Note: the most recent version of this tutorial can be found here and a short overview slide show here.

1 Introduction

Maximum common substructure (MCS) algorithms rank among the most sensitive and accurate methods for measuring structural similarities among small molecules. This utility is critical for many research areas in drug discovery and chemical genomics. The MCS problem is a graph-based similarity concept that is defined as the largest substructure (sub-graph) shared among two compounds (Wang et al. 2013; Cao, Jiang, and Girke 2008). It fundamentally differs from the structural descriptor-based strategies like fingerprints or structural keys. Another strength of the MCS approach is the identification of the actual MCS that can be mapped back to the source compounds in order to pinpoint the common and unique features in their structures. This output is often more intuitive to interpret and chemically more meaningful than the purely numeric information returned by descriptor-based approaches. Because the MCS problem is NP-complete, an efficient algorithm is essential to minimize the compute time of its extremely complex search process. The fmcsR package implements an efficient backtracking algorithm that introduces a new flexible MCS (FMCS) matching strategy to identify MCSs among compounds containing atom and/or bond mismatches. In contrast to this, other MCS algorithms find only exact MCSs that are perfectly contained in two molecules. The details about the FMCS algorithm are described in the Supplementary Materials Section of the associated publication (Wang et al. 2013). The package provides several utilities to use the FMCS algorithm for pairwise compound comparisons, structure similarity searching and clustering. To maximize performance, the time consuming computational steps of fmcsR are implemented in C++. Integration with the ChemmineR package provides visualization functionalities of MCSs and consistent structure and substructure data handling routines (Cao et al. 2008; Backman, Cao, and Girke 2011). The following gives an overview of the most important functionalities provided by fmcsR.

2 Installation

The R software for running fmcsR and ChemmineR can be downloaded from CRAN (http://cran.at.r-project.org/). The fmcsR package can be installed from an open R session using the BiocManager::install() command.

if (!requireNamespace("BiocManager", quietly=TRUE))
    install.packages("BiocManager")
BiocManager::install("fmcsR")

3 Quick Overview

To demo the main functionality of the fmcsR package, one can load its sample data stored as SDFset object. The generic plot function can be used to visualize the corresponding structures.

library(fmcsR) 
data(fmcstest)
plot(fmcstest[1:3], print=FALSE)

The fmcs function computes the MCS/FMCS shared among two compounds, which can be highlighted in their structure with the plotMCS function.

test <- fmcs(fmcstest[1], fmcstest[2], au=2, bu=1) 
plotMCS(test,regenCoords=TRUE)

4 Documentation

library("fmcsR") # Loads the package 
library(help="fmcsR") # Lists functions/classes provided by fmcsR 
library(help="ChemmineR") # Lists functions/classes from ChemmineR 
vignette("fmcsR") # Opens this PDF manual 
vignette("ChemmineR") # Opens ChemmineR PDF manual

The help documents for the different functions and container classes can be accessed with the standard R help syntax.

?fmcs 
?"MCS-class" 
?"SDFset-class"

5 MCS of Two Compounds

5.1 Data Import

The following loads the sample data set provided by the fmcsR package. It contains the SD file (SDF) of 3 molecules stored in an SDFset object.

data(fmcstest) 
sdfset <- fmcstest
sdfset 
## An instance of "SDFset" with 3 molecules

Custom compound data sets can be imported and exported with the read.SDFset and write.SDF functions, respectively. The following demonstrates this by exporting the sdfset object to a file named sdfset.sdf. The latter is then reimported into R with the read.SDFset function.

write.SDF(sdfset, file="sdfset.sdf") 
mysdf <- read.SDFset(file="sdfset.sdf")

5.2 Compute MCS

The fmcs function accepts as input two molecules provided as SDF or SDFset objects. Its output is an S4 object of class MCS. The default printing behavior summarizes the MCS result by providing the number of MCSs it found, the total number of atoms in the query compound \(a\), the total number of atoms in the target compound \(b\), the number of atoms in their MCS \(c\) and the corresponding Tanimoto Coefficient. The latter is a widely used similarity measure that is defined here as \(c/(a+b-c)\). In addition, the Overlap Coefficient is provided, which is defined as \(c/min(a,b)\). This coefficient is often useful for detecting similarities among compounds with large size differences.

mcsa <- fmcs(sdfset[[1]], sdfset[[2]]) 
mcsa 
## An instance of "MCS" 
##  Number of MCSs: 7 
##  CMP1: 14 atoms 
##  CMP2: 33 atoms 
##  MCS: 8 atoms 
##  Tanimoto Coefficient: 0.20513 
##  Overlap Coefficient: 0.57143
mcsb <- fmcs(sdfset[[1]], sdfset[[3]]) 
mcsb 
## An instance of "MCS" 
##  Number of MCSs: 1 
##  CMP1: 14 atoms 
##  CMP2: 25 atoms 
##  MCS: 14 atoms 
##  Tanimoto Coefficient: 0.56 
##  Overlap Coefficient: 1

If fmcs is run with fast=TRUE then it returns the numeric summary information in a named vector.

fmcs(sdfset[1], sdfset[2], fast=TRUE)
##           Query_Size          Target_Size             MCS_Size Tanimoto_Coefficient 
##           14.0000000           33.0000000            8.0000000            0.2051282 
##  Overlap_Coefficient 
##            0.5714286

5.3 Class Usage

The MCS class contains three components named stats, mcs1 and mcs2. The stats slot stores the numeric summary information, while the structural MCS information for the query and target structures is stored in the mcs1 and mcs2 slots, respectively. The latter two slots each contain a list with two subcomponents: the original query/target structures as SDFset objects as well as one or more numeric index vector(s) specifying the MCS information in form of the row positions in the atom block of the corresponding SDFset. A call to fmcs will often return several index vectors. In those cases the algorithm has identified alternative MCSs of equal size.

slotNames(mcsa) 
## [1] "stats" "mcs1"  "mcs2"

Accessor methods are provided to return the different data components of the MCS class.

stats(mcsa) # or mcsa[["stats"]] 
##           Query_Size          Target_Size             MCS_Size Tanimoto_Coefficient 
##           14.0000000           33.0000000            8.0000000            0.2051282 
##  Overlap_Coefficient 
##            0.5714286
mcsa1 <- mcs1(mcsa) # or mcsa[["mcs1"]] 
mcsa2 <- mcs2(mcsa) # or mcsa[["mcs2"]] 
mcsa1[1] # returns SDFset component
## $query
## An instance of "SDFset" with 1 molecules
mcsa1[[2]][1:2] # return first two index vectors 
## $CMP1_fmcs_1
## [1]  3  8  7  4  9  5 11  1
## 
## $CMP1_fmcs_2
## [1]  3  8  7  4  9  5  1 13

The mcs2sdfset function can be used to return the substructures stored in an MCS instance as SDFset object. If type='new' new atom numbers will be assigned to the subsetted SDF, while type='old' will maintain the atom numbers from its source. For details consult the help documents ?mcs2sdfset and ?atomsubset.

mcstosdfset <- mcs2sdfset(mcsa, type="new")
plot(mcstosdfset[[1]], print=FALSE)