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QuantumMechanicalApproachestoStructurallyInformedDesign

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JoséDuca

NovartisInstitutesforBioMedicalResearch

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JasonB.Cross

UniversityofTexasMDAndersonCancerCenter

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Quantum Mechanical Approaches to Structurally InformedDesign

Jos�e S. Duca*[a] and Jason B. Cross[b]

This review focuses on the application of molecular model-

ing and structure-informed design (SID) to drug discovery.

Routine utilization of quantum mechanical techniques allows

generation of SID hypotheses, based on first principles. The

authors introduce the concept of combining information

from electrostatic potential surfaces and nonbonding orbi-

tals to determine the nature and directionality of intermo-

lecular interactions, particularly those that are infrequently

exemplified in the protein data bank. VC 2013 Wiley Periodi-

cals, Inc.

DOI: 10.1002/qua.24561

Introduction

For more than a century, enzymatic activity has been under-

stood in terms of binding processes in which a compound

interacts with an enzyme as a key would do with its lock. The

“lock and key” model, proposed by Fischer in about 1890[1] to

describe the interactions of a protein and a substrate, relies on

the complementarity of physical properties such as shape,

molecular size, solvation, and intermolecular interactions,

which are central for ligand recognition and modulation of the

pharmacological response of the target protein.

Since the first entry in the Protein Data Bank[2] (RCSB PDB;

www.pdb.org) was created in 1972 (PDB code 1sbt[3]), more

than 90,000 X-ray and NMR models have been made available

in the PDB,[4] in what constitutes the primary source for struc-

turally informed design (SID). High-resolution X-ray and NMR

models provide valuable information to elucidate the struc-

tural basis for molecular recognition and design of novel

target-modulating compounds. They also serve as structural

templates for homology modeling of proteins that have no

structure yet solved.

The number of structural models deposited in the PDB has

increased rapidly over the last 10 years (Fig. 1). In the last two

years alone, approximately 15,000 structures (ca. 25% of the

entire PDB) were released. This represents an average of �600

structures per month, highlighting the need for tools and

techniques that can make use of this information. Several sci-

entific and technical advances have progressed in parallel with

this increase in protein structural data. Along with increases in

computing power, memory, and storage, software tools have

been developed that aim to rapidly characterize, categorize,

and sort the molecular interactions observed in the PDB (i.e.,

IsoStar,[5] SuperStar,[6] and MED-SuMo[7]) and statistical poten-

tials have been developed based on this data (i.e., DOPE,[8]

PMF,[9] and DFIRE[10]).

Such wealth of structural information can be highly valuable

in the hands of an expert SID scientist, whom will be able to

take advantage of structure-function relationships based upon

visualization and interpretation of structural data. The ability

to observe and infer information beyond atom coordinates

distinguishes such expertise. In addition, the data in these

structures contains an element of uncertainty, because the

atomic coordinates are merely a model fit to the experimental

data and are subject to a variety of errors, including model

over fitting, missing or incorrect atoms, and incorporation of

highly strained small molecule ligands. There are many inter-

esting examples to highlight in the PDB; for the scope of this

review we will showcase a few examples of unusual structural

interactions, including halogen and sulfur mediated

interactions.

Effective SID requires the careful analysis of the structural

model and the identification of “anchors” for maximizing

ligand–receptor interactions. The PDB is a rich source of inter-

molecular interactions; most of them are widely known and

seen quite often, while others may be more subtle or infre-

quent. Commonly observed ligand–receptor interactions

include hydrogen bonds, salt bridges, and hydrophobic con-

tacts. Focusing on hydrogen bonds, the most frequently seen

acceptors are neutral or charged oxygen atoms and neutral

nitrogen atoms. Common donors include neutral oxygen

atoms and neutral or charged nitrogen atoms. Halogens are

also able to participate in “nonclassical” hydrogen bonds as an

acceptor, or in a role analogous to a hydrogen bond donor in

halogen bonds, but these types of interactions are seen less

frequently in the PDB.[11] Many force fields and modeling tools

that utilize fitted information derived from structural data can

easily reproduce common interactions that have many experi-

mental examples, but have a limited ability to accurately

reproduce infrequent interactions.[12] Atypical interactions that

are seldom encountered in crystallographic models may chal-

lenge us to rethink and reinterpret SID. This is where first

[a] J.S. Duca

Computer-Aided Drug Discovery, Novartis Institutes for BioMedical

Research, 100 Technology Square, Cambridge, Massachusetts 02139

E-mail: jose.duca@novartis.com

[b] J.B. Cross

Discovery Technologies, Cubist Pharmaceuticals, Inc., 65 Hayden Avenue,

Lexington, Massachusetts 02421

VC 2013 Wiley Periodicals, Inc.

International Journal of Quantum Chemistry 2014, 114, 305–313 305

REVIEWWWW.Q-CHEM.ORG

principle methods, such as quantum mechanics, can be helpful

in deciphering and interpreting the underlying sources of such

interactions.

SID of Halogen-Mediated Interactions

The value of halogen bonding and halogen interactions in

rational drug design has been recently emphasized in several

articles and reviews.[11,13–17] Much of this discussion has cen-

tered on the apparent incongruity of halogens, generally

regarded as electronegative atoms, being able to functionally

act as “nonclassical” hydrogen-bond acceptors, or in a manner

analogous to hydrogen bond donors in halogen bonds.[18]

Inspection of electrostatic potentials (Fig. 2) shows a region of

positive potential at the distal end of the halogen, in the cases

of Cl, Br, and I, that has been termed the “r-hole.”[19] Interac-

tions involving these groups are highly directional, owing to

the negative electrostatic potential that rings the central por-

tion of the halogen; in fact, this region of negative potential

can itself act as a hydrogen bond acceptor.[13] In the case of

fluorine, the halogen atom retains its overall negative potential

and remains capable of behaving as a hydrogen bond

acceptor in a more traditional sense. However, fluorine atoms

attached to strongly electron withdrawing groups can exhibit

a “r-hole,”[20,21] but these types of moieties are generally not

seen in approved drugs. Fluorine atoms can also be used to

modulate the electrostatic potential around another halogen

atom by incorporating them into neighboring ring positions,

effectively increasing the size of the “r-hole” and strength of

interactions with the halogen.[22]

As noted previously, the few examples of halogen-mediated

interactions in the PDB present a challenge in predicting the

“correct binding pose” when these interactions dominate

ligand binding. Additionally, in some cases weak interactions

may change the balance favoring one binding mode over

another; it is up to an expert SID scientist to (a) be aware of

such possible binding modes and to (b) assess their likelihood.

Both scenarios require a heavy reliance on structural models

and a wide familiarity with the PDB as a whole.

An example of subtle structural differences resulting in

flipped binding modes is illustrated by the CDK2-inhibitor coc-

rystal structures solved by Schering-Plough scientists (Fig.

3).[24] Two compounds containing classical moieties that are

known to interact with kinase hinges were crystallized in dif-

ferent binding modes: (a) a pyrazolopyridine group in a tradi-

tional hinge binding mode, despite having a chlorophenyl

moiety present (PDB code 2r3f ), and (b) an imidazopyrazine in

a flipped mode to accommodate a fluorobenzene interaction

with the hinge NH (PDB code 2r3g). Both of these X-ray struc-

tures are of high resolution (1.50 A for 2r3f, 1.55 A for 2r3g)

with clear and unambiguous electron density in the ligand

binding site. In the case of the flipped binding mode, the fluo-

rine acts as a “nonclassical” hydrogen bond acceptor, with a

bond distance of 3.1 A to the hinge nitrogen and a CAF---

HAN angle of 148�. The binding geometry is consistent with

an energetically favorable interaction based on calculated con-

tact energies[12] and geometry optimization of model systems

(optimized F---N bond length of fluorobenzene 1 N-methylace-

tamide is 3.2 A at B3LYP/6-311G*). This also suggests the

overall electronegative character of the fluorine atom allows it

to form a productive interaction with the hinge NH that may

not be possible for chlorine with its modest “r-hole” character.

The similar IC50 values and known propensity of both imidazo-

pyrazines and pyrazolopyrimidines to bind to the CDK2 hinge

seem to indicate that both binding modes may be isoener-

getic, or at least accommodated within the binding site.

An additional example of a fluorobenzene interacting with a

kinase hinge was reported for TGF-beta receptor I kinase, PDB

code 1rw8[25] (Fig. 4). Again, the fluorine acts as an acceptor at

a distance of 2.9 A from the hinge nitrogen and a CAF---HAN

angle of �136�. One of the hydrogen atoms on the phenyl

ring adjacent to the fluoro group is located about 2.7 A from

a hinge carbonyl oxygen (CACO distance of 3.6 A) and may

be involved in a “nonclassical” hydrogen bond.

Another recent example (Fig. 5) shows a series of fluoroben-

zene moieties interacting with an NS5b beta-loop, which is

structurally reminiscent of a kinase hinge[26] (PDB code 3skh).

Jos�e Duca is Head of Computer Aided Drug Discovery (CADD) in Cambridge, Novartis

Institutes for BioMedical Research (NIBR). Duca joined Novartis in 2010. Previously he had

been with the Schering-Plough Research Institute and Merck Research Laboratories in

Kenilworth, NJ, USA for 10 years and with Tony Hopfinger’s group in the College of Phar-

macy at the University of Illinois at Chicago as a Postdoctoral Fellow. He received his

Ph.D. in Chemistry from the National University of C�ordoba, Argentina.

Jason Cross is a Senior Scientist and heads the Molecular Modeling group at Cubist Phar-

maceuticals. He received a B.Sc in Biochemistry from the University of Windsor in 1997

and a Ph.D. in Physical Chemistry from Wayne State University in 2002 after studying

under Berny Schlegel. Following a postdoctoral position at Pfizer, he went on to provide

computational chemistry support for drug discovery projects at Affinium Pharmaceuticals

and Wyeth before joining Cubist Pharmaceuticals in 2009.

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306 International Journal of Quantum Chemistry 2014, 114, 305–313 WWW.CHEMISTRYVIEWS.ORG

In this particular example, the fluorobenzene acts as a

“nonclassical” hydrogen bond acceptor interacting with a

backbone NH (CAF---HAN bond length �3.0 A, CAF---HAN

bond angle �162�). This group was modified during the lead

optimization process into a pyridone,[27] maintaining similar

interactions with the beta-loop through polar isosteric

replacement.

As mentioned earlier, the nature of these halogen mediated

contacts can be understood in terms of the electrostatic

potential of the molecular fragments that take part of the

interaction. However, it is also important to understand the

directionality of these interactions. While it is possible to

describe the “r-hole” and halogen bonding phenomenon

quite well using electrostatic potentials,[28] we have found the

incorporation of nonbonding orbitals into the description of

these interactions quite instructive.

The electrostatic potential maps of halobenzenes (Fig. 2)

show that the electron withdrawing nature of the halogen

atom decreases the effective negative potential on the ben-

zene ring by shifting it to the CAX bond. The “tip” of the CAF

bond has the most strongly negative electrostatic potential. In

Figure 1. Number of X-ray structures deposited per year in the PDB until 2012.

Figure 2. Electrostatic potential maps of a) benzene, b) fluorobenzene, c) chlorobenzene, d) bromobenzene, and e) iodobenzene. Maps were generated

using Jaguar v79025 as included in Maestro v9.3; geometries were fully optimized using B3LYP/LACVP**(6d). Surface isocontours at 210 kT/e (red) and

120 kT/e (blue) are shown.[23] Graphics generated with PyMol (The PyMOL Molecular Graphics System, Version 1.3 Schr€odinger, LLC).

REVIEWWWW.Q-CHEM.ORG

International Journal of Quantum Chemistry 2014, 114, 305–313 307

the case of CACl and CABr, there is a mixture of negative and

positive potential along these bonds with the region of nega-

tive electrostatic potential situated in an annular arrangement.

For CAI bonds, the balance is shifted toward positive electro-

static potential. These illustrations provide an explanation of

the rich and varied types of interactions halobenzenes can par-

ticipate in: fluorobenzene acting as an acceptor, chloro- and

bromobenzenes with mixed propensities for acting as accept-

ors and in halogen bonds, and iodobenzenes primarily partici-

pating in halogen bonds in the presence of carbonyl groups.

Although, iodobenzenes are often avoided in drugs due to

concerns over metabolic lability, thyroid hormone thyroxin (T4)

is used to treat hypothyroidism (PDB entries 1eta[29] and

2rox[30] are examples of T4 bound to transthyretin) and some

recent MEK1 inhibitors also incorporate this moiety (PDB codes

3orn,[31] 3sls,[32] and 3mbl[33]). While they prove very useful in

rationalizing the nature of halobenzene interactions, electro-

static potential maps offer limited information about

Figure 3. Crystallographic complexes of CDK2 and two ligands. The cyan

ligand (PDB code 2r3g) displays a hinge:halogen-mediated interaction

between a backbone nitrogen (blue) and fluorine atom (green), while the

pyrazolopyridine nitrogen (blue) acts as an acceptor (PDB code 2r3f, white

ligand).[23] Graphics generated with PyMol.

Figure 4. Crystal structure of TGF-beta receptor I kinase (PDB code 1rw8)

interacting with an inhibitor (cyan). A fluorobenzene (fluorine in green)

interacts with an NH (nitrogen in blue) and CO (oxygen in red) of the

hinge.[23] Graphics generated with PyMol.

Figure 5. a) Crystal structure of NS5b interacting with an indole-based

inhibitor (PDB code 3skh, cyan). The fluoro group (green) of fluorobenzene

interacts with an NH (nitrogen in blue) of the beta-loop. b) Overlay of two

X-ray structures of NS5b and indole inhibitors, where the fluorobenzene

moiety (PDB code 3skh, cyan) is modified to a pyridone group (PDB code

3u4o, yellow).[23] Graphics generated with PyMol.

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308 International Journal of Quantum Chemistry 2014, 114, 305–313 WWW.CHEMISTRYVIEWS.ORG

directionality of such contacts. However, r* antibonding orbi-

tals of the involved fragments can be quite informative in this

regard.

The r* antibonding orbitals of benzene and the four halo-

benzenes are compared in Figure 6. For the sake of this dis-

cussion we will focus only on the graphical representation,

which is what we have found to be most useful for explaining

intermolecular interactions to medicinal chemists in drug dis-

covery teams.

As expected for a symmetrical molecule, benzene has a uni-

form orbital distribution along its CAH bonds. This distribution

is maintained for the most part in the case of fluorobenzene,

except for the CAF bond, which presents a modest antibond-

ing character. This differs from the other halobenzenes, which

show predominant r* antibonding orbitals along their CAX

bonds. This suggests that fluorobenzene may rely on two

interaction points; one being an acceptor on the CAF

(described above in terms of its electrostatic potential) and

one being a donor on an adjacent CAH bond as both contain

a large antibonding component. Based on the molecular

orbital picture, the other three halobenzenes appear to inter-

act primarily through the CAX bond. In that sense, a fluoro-

benzene can be compared directly to a pyridone group, which

primarily forms interactions via its carbonyl and NH moieties.

The representation of the pyridone electrostatic potential

maps and r* antibonding orbitals are shown in Figure 7 and

are remarkably similar to the fluorobenzene maps, although

fluorobenzene is symmetric around the CAF bond in contrast

to the asymmetry of the pyridone ring.

As illustrated in the X-ray structures in Figure 5, the fluoro-

benzene ring appears to act as a bioisosteric replacement of a

pyridone moiety. Examination of the SAR for this class of com-

pounds[26] suggests that the fluorobenzene ring is not as

potent a binder as the pyridone, but the crystallographic evi-

dence shows that similar protein–ligand interactions are main-

tained. This picture is consistent with the electrostatic

potentials maps and r* antibonding orbitals (Fig. 7), which

show slightly more pronounced regions of negative and posi-

tive electrostatic potential, as well as minor differences in size

and shape of the r* antibonding orbitals adjacent to the pyri-

done as compared to the fluorobenzene. This implies that the

same type of interaction is likely occurring in examples shown

in Figures 3 and 4 as well, and that although no pyridone ana-

logs were exemplified as experimental verification one could

Figure 6. r* antibonding orbitals of a) benzene, b) fluorobenzene, c) chlorobenzene, d) bromobenzene, and e) iodobenzene. Maps were generated using

Jaguar v79025 as included in Maestro v9.3; geometries were fully optimized using B3LYP/LACVP**(6d). Orbital isocontours at 20.05 (red) and 10.05 elec-

trons/bohr3 (blue) are shown.[23] Graphics generated with PyMol.

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International Journal of Quantum Chemistry 2014, 114, 305–313 309

expect substitution of the pyridone for fluorobenzene to

improve compound potency.

SID of Other Nontraditional Hinge BindingMotifs

Another interesting example of an uncommon interaction is

contained in a recently published Chk1 kinase X-ray structure

(PDB code 3u9n).[34] In this case, the cocrystallized structure of

the Chk1 kinase-inhibitor complex showed a thiazole group

acting as a hinge binder with the sulfur atom facing the hinge

backbone ANH and ACO groups (Fig. 8a). Although it is possi-

ble that nonproductive interactions can be tolerated when

there are other compensatory interactions between the pro-

tein binding site and ligand, the SAR for this series suggests

that the thiazole is engaged in an energetically favorable inter-

action. The Chk1 IC50 for the crystallized ligand is 75 nM, while

direct replacement of the thiazole ring with isoxazole (Cpd 15

from ref. 34), which should be able to interact with the NH of

Cys87, results in a significant loss in activity (Chk1 IC50 5 3400

nM). Similarly, other thiazole regioisomers show greatly dimin-

ished activity (Chk1 IC50> 21 lM), illustrating that the arrange-

ment of atoms in the thiazole are critical for activity of the

compound. Once again, we resort to electrostatic potential

maps and r* antibonding orbitals to interpret this nonobvious

interaction of the inhibitor fragment and its surrounding

residues.

The location of the thiazole adjacent to and blocking the

hinge is unique in our experience. The sulfur atom is located

somewhat in between the NH of Cys87 and the CO of Glu85

(distances of 3.5 and 3.3 A, respectively). The environment

around the thiazole seems to indicate that the main polar

interaction takes place due to the overlap of positive electro-

static potential around the CAH and the CO group of Glu85,

as shown in Figure 8b. No substantial contribution to the neg-

ative electrostatic potential in the plane of the thiazole ring

originates from the sulfur atom, which is driven by the most

electronegative atom in the fragment. However, it has been

demonstrated that there are concentrations of negative elec-

trostatic potential above and below the plane of the ring adja-

cent to sulfur atoms in thiazoles,[35] which can participate in

interactions with electrophiles, consistent with the position of

the NH group of Cys87. Even though the electrostatic poten-

tial map is more complex for the whole inhibitor (Fig. 8c), the

contribution of the S atom remains the same. From the latter

maps, it can be observed that the highest negative potential

is located around the oxygen of the benzofuran, while most of

the hydrogen atoms facing the hinge are positively polarized,

especially the CAH adjacent to the thiazole sulfur. The small

variation of the electrostatic maps around the thiazole S is a

result of its high polarizability.

The orientation of the inhibitor in front of the hinge can be

understood by analyzing the r* nonbonding orbitals of the thi-

azole fragment, Figure 9. Because of the orthogonal orientation

of the S r* nonbonding orbitals, the preferred orientation of thi-

azole will be in between the CO and NH of the hinge instead of

directly in front of either of them as in the case of the haloben-

zenes. For comparison, the r* nonbonding orbitals of

Figure 7. Pyridone ring a) electrostatic potential maps and b) r* antibonding orbitals. Fluorobenzene ring c) electrostatic potential maps and d) r* anti-

bonding orbitals, for comparison. Maps were generated using Jaguar v79025 as included in Maestro v9.3; geometries were fully optimized using B3LYP/

LACVP**(6d). Surface isocontours at 210 kT/e (red) and 120 kT/e (blue) are shown. Orbital isocontours at 20.05 (red) and 10.05 electrons/bohr3 (blue)

are shown.[23] Graphics generated with PyMol.

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310 International Journal of Quantum Chemistry 2014, 114, 305–313 WWW.CHEMISTRYVIEWS.ORG

Figure 8. Chk1 kinase-inhibitor cocrystal structure (PDB code 3u9n) showing a) the hinge binding region with a sulfur atom (yellow) of the thiazole ring

interacting with backbone NH (nitrogen in blue) and CO (oxygen in red) groups. b) The electrostatic potential map of thiazole fragment in the binding

pocket, and c) electrostatic potential map of complete inhibitor in the binding pocket. The maps were generated using Jaguar v79025 as included in Mae-

stro v9.3; geometries were fully optimized using B3LYP/LACVP**(6d). Surface isocontours at 210 kT/e (red) and 120 kT/e (blue) are shown.[23] Graphics

generated with PyMol.

Figure 9. The r* antibonding orbitals of a) thiazole and b) thiophene. Maps were generated using Jaguar v79025 as included in Maestro v9.3; geometries

were fully optimized using B3LYP/LACVP**(6d). Orbital isocontours at 20.05 (red) and 10.05 electrons/bohr3 (blue) are shown.[23] Graphics generated with

PyMol.

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International Journal of Quantum Chemistry 2014, 114, 305–313 311

thiophene were also calculated, see Figure 9b. The symmetrical

nature of the fragment is transferred to the orbitals which are

identical in size and orientation while in the case of thiazole the

effect of the nitrogen atom in the ring causes the r* nonbond-

ing orbital directly opposite it to be smaller. Also note that nei-

ther thiophene nor thiazole present considerable contributions

from their CAH bonds, with the sulfur atom dominating the

picture. The experimental evidence that shows that 2-carbonyl

substituted thiophenes adopt a preferred intramolecular syn-

conformation,[36,37] that nucleoside thiazoles display a prefer-

ence for intramolecular interactions between thiazole sulfur and

furanose oxygen,[38] and that short sulfur to carbonyl oxygen

distances are observed for oxathiazane and thiazolidine com-

pounds.[39] The nature and directionality of these interactions

can be interpreted by the combined use of electrostatic poten-

tials maps and r* antibonding orbitals. Similar interactions,

intermolecular in this case, appear to take place between the

carbonyl of Glu85 and the thiazole moiety of the ligand.

A Path Forward For SID

Biased by the existing knowledgebase of kinase X-ray crystal

structures, most SID scientists would not select the binding

mode with fluorine as a hinge binder even if it was seen as one

of the docking poses returned by a trusted model. Similarly, the

interaction of a thiazole with the hinge is not obvious in the

absence of crystallographic data. How do we increase our chan-

ces of success and accuracy? Moreover, does it make sense to

obtain only a few crystallographic models on congeneric series

of compounds assuming the binding mode will be the same?

As the modeling community has demonstrated an increased

ability in retrospectively explaining frequent protein–ligand inter-

actions, we believe that utilization of quantum mechanical calcu-

lations will improve the likelihood of prospectively predicting

nonobvious interactions. Even though there are recent examples

of scoring functions that incorporate halogen bonding terms,[40]

halogen and sulfur-containing heterocycles remain difficult to

model and most often require quantum mechanical descriptions

to explain their behavior. We present in this review a different

way of thinking about the nature and directionality of these

interactions that is generally applicable to other nontraditional

and infrequently observed interactions. Routine inspection of

structures in the PDB and the scientific literature helps in finding

and utilizing unusual interactions, but still it takes a trained mod-

eler’s eye (who can interpret the electrostatic potential maps or

the r* antibonding orbitals) to further improve the quality of SID.

Keywords: X-ray crystal structures • intermolecular interactions

• SID • halogen bonding • drug discovery

How to cite this article: J.S. Duca, J.B. Cross. Int. J. Quantum

Chem. 2014, 114, 305–313. DOI: 10.1002/qua.24561

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Received: 28 July 2013Revised: 16 September 2013Accepted: 18 September 2013Published online 7 October 2013

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