mutation of the protein to be predicted. In addition, as for other Swap-Based methods, this free energy change can be decomposed into components that can be used for visualisation. These components allow the change in binding free energy to be understood in terms of changes in specific ligand-protein interactions, or changes in the solvating water network in the active site. This method allows drug designers to pro-actively screen a new drug computationally against a range of likely protein mutants, thereby enabling the drug designer to get one step ahead of nature. Alternatively, it allows drug designers to investigate the molecular basis for reduced binding affinity in known drug-resistant mutants of a protein. This information would be useful for the development of the subsequent generations of the drug.
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