REMOTEDISC Distance Geometry Method

As noted above, distance geometry represents molecules in terms of interatomic distances rather than Cartesian coordinates. - Because distances between atoms do not change with rotation and translation of the whole molecule, the analysis of distance matrices can detect if and how certain atoms of two or more molecules overlap without performing a superposition. Several variants of distance geometry have been used in 3D-QSAR. We will cover only the latest, REMOTEDISC (receptor modeling from three-dimensional structure and physicochemical properties of the ligand molecules). - In contrast to MSA and MTD, this method is quite CPU intensive, partly because many of the decisions are made computationally rather than by the user. 

Assignment of Physicochemical Properties to Ligand Atoms to Calculate Biological Activity REMOTEDISC computes the biological activity as in Eq. [7].  

Embodied in Eq. [7] are two key assumptions. First, the interaction energy between a ligand and receptor can be partitioned into the individual interaction energies between an atom or a group of atoms of the molecule with the complementary receptor atoms. Second, as in Eq. [5] for explicit receptor binding site models, the lower the internal energy of the molecule required to attain the receptor-bound conformation, the higher will be the potency. 

This step considers, one at a time, several conformations of the most potent compounds as candidates to serve as the reference struaure. Conformations are tested as the reference according to the priority score P calculated from Eq. [8]  

The trial reference structure is used to superimpose all conformations of the remaining compounds. The atom-centered parameters can be used to compute molecular similarity indices to aid in selecting the best alignment. - Alternatively, several superposition modes might be tried until a solution with acceptable statistics is found. 

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A distance geometry approach using a three-dimensional structure-directed QSAR method (REMOTEDISC)was employed to analyze the inhibition of [ H]diazepam binding by 29 benzodiazepines (115). The results of the method, which uses three-dimensional structure, conformational energies, and atom-based physiochemical properties to model the receptor binding cavity were based on Equation 5.12. 

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