Assessing the geometric diversity of cytochrome P450 ligand conformers by hierarchical clustering with a stop criterion.

Jamel Eddine Meslamani (1) , François André (2) , Michel Petitjean (2, 3)

1 LIT - Laboratoire d'Innovation Thérapeutique
2 IBITECS - Institut de Biologie et de Technologies de Saclay
3 SMPSD - Système membranaires, photobiologie, stress et détoxication

An algorithm is presented, which exhibits a computed number of rigid conformers of an input small molecule, covering the geometric diversity in the conformational space, with minimal structural redundancy. The algorithm calls a conformer generator, then performs an agglomerative hierarchical clustering with the modified clustering gain as the stop criterion. The number of classes is computed without an arbitrary parameter. A representative conformer is selected in each class, and nonrepresentative conformers are discarded. For illustration, the algorithm has been applied on a database containing 70 ligands of the cytochrome CYP 3A4, showing that the structural flexibility of each ligand is indeed handled via a small number of its representative conformers. The method is valid for all small molecules.

Domaines: Chimie organique

Jamel Eddine Meslamani, François André, Michel Petitjean. Assessing the geometric diversity of cytochrome P450 ligand conformers by hierarchical clustering with a stop criterion.. Journal of Chemical Information and Modeling, 2009, 49 (2), pp.330-7. ⟨10.1021/ci800275k⟩. ⟨hal-00849250⟩