Goodford describes, in 1985, a method for probing proteins computationally to find putative binding sites. For budding computational chemists this is a must read. For medicinal chemists, the understanding of the techniques and an ability to evaluate the results is highly useful. The method applies a grid over the protein and then probes with ‘spheres’ that represent a small number of chemical groups [NH3+, =O, O-, OH, CH3, H2O]. Using a consideration of the molecular physics, Lennard-Jones potentials and electrostatic interactions were calculated and a model for hydrogen bonding applied for each of these groups, hence the energy of binding is estimated. The paper has several examples of the algorithm probing phospholipase-A2 structures.
We think every methodology paper should start a ‘Discussion’ session with the phrase – “Before assessing the findings, it is necessary to consider the shortcomings of the method.” It is worth reading the paper for this section alone and the detailed self-assessment of the method.
Methods for determining binding sites within proteins is an area of continuous development and exciting for AI drug discovery. The combination of protein folding algorithms, binding pocket determination and directed screening to select small sets of compounds to screen offers a genuine opportunity to reduce the cost and time to drug discovery research.
A computational procedure for determining energetically favorable binding sites on biologically important macromolecules
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