Chem Biol Drug Des 2006; 67: 5–12
Journal compilation ª 2005 Blackwell Munksgaard
Perspective
Structural Interaction Fingerprints: A New
Approach to Organizing, Mining, Analyzing, and
Designing Protein–Small Molecule Complexes
Juswinder Singh*, Zhan Deng, Gaurav
Narale and Claudio Chuaqui
Computational Drug Design Group, Department of Research
Informatics, Biogen Idec, 12 Cambridge Center, Cambridge, MA
02142, USA
*Corresponding author: Juswinder Singh, singhjus@yahoo.com
The combination of advances in structure-based
drug design efforts in the pharmaceutical industry
in parallel with structural genomics initiatives in
the public domain has led to an explosion in the
number of structures of protein–small molecule
complexes structures. This information has critical
importance to both the understanding of the
structural basis for molecular recognition in biolo-
gical systems and the design of better drugs. A
significant challenge exists in managing this vast
amount of data and fully leveraging it. Here, we
review our work to develop a simple, fast way to
store, organize, mine, and analyze large numbers
of protein–small molecule complexes. We illustrate
the utility of the approach to the management of
inhibitor complexes from the protein kinase fam-
ily. Finally, we describe our recent efforts in apply-
ing this method to the design of target-focused
chemical libraries.
Received 25 October 2005
The past decade has witnessed a dramatic increase in the number of
protein–small molecule complex structures from experimental as well
as in silico approaches. Over 5000 small molecule complexes have
been deposited in public databases [1], and it is likely that a much
greater number have been determined within the pharmaceutical
industry. With significant progress in structural genomics initiatives
[2] and advances of high-throughput crystallography [3] and high-
throughput NMR technology [4], the total number of structures will
grow at an even greater speed. In parallel to the growth of experi-
mentally determined structures, a wealth of in silico structural infor-
mation is also being generated from virtual screening efforts. The
ability to fully leverage this experimental and in silico information
hinges on the ability to organize, analyze, and mine the structural
data to both derive insights into molecular recognition in biological
systems as well as facilitate the design of novel therapeutics.
Several approaches exist for analyzing the interactions of protein–
small molecule complexes. For example, LIGPLOT generates two-
dimensional (2D) schematics of protein–small molecule complexes
ª 2005 The Authors
doi: 10.1111/j.1747-0285.2005.00323.x
that describe the intermolecular interactions including the strengths
of hydrogen bonds and hydrophobic interactions [5]. In addition to
2D approaches, a variety of sophisticated computer graphics pro-
grams such as InsightII (Accelrys Inc., Burlington, MA, USA), VIDA
(Open Eye, Cambridge, MA, USA), Sybyl (Tripos Inc., St Louis, MO,
USA), and Maestro (Schrodinger Inc., New York, NY, USA) are avail-
able for analyzing the 3D structure of proteins and their complexes
[6]. Although these 2D and 3D approaches are useful when examin-
ing small numbers of structures, the analysis of large datasets is
not feasible. In addition to visual analysis of complexes, it is also
common to use energy-based methods to evaluate how favorable
the binding interactions are between a protein and a small mole-
cule complex. These scoring methods are commonly used to rank
and filter large datasets of virtual screening results [7]. Recent
studies have demonstrated that docking algorithms and the underly-
ing energy-scoring functions are usually able to recapitulate the
crystallographically observed binding modes from the set of gener-
ated ligand poses. However, these same scoring functions are poor
at identifying the correct binding mode from incorrect ones, leading
to a large number of high-scoring false positives that result in
lower enrichment rates for virtual screening [8].
We review our published work to develop a simple and robust
approach for representing and analyzing 3D protein–ligand com-
plexes called SIFt [9, 10]. We will show how this method can be
applied to visualizing, organizing, analyzing, and mining of protein–
inhibitor complexes. To illustrate the utility of the approach, we
apply it to the analysis of the protein kinase family as its family
members are attractive targets for drug design and there exist over
93 complexes in the public databanks. Finally, we will describe
recent work showing how the method can be applied to focusing
large chemical libraries to drug targets.
Materials and Methods
What is a SIFt fingerprint?
SIFt stands for Structural Interaction Fingerprint, which is a 1D binary fingerprint repre-
sentation of the intermolecular interactions in a 3D protein–inhibitor complex [9, 10].
The fingerprint representation of the interaction patterns is compact, and allows for
rapid clustering and analysis of large numbers of complexes.
The SIFt methodology has been described in detail previously [9, 10]. The SIFt is calcu-
lated on a set of input 3D protein–small molecule complexes. The protein structure
may have been determined experimentally by NMR or crystallography, or generated
through homology modeling. The small molecule structure may also have been deter-
mined experimentally or through in silco molecular modeling studies. The SIFt is gener-
ated by first defining the union of those residues that are in contact between the
protein and the small molecule complex. The resulting panel of ligand binding site
5
Singh et al.

A B

Figure 1: The procedure used in the generation of the SIFt fingerprint. (A) 3D binding site of a kinase with a small molecule inhib-
itor bound. (B) Sequence of the positions in the binding site in contact with the small molecule, together with their location in the structure of the kinase
(g-loop and b3 to b4). Each binding site position is then represented by a bitstring, with each bit switched to 'on' depending upon whether it is involved in a
contact, whether the contact is with the main chain, side chain of the protein, and if the interaction is polar, apolar, hydrogen bond acceptor/donor. (C) Concat-
enation of all bitstrings for each binding site residue. This process is repeated for all ligands.

residues, which act as a mask covering all of the interactions occurring between the
protein and the ligands, is then used as the common reference frame to construct the
interaction fingerprints (Figure 1).
For a group of structures involving the same target protein (e.g., docking results), the
ligand binding site is defined as the list of residues comprising the union of all resi-
dues involved in ligand binding over the entire library of structures. For the protein kin-
ase–ligand complex structures, however, as the target proteins involved are different, a
sequence alignment of the protein binding sites is needed which can be based upon
sequence and/or structural information.
After all the ligand binding site residues are identified and all the protein–ligand inter-
molecular interactions are calculated, the next step is to classify these interactions.
Our current implementation of SIFt uses seven bits for each binding site residue, repre-
senting seven different types of interactions. The seven bits are switched on or off if
the following interactions are observed: 1) if a contact is involved at this position;
2) whether it involves the main-chain atoms; 3) whether it involves the side chain;
4) whether it is a polar interaction; 5) whether it is a non-polar interaction; 6) whether
it is a hydrogen bond acceptor; 7) whether it is a hydrogen bond donor. By doing so,
each residue is represented by a seven-bit-long bit string. The whole interaction finger-
print of the complex is finally constructed by sequentially concatenating the bit string
of each binding site residue together, according to the ascendant residue number order.
This results in each interaction fingerprint being the same length, enabling easy com-
parison of interactions at a particular binding site position across a series of com-
plexes.
Building profiles of protein–inhibitor complexes
We have developed a profile-based approach termed p-SIFt [9] that enables us to
describe the conservation of interactions between a set of protein–ligand receptor
complexes. The p-SIFt approach is based upon profiling methods that have been
developed previously to analyze and mine protein sequences and structures for dis-
tantly related family members [11, 12]. A sequence profile is essentially a position-
specific scoring matrix encoding the probability of finding any of the 20 amino acid
residues at that position in the target sequence. In the case of p-SIFt, the SIFts
derived from a set of probe structures are used to derive a position-dependent pro-
file encoding the probability that a given interaction at that position is present
(Figure 2). The probe set of structures may correspond to gene families, e.g., kinas-
es, or to subfamilies of structures representing ligands with a particular activity or
selectivity profile.
We have used the Tanimoto coefficient as a measure to compare the similarity
between two SIFt fingerprints, between two p-SIFts, and also between a SIFt and
a p-SIFt profile [13]. A set of SIFt patterns can be clustered using the
Tanimoto similarity measure by applying a standard hierarchical clustering algorithm
[13].
Knowledge-based constraints in focusing
chemical libraries
We have developed a new strategy for designing and filtering target-specific chemical
libraries based on r-SIFt [14]. r-SIFt is a variation of SIFt that was designed specifically
for analyzing compounds of a combinatorial library, and where the 'r' in r-SIFt stands
for the various R-groups of a combinatorial library. The main difference between the
original SIFt and r-SIFt lies in the meanings of the interaction bits that comprise the
entire fingerprints. In r-SIFt, the bits represent whether or not a certain R-group or core
fragment of the compound satisfies a contact interaction (i.e., within a distance thresh-
old) with a particular protein residue.
r-SIFt incorporates the binding interactions of variable fragments in a combinatorial
library. It enables target-specific constraints from structures of protein–small mole-
cule complexes in a binding site to be used to focus a combinatorial library [14].
Our r-SIFt-based library-focusing strategy consists of the following major computa-
tional steps, as illustrated in Figure 3: 1) library enumeration and docking wherein a
combinatorial library is enumerated, and a small subset with maximized chemical
diversity is selected and carefully docked onto the target molecule; 2) calculation of
2D molecular descriptors of all the variable R-groups used in constructing the large
combinatorial library; 3) construction of r-SIFt patterns of the docking posed from
step 1; 4) clustering and classification of r-SIFt patterns where compounds that are
able to bind to the target molecule with the desired binding mode (dockable com-
pounds) are differentiated from non-dockable compounds; 5) generation of predictive
models. Based on the classification from step 4 and using the 2D descriptors as
predictive variables, a decision tree model is built to predict the dockability of the
compounds. This model can be then used to filter the original large combinatorial
library.
To evaluate this strategy, we enumerated several different combinatorial libraries
using a pyridinyl imidazole inhibitor of p38 (PDB code: 1ouk) as the template scaf-
fold, varying R1, R2, and R3 independently (one at a time) and also simultaneously.
Based on the co-crystal structures of 1ouk and other similar inhibitors considered

6 Chem Biol Drug Des 2006; 67: 5–12

 Structural Interaction Fingerprints

B Site
1
0.8
0.6
0.4
0.2
0
0 50 100 150 200 250 300 350 400
Bit_idx

Figure 2: The procedure used to generate a p-SIFt from a set of SIFts is illustrated in panel (A). The profile shown
corresponds to the p-SIFt generated from the 93 kinase structures using all seven bits to compute the SIFts is shown in panel (B). The p-SIFt is annotated with a top-
most bar delineating the general kinase structural features for that portion of the fingerprint; the bar below consists of alternating blocks corresponding to each resi-
due (site in the uniform PKA numbering scheme) in the kinase used to construct the fingerprint; finally, the third bar consists of blocks for each bit representing the
interaction features at that site. Reprinted in part with permission from J Med Chem 48 (1), 121–133, 2005. Copyright (2004) American Chemical Society.

A 2. Calculate
Virtual library Molecular
descriptors
1. Dock
5. Build Decision tree
Docking poses predictive
models
3. Generate r-SIFts
Native versus
r-SIFt patterns non-native
4. Cluster clusters

B C

Figure 3: (A) An overview of the major computational steps in r-SIFt. (B) The Markush definition of the imidazole combinatorial lib-
rary based upon the p38 pyrimidyl inhibitor in the pdb complex 1ouk. (C) A classification model based upon the p38 pyrimdyl inhibitor library.

Chem Biol Drug Des 2006; 67: 5–12 7

Singh et al.
to be in the 'native binding mode,' the R1 groups are expected to interact with
the hydrophobic pocket of p38. The R2 portion of 1ouk-inh, on the other hand, is
positioned in the vicinity of the adenine-binding site in the hinge region, whereas
the R3 group interacts with the phosphate-binding region (P-loop).
These enumerated libraries were subjected to the aforementioned r-SIFt library
focusing analysis. In each case, a decision tree predictive model for each respect-
ive R-group was generated. Its performance was evaluated using 10-fold cross-val-
idated predictive accuracy on the test set, which was set aside
during model building. In addition, the reagent enrichment factor (EF) is
measured by the increased concentration of dockable compounds in the selection
pool.
(concentration of dockable compounds in final selection pool)
EF ¼
(concentration of dockable compounds in original library)
Details of the analysis procedure are reported elsewhere [14].
Protein kinase-inhibitor dataset
The protein kinase family exemplifies the challenges faced with the large amount of
structural data being generated not only on specific drug targets, but also at the gene
family level. Here we use 93 small molecule complexes that have been deposited in
the public domain, which comprise examples from 34 different kinase family members,
14 different protein kinase subfamilies, and 54 unique kinase small molecule ligands/
inhibitors (Deng et al., unpublished results).
Results
Conserved binding interactions across kinase
inhibitors
The majority of known kinase inhibitors bind to the ATP site, and
few inhibitors have been described that target the substrate binding
site. We have used SIFt to examine conserved interactions across
protein kinase–inhibitor complexes [9, 10]. These conserved interac-
tions can be used to understand critical determinants for inhibitor
binding and selectivity. They can also be used to screen for novel
templates.
We determined the degree of conservation of interactions in 93
protein–kinase inhibitor complexes by exploring the frequency of
contacts at each of the 56 positions that are involved in binding.
These residues include (using the numbering system from the
cAMP-dependent protein kinase structure; pdbcode 1ATP): the gly-
cine-rich loop, which is a conserved signature of the family and
plays a role in binding of ATP (47–57); the hinge region, which is
located between the N- and C-terminal domains and plays a role
in hydrogen-bonding the adenine moiety of ATP (123–125, 127,
130); b3 (70, 72); the hydrophobic pocket region (95, 104, 105,
118, 119); the 'gatekeeper' residue whose size determines inhibitor
access (120); and the activation segment, which is targeted by
several inhibitors that stabilize the inactive conformation of the
kinase.
We found that 20% of the contact interactions are conserved (‡0.7)
over the 93 structures as a whole, 11% are intermediate
(0.4 £ intermediate < 0.7) in conservation, whereas 69% are vari-
able (<0.4). The canonical interactions are common to all inhibitors
and clearly play a critical role in inhibitor binding to the protein
kinase family. These interactions could be used as a basic kinase-
like binding filter in virtual screening for novel kinase inhibitors.
8 Chem Biol Drug Des 2006; 67: 5–12
Clustering of kinase inhibitors based upon
interaction fingerprints
A dendrogram derived from comparison of interaction fingerprints
of the 93 protein–inhibitor complexes is shown in Figure 4. The
objective was to cluster together kinase–inhibitor complexes show-
ing similar interaction patterns. The approach involves computing
the similarity metric (Tanimoto coefficient) between all of the fin-
gerprints and then using a hierarchical clustering algorithm to
group similar interaction fingerprints together. The dendrogram
revealed four major clusters (Figure 4) consisting of ATP analogs,
p38 inhibitors, CDK2 inhibitors, as well as those kinase inhibitors
that bind to the ATP site but recognize a distinct conformational
state in the activation segment of the kinase termed DFG-out. A
significant number of protein kinase inhibitors stabilize this con-
formational state of the enzyme including GleevecTM [15]. In addi-
tion to these four major clusters, about one-third of the structures
are either singletons or form tiny clusters. Interestingly, the major
clusters represent different grouping examples of protein–ligand
complexes: the first one is made up of the same protein and
chemically similar compounds (e.g., p38 in complex with trisubsti-
tuted imidazoles); the second group contains the same protein but
with a variety of ligands (e.g., CDK2 in complex with different
CDK2 chemotypes); the third cluster contains different proteins in
complex with chemically similar ligands (e.g., different protein
kinases bound to ATP and ATP analogs); and the fourth are those
inhibitors that recognize the inactive conformational state (e.g.,
c-Abl in complex with STI-571).
Profile analysis of kinase complexes and its
application to selective enrichment of
inhibitors
The p38, CDK2, and ATP SIFt clusters represent a set of structures
having similar conserved and variable interactions. In order to com-
pare within and between these clusters we have developed a pro-
file-based methodology, p-SIFt [9]. The p-SIFt approach is analogous
to profile-based techniques that have proven to be very useful in
the analysis and database mining of groups of protein sequences
and structures [11, 12]. The use of profiles provides a sensitive
means to compare and contrast multiple inhibitors binding to a drug
target. A structural interaction fingerprint profile (p-SIFt) represents
the degree to which interactions are conserved across a set of lig-
and–receptor complexes. The p-SIFt is derived from an array of SIFt
patterns, and its derivation from a set of SIFts is shown in Figure 2.
Because the interaction fingerprint represents the binding mode of
a ligand to a target protein, similar fingerprints imply that the cor-
responding ligands make similar interactions with the protein.
A useful means to compare p-SIFts is to plot a difference profile
computed by the direct subtraction of one p-SIFt from another. This
enables a simple and fast way to identify similarities and differ-
ences between protein sets of complexes. The difference profile
between p38 and CDK2 highlights the importance of the gatekeeper
residue in controlling access of small molecule inhibitors to the bind-
ing site of kinases (Figure 5). The box in Figure 5 highlights interac-
tions that occur in the hydrophobic pocket of p38 but not in CDK2.
This is due to the small Thr 'gatekeeper' in p38 rendering the resi-
dues making up the hydrophobic pocket accessible to small molecule
 Structural Interaction Fingerprints

A B

Figure 4: (A) Hierarchical clustering of SIFts from 93 protein kinase small molecule crystal structures. On the
right are the dendrogram and the corresponding distance matrix. SIFts are reorganized according to the order given by the dendro-
gram. Six different regions are labeled above the SIFt heat map. Three major clusters (1–3) are labeled on the left-hand side of the heat map and also a cluster
corresponding to the DFG-out conformation of the kinases. (B) Comparison of the binding modes of the three different kinase clusters.

catalytic Mg
A G-loop β3 to β4 β5 and hinge loop loop

-
1
p38 – CDK2

Figure 5: (A) The contact-

only difference profiles –1
47 56 74 94 106 120 130157 166 185
between p38 and CDK2. The
difference plots range from )1 to 1, PKA residue number
where a value of 0 indicates that the
interaction is conserved to the same B p38 CDK2
degree in the two sets of structures,
whereas a value of )1 or 1 denotes
that a conserved interaction in one set
of structures is not conserved in the
other. The blocks indicate the residues
involved in the hydrophobic pocket of
p38. (B) Binding sites for p38 and CDK2
with box highlighting the hydrophobic
pocket and a cpk representation of gat-
ekeeper residue.

inhibitors (see box in Figure 5B), whereas bulky residues at position The difference profiles exhibit clear regions where inhibitors bind
120, such as the Phe in CDK2, restrict access to the hydrophobic to protein kinases in unique ways. These observations suggest that
pocket, limiting the contacts available to a putative inhibitor. p-SIFts can be used to model the selectivity of inhibitors based on

Chem Biol Drug Des 2006; 67: 5–12 9

Singh et al.
the types of interactions they are able to satisfy when binding to
the kinase. In order to validate the use of p-SIFts as selectivity fil-
ters, we carried out a self-recognition experiment using the set of
93 X-ray structures as a test data set. The p-SIFTs derived from
50% of the complexes making up the ATPg, p38, and CDK2 clusters
were all successful at recognition of their own members relative to
the counter targets [9]. This supports the application of profiles to
filtering docking results selectively against specific drug targets.
SIFt-based screening for p38 inhibitors
Our SIFt analysis has identified clear interaction preferences for
ATP, p38, and CDK2 clusters as well as a canonical set of con-
served interactions common to all ligands bound to kinases at the
ATP binding site. In this section, we will demonstrate how p-SIFt
can be applied in a VS workflow that can be tailored to a specific
target without having to rely solely on the ambiguities of energy-
based scoring. To this end, we have tested the performance of
p-SIFt-based scoring in a typical database enrichment application
using p38 as the target [9].
A database containing 16 known inhibitors of p38 was spiked into
a background of 1000 diverse commercially available compounds
and docked against the X-ray structures of p38 (PDB code 1a9u).
We then analyzed whether p-SIFT provided any advantage over
popular scoring functions in enrichment of inhibitors by plotting the
percentage of actives recovered as a function of the percentage of
the database screened.
For p38, the enrichment obtained by applying p-SIFt scoring provi-
ded markedly superior results over those obtained using energy
scoring functions. In Figure 6, the enrichment curves and cumulative
enrichment factors for p38 are presented, comparing the traditional
and p-SIFt scoring approaches. p-SIFt scoring performs close to the
100
90
80
70
% actives recovered
60
50
40
p-SIFt scoring
Traditional chemscore
Traditional PMF
30
Random
20
10
0 whole combinatorial library, which could be extremely time consu-
0 2 4 6 8 10 12 14
% Library screened
Figure 6: Enrichment curves obtained for VS against
p38. The enrichment curves were derived using the scoring methods des-
cribed in Ref. [9]. The ChemScore and PMF curves were obtained using the
traditional scoring scheme, using the ChemScore and PMF scoring functions,
respectively, for both final pose selection and ligand ranking. Other scoring
functions performed similarly under the traditional scoring scheme. The dis-
tribution of hits expected by chance is shown in black.
10
ideal enrichment curve over the first 2% of the database, meaning
that 14 of the 16 known p38 actives were in the top 20 ranked lig-
ands. Upon examination of the docking poses it was discovered
that for the other two inhibitors correct poses were never gener-
ated in the initial pose pool.
Both SIFt and p-SIFt have been demonstrated to be effective know-
ledge-based pose filters. We have shown that when applied in con-
junction with energy-based scoring functions it is possible to derive
hybrid-scoring schemes that can yield significantly improved data-
base enrichment rates. The SIFt component of the hybrid scheme
complements the physics- or rules-based functions by eliminating
false poses and thus effectively compensating for the weakest fea-
ture of the scoring functions. In fact we were able to show that
once incorrect binding modes are removed, all of the scoring func-
tions tested performed equally well in database enrichment against
CDK2 kinase [9].
Structure-based focusing of chemical libraries
The past decade has witnessed significant advances in combina-
torial chemistry. With the discovery and availability of more rea-
gents and reaction schemes, as well as the advances of
chemical synthesis methods, the number of compounds that
are synthetically feasible is daunting. How to intelligently lever-
age the 3D structural information of target molecules and use it
in designing target-focused libraries is of great interest in the
field.
Figure 3 shows the general workflow of our proposed strategy for
designing target-focused chemical libraries, where information on
the desired binding mode can be directly embedded into the rea-
gent selection process. Key to this approach is to use the r-SIFt
method to effectively classify compounds based on whether or not
they can interact with the target while satisfying desired binding
patterns, then use machine learning techniques to build filtering
rules that can be applied to large libraries.
To investigate the performance of an r-SIFt based library filtering
strategy, we focused a large combinatorial library down to an
optimal set of commercially available reagents for each variable
R-group. The goal of this example was to build filtering rules for
each of the variable R-group from small subsets of representative
reagents. The rules can be then used to filter very large original
reagent libraries to identify a list of suitable reagents that would
be able to constitute dockable compounds (i.e., compounds that
will be predicted to bind in the desired binding mode to the tar-
get by docking programs), thus eliminating the need to screen the
16 ming.
The combinatorial chemical library was based upon an imidazole
inhibitor of p38 (pdbcode 1ouk; Figure 3B), which we defined as an
imidazole core attached to R1, R2, and R3. We first built decision
tree predictive models for each of the variable group (R1, R2, and
R3) from libraries where a single R-group was varied independently,
while keeping the other R groups fixed. Our results showed that
these independent models had 60–80% accuracy at predicting
Chem Biol Drug Des 2006; 67: 5–12

Lead
discovery
Confirm
Figure 7: Integration of SIFt
into the structure-based
drug design workflow. The
experimental structures of a drug target
in complex with small molecules are
used to generate SIFt and p-SIFt. This
•Incorporate structural
is used to filter a virtual chemical lib-
information of protein-
rary, which is used to identify com-
SM complexes into VS
pounds for testing. These are confirmed paradigm
as hits and their structures are deter-
mined, thus leading to further cycles of
structure-based drug design.
respective R-groups that would dock with desired binding mode,
and 70–80% accuracy for R-groups that would not dock. Interest-
ingly, these predictive models generated from the 1ouk-inh template
were found transferable to other templates, as long as the
R-groups were targeted at the same binding locus. To further test
the validity of treating R1, R2, and R3 as independent, we carried
out the r-SIFt procedure on a library where both R1 and R2 were
varied simultaneously. The accuracies of the R1 and R2 models
derived from this coupled library were found to be comparable to
those obtained from the independent R-group libraries. Finally, to
evaluate the accuracy of our approach on the full combinatorial lib-
rary, a combinatorial library based on 1ouk p38 small molecule tem-
plate varying R1, R2, and R3 simultaneously was enumerated and a
test subset focused using the independent R-group predictive mod-
els. Using r-SIFt focusing, we were able to select a small pool of
compounds in which the concentration of dockable compounds was
24-fold higher than that in the original library, thus the reagents
selected were enriched by 24-fold for compounds able to adopt the
desired binding mode.
Conclusion and Future Directions
We have described a novel approach called SIFt, which takes 3D
interaction patterns from protein complexes and translates them
into 1D fingerprints that are easy to store, mine, and analyze. In
addition to our work on SIFt, several other groups have recently
reported using new approaches to handling protein–ligand com-
plexes [16, 17]. These approaches should provide a valuable set of
tools for structural biologists and computational chemists to man-
age the large amounts of structural data on protein–small molecule
complexes that are being generated.
In the era of whole genome analysis, the ability to understand
the selectivity determinants against whole protein families is a
significant challenge. Our results with p-SIFt suggest that it is
able to selectively enrich compounds against specific kinases.
Chem Biol Drug Des 2006; 67: 5–12
Structural Interaction Fingerprints
•Structures of many
drug targets are
known
Xray Complex
Knowledge-
SIFT
hits based lead profile
discovery
Virtual
•Clear preferences in
screening interaction patterns of
scaffolds inhibitors
With r-SIFt we have proven that we are able to explore very
large chemical libraries and achieve high enrichment rates for
those compounds likely to bind without the time-consuming effort
of docking the whole library. r-SIFt should provide a powerful
compliment to combinatorial chemistry to identify which areas of
chemical space are most productive in terms of binding to a
receptor. We also envision that p-SIFt will enable virtual chemical
libraries to be computationally tested against panels of drug tar-
get family members and enable identification of selective or pan
inhibitors (Figure 7). The combination of these tools coupled with
high-throughput experimental approaches should allow us to fully
leverage the potential of the vast amount of structural data being
generated on drug targets.
Acknowledgments
We would like to thank Rainer Fuchs, Donovan Chin, Alexey Lugovskoy, Prashant Singh,
Jennifer Campbell, and Herman van Vlijmen for useful discussions during the course of
this work.
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