pharmACOphore: Multiple Flexible Ligand Alignment Based on Ant Colony Optimization

Abstract

The flexible superimposition of biologically active ligands is a crucial step in ligand-based drug design. Here we present pharmACOphore, a new approach for pairwise as well as multiple flexible alignment of ligands based on ant colony optimization (ACO; Dorigo M. Stützle T. Dorigo M. Stützle T. Ant Colony OptimizationMIT PressCambridge, MA, USA2004). An empirical scoring function is used, which describes ligand similarity by minimizing the distance of pharmacophoric features. The scoring function was parametrized on pairwise alignments of ligand sets for four proteins from diverse protein families (cyclooxygenase-2, cyclin-dependent kinase 2, factor Xa and peroxisome proliferator-activated receptor γ). The derived parameters were assessed with respect to pose prediction performance on the independent FlexS data set ( Lemmen C. Lengauer T. Klebe G. Lemmen C. Lengauer T. Klebe G. J. Med. Chem.) in exhausting pairwise alignments. Additionally, multiple flexible alignment experiments were carried out for the pharmacologically relevant targets trypsin and poly (ADP-ribose) polymerase (PARP). The results obtained show that the new procedure provides a robust and efficient way for the pairwise as well as multiple flexible alignment of small molecules.

A combinatorial TIR1/AFB–Aux/IAA co-receptor system for differential sensing of auxin

“…The best docking poses were selected by conformational clustering analysis and the binding score. The refined AFB5 structure and the TIR1 structure (after 3D-protonated with MOE 49 ) were taken for docking of IAA and picloram as ligands using PLANTS with the ChemPLP scoring function and the Lennard Jones potential for intra ligand energy calculations 50 . For each ligand and protein, 30 docking poses were calculated from which the most favored (lowest docking scores) were compared (Supplementary Fig.…”

Reliability analysis and optimization of the consensus docking approach for the development of virtual screening studies

“…This docking software uses Ant Colony Optimization, a state-ofthe-art global optimization algorithm to find minima of a scoring function representing favorable complex structures 62 . ChemPLP scoring function was employed to score protein-ligand interactions as well as intra-ligand clash terms.…”

Nanodiscs for INPHARMA NMR Characterization of GPCRs: Ligand Binding to the Human A2A Adenosine Receptor

“…This finding is in line with the plasticity of the receptor mentioned above. To allow this adaptation for ligands without available X-ray structures for complexes of A 2A R, such as with SYN and PQA, multiple possible ligand poses were predicted using a docking [11] as well as a pharmacophore approach, [12] based on the existing crystal structures of ZMA, XAC, and CAF with A 2A R (PDB IDs: 4EIY, 3REY, and 3RFM, respectively). These were visually inspected, which led to a total of three poses for PQA (Figure 3).…”