Molecular Discovery Grid v22.0.3c
Molecular Discovery Grid v22.0.3c | 17.20 Mb
Programme GRID is a computational procedure for determining energetically favourable binding sites on molecules of known structure. It may be used to study individual molecules such as drugs, molecular arrays such as membranes or crystals, and macromolecules such as proteins, nucleic acids, glycoproteins or polysaccharides. Several different molecules can be processed one after the other.
The best-known application of GRID in Structure-Based Drug Design [ Nature 363, 418-423 (1993) ] shows the potentiality of the approach. Potent inhibitors based on the crystal structure of influence virus sialidase were designed, leading to the recently approved drug RELENZA® from Glaxo.
Moreover GRID can be used to understand the structural differences related to enzyme selectivity, a fundamental field in the rational design of drugs [ J.Med.Chem. 43, 3033-3044 (2000) ].
GRID maps can also be used as descriptors input in statistical procedures like CoMFA, GOLPE or SIMCA for QSAR or 3D-QSAR analyses [ J.Med.Chem. 40, 4089-4102 (1997) ]. Successful applications of GRID are reported in the field ADME and metabolism through VolSurf program and MetaSite program.GRID may be used after a novel ligand has been designed and fitted to its receptor. The GRID map is then searched for places at which water molecules have NOT been displaced by the ligand from the site. These remaining waters should all be making appropriate hydrogen-bonding contacts to the atoms of the ligand, or to the receptor, or to neighbouring water molecules.
However, it often happens that water molecules could be trapped in hydrophobic regions between the ligand and receptor molecules, at places where they cannot make appropriate hydrogen bonds. It is not easy to detect this possibility without using GRID. These trapped waters are unfavourable and tend to destabilise ligand binding. The design of the ligand molecule should therefore be modified, so that the unfavourably trapped water molecules will be displaced when the new modified ligand binds.
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