Outliers in SAR and QSAR: 2. Is a flexible binding site a possible source of outliers?

Abstract

Structure-activity relationship (SAR) and/or quantitative structure-activity relationship (QSAR) studies play an important role in a lead optimization of drug discovery research. When there is a lack of ligand-bound protein structural information, one of the assumptions in SAR and QSAR studies is that similar analogs bind to the same binding site in a similar binding mode. In such studies, outliers have often been observed, especially in QSAR. However, most of these studies have focused their attention on the development of QSAR and left outliers unattended. We searched ligand-bound X-ray crystal structures from the protein structure database to find evidences that could indicate a possible source of outliers in SAR or QSAR. Our results showed the possibility of conformational changes in a flexible binding site as one possible source of outliers.

Computational Methods in Drug Discovery

“…This collection has provided not only access to models for novel applications, but allows the analysis of QSAR models to identify challenges for the field. Kim (2007) examined the C-QSAR data base for outlier patterns, i.e., compounds that showed poor prediction when the average prediction for the model was good. They found that of over 47 QSAR models examined, the number of compounds scoring as outliers ranged from 3 to 36%.…”

“…They found that of over 47 QSAR models examined, the number of compounds scoring as outliers ranged from 3 to 36%. Twenty-six of the 47 datasets showed 20% or more compound outliers (Kim, 2007). They presented several theories as to why QSAR models are so sensitive to the generation of outliers.…”

“…These different binding modes/sites may reflect different structure-activity relationships for molecules within a given dataset. In other words, analogous compounds that do not share the same binding mode can present difficulties in the classifications of ligands (Kim, 2007). Hristozov et al (2007) analyzed the performance of different descriptors across a range of benchmarking datasets and found that the performance of a particular descriptor was often dependent on the activity class.…”

Perspective: Alchemical free energy calculations for drug discovery

“…19,70,89 In cases where the ligand binding mode is maintained as functional groups are modified, conventional relative free energy calculations may often work well without any special treatment of alternate potential binding modes. However, small modifications to ligands do on occasion yield big differences in ligand binding orientation, 65,88,[90][91][92][93][94][95][96][97] and there is currently no way to know when this will happen. For example, Stout et al developed a series of thymidylate synthase (TS) inhibitors based on phenolphthalein and phthalein derivatives.…”

In silico ligand based design of indolylpiperidinyl derivatives as novel histamine H1 receptor antagonists

“…There may be a lack of certain descriptors or parameters to describe QSAR for entire compounds. A different mechanism mode may even be a reason (21). Table 3.…”