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

Ye Hu,Jürgen Bajorath,Bijun Zhang,Antonio De La Vega De León

doi:10.12688/f1000research.3-36.v1

Abstract

Matched molecular pairs (MMPs) are widely used in medicinal chemistry to study changes in compound properties including biological activity, which are associated with well-defined structural modifications. Herein we describe up-to-date versions of three MMP-based data sets that have originated from in-house research projects. These data sets include activity cliffs, structure-activity relationship (SAR) transfer series, and second generation MMPs based upon retrosynthetic rules. The data sets have in common that they have been derived from compounds included in the latest release of the ChEMBL database for which high-confidence activity data are available. Thus, the activity data associated with MMP-based activity cliffs, SAR transfer series, and retrosynthetic MMPs cover the entire spectrum of current pharmaceutical targets. Our data sets are made freely available to the scientific community.

Highlights

The matched molecular pair (MMP) concept is widely applied in medicinal chemistry[1,2,3,4]
As a follow-up on the original publications in which MMP-cliffs[12], structure-activity relationship (SAR) transfer series[14], and retrosynthetic combinatorial analysis procedure (RECAP)-MMPs16 were introduced, all corresponding data sets have been re-generated on the basis of ChEMBL release 17, providing up-to-date versions for release
MMP-cliffs Figure 1 illustrates small chemical changes in compound pairs leading to large potency differences that are captured by MMPcliffs

Summary

Introduction

The matched molecular pair (MMP) concept is widely applied in medicinal chemistry[1,2,3,4]. MMPs are attractive tools for computational analysis because they can be algorithmically generated and they make it possible to associate defined structural modifications at the level of compound pairs with chemical property changes, including biological activity[2,3,4]. Hu et al have compiled a useful set of matched pair datasets based on the CHEMBL database of biological activity. As a result of switching the method for generating MMPs from cleavage of single bonds to a RECAP-based method, the pool of MMPs includes substitutions of internal fragments (e.g. in Figure 3c) as well as substitution of a terminal R-group (as in Figure 3 examples a, b, and d) Both types of MMPs involve replacement of a single structural fragment, it may be desirable for many applications to distinguish between core scaffold replacement and R-group variation.

Methods

Results

Conclusion