Atomic interactions and profile of small molecules disrupting protein-protein interfaces: the TIMBAL database.
Growing evidence of the possibility of modulating protein-protein interactions with small molecules is opening the door to new approaches and concepts in drug discovery. In this paper, we describe the creation of TIMBAL, a hand-curated database holding an up to date collection of small molecules inhibiting multi-protein complexes. This database has been analysed and profiled in terms of molecular properties. Protein-protein modulators tend to be large lipophilic molecules with few hydrogen bond features. An analysis of TIMBAL's intersection with other structural databases, including CREDO (protein-small molecule from the PDB) and PICCOLO (protein-protein from the PDB) reveals that TIMBAL molecules tend to form mainly hydrophobic interactions with only a few hydrogen bonding contacts. With respect to potency, TIMBAL molecules are slightly less efficient than an average medicinal chemistry hit or lead. The database provides a resource that will allow further insights into the types of molecules favoured by protein interfaces and provide a background to continuing work in this area. Access at http://www-cryst.bioc.cam.ac.uk/timbal.
Higueruelo
Alícia P
AP
Department of Biochemistry, University of Cambridge, UK. alicia@cryst.bioc.cam.ac.uk
Schreyer
Adrian
A
Bickerton
G Richard J
GR
Pitt
Will R
WR
Groom
Colin R
CR
Blundell
Tom L
TL
D030562:Databases, Protein; D015195:Drug Design; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry*
D011506:Proteins