De novo ligand design to an ensemble of protein structures

• Published in: Proteins, structure, function, and bioinformatics Vol. 64; no. 1; pp. 43 - 59
• Main Authors: Todorov, N.P., Buenemann, C.L., Alberts, I.L.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.07.2006
• Subjects: Binding Sites; Computer Simulation; Drug Design; free energy; HIV Protease - chemistry; HIV Protease - metabolism; HIV-1 - enzymology; homology models; Human immunodeficiency virus; Ligands; Matrix Metalloproteinase 1 - chemistry; Matrix Metalloproteinase 1 - metabolism; Models, Theoretical; molecular design; Protein Conformation; protein-ligand interaction; Proteins - chemistry; Proteins - metabolism; structure generation; X-Ray Diffraction
• ISSN: 0887-3585; 1097-0134
• DOI: 10.1002/prot.20928

We describe a combinatorial method for de novo ligand design to an ensemble of receptor structures. Receptor conformations, protonation states, and structural water molecules are considered consistently within the framework of de novo ligand design. The method relies on Monte Carlo optimization to search the space of ligand structures, conformations, and rigid‐body movements as well as receptor models. The method is applied to an ensemble of HIV protease and human collagenase receptor models. Ligand structures generated de novo exhibit the correct hydrogen‐bonding pattern in the core of the active site, with hydrophobic groups extending into the receptor S1 and S1′ pocket space. Furthermore, it is shown that known ligands are recovered in the correct binding mode and in the native, most tightly binding receptor model. Proteins 2006. © 2006 Wiley‐Liss, Inc.