Toward similarity measures for macromolecular bodies: Medla test calculations for substituted benzene systems

Abstract

AbstractA new method is proposed for the evaluation of numerical similarity measures for large molecules, defined in terms of their electron density (ED) distributions. The technique is based on the Molecular Electron Density Lego Assembler (MEDLA) approach, proposed earlier for the generation of ab initio quality electron densities for proteins and other macromolecules. The reliability of the approach is tested using a family of 13 substituted aromatic systems for which both standard ab initio electron density computations and the MEDLA technique are applicable. These tests also provide additional examples for evaluating the accuracy of the MEDLA technique. Electron densities for a series of 13 substituted benzenes were calculated using the standard ab initio method with STO‐3G, 3‐21G, and 6‐31G** basis sets as well as the MEDLA approach with a 6‐31G** database of electron density fragments. For each type of calculation, pairwise similarity measures of these compounds were calculated using a point‐by‐point numerical comparison of the EDs. From these results, 2D similarity maps were constructed, serving as an aid for quick visual comparisons for the entire molecular family. The MEDLA approach is shown to give virtually equivalent numerical similarity measures and similarity maps as the standard ab initio method using a 6‐31G** basis set. By contrast, significant differences are found between the standard ab initio 6‐31G** results and the standard ab initio results obtained with smaller STO‐3G and 3‐21G basis sets. These tests indicate that the MEDLA‐based similarity measures faithfully mimic the actual, standard ab initio 6‐31G** similarity measures, suggesting the MEDLA method as a reliable technique to assess the shape similarities of proteins and other macromolecules. The speed of the MEDLA computations allows rapid, pairwise comparisons of the actual EDs for a series of molecules, requiring no more computer time than other simplified, less detailed representations of molecular shape. The MEDLA method also reduces the need to store large volumes of numerical density data on disk, as these densities can be quickly recomputed when needed. For these reasons, the proposed MEDLA similarity analysis technique is likely to become a useful tool in computational drug design. © 1995 John Wiley & Sons, Inc.