Accurate Reproduction of 161 Small-Molecule Complex Crystal Structures using the EUDOC Program: Expanding the Use of EUDOC to Supramolecular Chemistry

Qi Wang,Yuan-Ping Pang,Mark Isalan

doi:10.1371/journal.pone.0000531

Abstract

EUDOC is a docking program that has successfully predicted small-molecule-bound protein complexes and identified drug leads from chemical databases. To expand the application of the EUDOC program to supramolecular chemistry, we tested its ability to reproduce crystal structures of small-molecule complexes. Of 161 selected crystal structures of small-molecule guest-host complexes, EUDOC reproduced all these crystal structures with guest structure mass-weighted root mean square deviations (mwRMSDs) of <1.0 Å relative to the corresponding crystal structures. In addition, the average interaction energy of these 161 guest-host complexes (−50.1 kcal/mol) was found to be nearly half of that of 153 previously tested small-molecule-bound protein complexes (−108.5 kcal/mol), according to the interaction energies calculated by EUDOC. 31 of the 161 complexes could not be reproduced with mwRMSDs of <1.0 Å if neighboring hosts in the crystal structure of a guest-host complex were not included as part of the multimeric host system, whereas two of the 161 complexes could not be reproduced with mwRMSDs of <1.0 Å if water molecules were excluded from the host system. These results demonstrate the significant influence of crystal packing on small molecule complexation and suggest that EUDOC is able to predict small-molecule complexes and that it is useful for the design of new materials, molecular sensors, and multimeric inhibitors of protein-protein interactions.

Highlights

In 1990, a computer was used to screen 10,000 chemicals in the Cambridge Structural Database (CSD) [1], leading to the identification of a haloperidol analog capable of inhibiting HIV1 and HIV-2 proteases with a Ki of
Because the uncertainty in calculating the interaction energy using the EUDOC program was estimated to be 0.7 kcal/mol [3], occasionally, a few EUDOC-generated complexes were considered to have the strongest interaction energy and compared to the crystal structure resulting in multiple mass-weighted root mean square deviations (mwRMSDs), if their interaction energies differed from the strongest interaction energy by #0.7 kcal/mol
This study shows that 31 (19%) of the 161 complexes could not be accurately reproduced with mwRMSDs of,1.0 Aby the EUDOC program if neighboring host(s) and/or guest(s) in the crystal structure were not included as part of the multimeric host system, whereas only 2 (1%) of these complexes could not be accurately reproduced with mwRMSDs of,1.0 Aif neighboring structures were included but water molecules were excluded from the host system

Summary

Introduction

In 1990, a computer was used to screen 10,000 chemicals in the Cambridge Structural Database (CSD) [1], leading to the identification of a haloperidol analog capable of inhibiting HIV1 and HIV-2 proteases with a Ki of

Methods

Results

Conclusion