TY - JOUR
T1 - Analyzing multitarget activity landscapes using protein-ligand interaction fingerprints
T2 - Interaction cliffs
AU - Méndez-Lucio, Oscar
AU - Kooistra, Albert J.
AU - Graaf, Chris De
AU - Bender, Andreas
AU - Medina-Franco, José L.
PY - 2015/2/23
Y1 - 2015/2/23
N2 - Activity landscape modeling is mostly a descriptive technique that allows rationalizing continuous and discontinuous SARs. Nevertheless, the interpretation of some landscape features, especially of activity cliffs, is not straightforward. As the nature of activity cliffs depends on the ligand and the target, information regarding both should be included in the analysis. A specific way to include this information is using protein-ligand interaction fingerprints (IFPs). In this paper we report the activity landscape modeling of 507 ligand-kinase complexes (from the KLIFS database) including IFP, which facilitates the analysis and interpretation of activity cliffs. Here we introduce the structure-activity-interaction similarity (SAIS) maps that incorporate information on ligand-target contact similarity. We also introduce the concept of interaction cliffs defined as ligand-target complexes with high structural and interaction similarity but have a large potency difference of the ligands. Moreover, the information retrieved regarding the specific interaction allowed the identification of activity cliff hot spots, which help to rationalize activity cliffs from the target point of view. In general, the information provided by IFPs provides a structure-based understanding of some activity landscape features. This paper shows examples of analyses that can be carried out when IFPs are added to the activity landscape model.
AB - Activity landscape modeling is mostly a descriptive technique that allows rationalizing continuous and discontinuous SARs. Nevertheless, the interpretation of some landscape features, especially of activity cliffs, is not straightforward. As the nature of activity cliffs depends on the ligand and the target, information regarding both should be included in the analysis. A specific way to include this information is using protein-ligand interaction fingerprints (IFPs). In this paper we report the activity landscape modeling of 507 ligand-kinase complexes (from the KLIFS database) including IFP, which facilitates the analysis and interpretation of activity cliffs. Here we introduce the structure-activity-interaction similarity (SAIS) maps that incorporate information on ligand-target contact similarity. We also introduce the concept of interaction cliffs defined as ligand-target complexes with high structural and interaction similarity but have a large potency difference of the ligands. Moreover, the information retrieved regarding the specific interaction allowed the identification of activity cliff hot spots, which help to rationalize activity cliffs from the target point of view. In general, the information provided by IFPs provides a structure-based understanding of some activity landscape features. This paper shows examples of analyses that can be carried out when IFPs are added to the activity landscape model.
UR - http://www.scopus.com/inward/record.url?scp=84923342620&partnerID=8YFLogxK
U2 - 10.1021/ci500721x
DO - 10.1021/ci500721x
M3 - Journal article
C2 - 25615841
AN - SCOPUS:84923342620
SN - 1549-9596
VL - 55
SP - 251
EP - 262
JO - Journal of Chemical Information and Modeling
JF - Journal of Chemical Information and Modeling
IS - 2
ER -