Matched molecular pair-based data sets for computer-aided medicinal chemistry

Concepts

(1) Activity cliffs are generally defined as pairs or groups of compounds that are structurally similar and have large differences in potency^9–11. Accordingly, activity cliffs usually have high SAR information content (because small chemical changes in similar or analogous compounds lead to large potency effects). The assessment of activity cliffs requires clearly defined similarity and potency difference criteria^9–11. The formation of an MMP can be considered as a similarity criterion, which is similarity metric-free and often chemically more intuitive than the use of calculated molecular similarity^11,12. MMP formation as a similarity criterion has led to the introduction of MMP-cliffs¹². For MMP-cliffs, a difference in potency of at least two orders of magnitude between cliff-forming compounds was set as a potency difference criterion¹². Figure 1 shows exemplary MMP-cliffs.

Figure 1. MMP-cliffs.

Six representative MMP-cliffs for three targets belonging to different target families are shown; (a) muscarinic acetylcholine receptor M3, (b) serine/threonine-protein kinase c-TAK1, (c) matrix metalloproteinase-2. The pK_i value of each compound is provided and the structural differences between cliff-forming compounds are highlighted in red.

(2) SAR transfer can be rationalized in different ways. For example, a compound series might display similar potency progression against two different targets¹³. Alternatively, two different compound series with corresponding analogs, i.e., series having different core structures and containing compounds with pairwise corresponding substitutions, might display similar potency progression against a given target¹⁴. Such SAR transfer series displaying similar target-specific SAR behavior are often sought after in medicinal chemistry as alternative compounds for optimization. Here we focus on these target-based SAR transfer series. Figure 2 shows an example.

Figure 2. SAR transfer series.

An exemplary target-based SAR transfer series is shown. Compound pairs are arranged in the order of increasing potency (from the bottom to the top). Potency progression is monitored by corresponding pairs of color-coded dots using a continuous color spectrum from green (lowest potency value (pK_i = 5.7) in the compound data set), over yellow to red (highest potency value; pK_i = 9.0). The pK_i value of each compound is provided. The core structures are drawn in black and the substituents in red. The compounds are active against serine/threonine-protein kinase D2.

(3) Computational generation of MMPs typically involves molecular fragmentation through the systematic deletion of exocyclic single bonds⁵. Hence, the resulting fragments representing a molecular core and substituent are not derived considering chemical reactions. Accordingly, a transformation relating MMP-forming compounds to each other might not necessarily be interpretable from a synthetic perspective. Hence synthetic accessibility of MMPs might be further improved by considering the reaction information during molecular fragmentation. This has been accomplished by applying the well-known retrosynthetic combinatorial analysis procedure (RECAP) rules¹⁵, leading to the introduction of RECAP-MMPs¹⁶. Representative examples are shown in Figure 3. In addition, examplary differences between standard MMPs and RECAP-MMPs are illustrated in Figure 4.

Figure 3. RECAP-MMPs.

In (a)–(d), four exemplary RECAP-MMPs representing different retrosynthetic rules are shown. For each RECAP-MMP, the chemical transformation is highlighted in red.

Figure 4. Standard MMPs vs. RECAP-MMPs.

Two pairs of compounds that form both standard MMPs and RECAP-MMPs are shown. For each pair, the structural differences between compounds are highlighted. The chemical transformation associated with the standard MMP is colored in red, while the transformation of the RECAP-MMP corresponds to the combination of fragments colored in red and blue.

MMP generation

For the generation of MMP-cliffs, SAR transfer series, and RECAP-MMPs, transformation size restrictions that limit transformations to meaningful chemical substitutions were introduced¹². Specifically, the common core structure had to be at least twice the size of each exchanged substructure. Furthermore, the difference in size of the exchanged fragments was limited to at most eight non-hydrogen atoms and the maximal size of an exchanged fragment was set to 13 non-hydrogen atoms¹². Therefore, the largest permitted transformations included, for example, the addition of a substituted ring to a compound or the replacement of a five- or six-membered ring with a substituted condensed two-ring system (with a maximum of 13 atoms). All possible transformation size-restricted MMPs and RECAP-MMPs were calculated using an in-house implementation of the algorithm by Hussain and Rea⁵ that utilizes the OpenEye toolkit¹⁷.

Compounds and activity data

Compound data were taken from the latest version of ChEMBL (release 17)^7,8. Only compounds with direct interactions (i.e., target relationship type “D”) against human targets at the highest confidence level (target confidence score 9) were selected. Two types of potency measurements were separately considered, i.e., K_i (equilibrium constant) and IC₅₀ (half-maximal inhibition concentration) values. In order to ensure high data confidence, inactive or inconclusive compounds and compounds with approximate measurements such as “>”, “<”, or “∼” were not considered. For compounds with multiple measurements against the same target, the geometric mean was calculated as the final potency annotation, provided that all values fell within one order of magnitude; otherwise, the compound was discarded. All qualifying compounds were further organized into target sets. A total of 661 and 1203 target sets (consisting of compounds with reported specific activity against a given target) were collected for the K_i- and IC₅₀-based subsets, respectively, as reported in Table 1. The target sets contained a total of 45,353 and 95,685 compounds and 77,421 and 135,291 potency measurements for the K_i and IC₅₀ subsets, respectively. These target sets provided the basis for the generation of all MMPs.

MMP-cliffs

Figure 1 illustrates small chemical changes in compound pairs leading to large potency differences that are captured by MMP-cliffs. For ease of structural interpretation, we currently prefer MMP-based activity cliff representations compared to alternative representations that rely on calculated similarity values¹¹. Table 2 provides the MMP-cliff statistics for the current data set. On the basis of K_i and IC₅₀ measurements, more than 20,000 and 25,000 MMP-cliffs were obtained, respectively, requiring an at least 100-fold difference in potency between cliff-forming compounds. The MMP-cliffs corresponded to ~5% of all MMPs that were generated from ChEMBL compounds with high-confidence activity data. They covered 293 and 500 different targets on the basis of K_i and IC₅₀ measurements, respectively. In addition to the more conservative potency difference cutoff, MMP-cliffs were also identified when a less stringent criterion was applied, i.e., two compounds forming an MMP were required to have a potency difference of at least one order of magnitude. In this case, as reported in Table 2, nearly 99,000 and more than 126,000 MMP-cliffs were detected in 392 and 726 targets for the K_i and IC₅₀ subsets, respectively. The proportion of MMP-cliffs increased to approx. 25%.

SAR transfer series

SAR transfer series are best rationalised as pairs of compound series active against the same target that have distinct core structures, and consist of corresponding pairs of analogs, as illustrated in Figure 2 for a small series with three pairs. Different from the original analysis of target-based SAR transfer¹⁴ that was based upon MMPs without transformation size restrictions, the current analysis has been carried out on the basis of size-restricted MMPs. This modification further supports SAR exploration (because only small chemical changes are considered) and explains a reduction in series numbers compared to the original publication. In Table 3, the numbers of different series available for the current data set are reported. A total of 1270 and 2109 matching series were obtained from the K_i and IC₅₀ subsets, respectively. Matching series met the structural requirement of consisting of at least three pairs of corresponding analogs. In addition, the potency values of compounds associated with individual series had to span at least two orders of magnitude. From these pre-selected matching series, 157 (K_i) and 513 (IC₅₀) SAR transfer series with at least approximate potency progression and activity against 42 and 54 targets, respectively, were obtained. A subset of 60 (K_i) and 322 (IC₅₀) SAR transfer series displayed strictly corresponding (regular) potency progression (often over different potency ranges)¹⁴. These series were active against 23 (K_i) and 27 (IC₅₀) different targets. The size of SAR transfer series with approximate and regular potency progression ranged from three to 12 corresponding pairs of analogs. On average, the SAR transfer series consisted of three to four pairs.

RECAP-MMPs

The replacement of systematic fragmentation of exocyclic single bonds with a set of 13 retrosynthetic rules for MMP generation reduced the number of MMPs that were obtained by more than half. RECAP-MMP numbers are reported in Table 4. However, (perhaps surprisingly) large numbers of RECAP-MMPs remained for further consideration and assessment of synthetic feasibility. From the K_i and IC₅₀ subsets, nearly 170,000 and more than 240,000 RECAP-MMPs were obtained with activity against 371 and 778 targets, respectively. Examples are shown in Figure 3.