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Antimicrobial Agents and Chemotherapy, November 2000, p. 2939-2947, Vol. 44, No. 11
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Anti-Human Immunodeficiency Virus Activities of
Nucleosides and Nucleotides: Correlation with Molecular
Electrostatic Potential Data
Travis
Mickle and
Vasu
Nair*
Department of Chemistry, The University of Iowa, Iowa
City, Iowa 52242
Received 23 February 2000/Returned for modification 26 May
2000/Accepted 28 July 2000
 |
ABSTRACT |
Examination of the anti-human immunodeficiency virus (HIV) data of
some normal and isomeric dideoxynucleosides (ddNs and
isoddNs), their three-dimensional (3-D) electron density patterns,
their electrostatic potential surfaces (EPS), and their conformational maps reveals some interesting correlations. For example, the EPS of
(S,S)-isoddA shows regions of high and low electrostatic
potential remarkably similar to those of
-D-3'-azido-3'-deoxythymidine (-D-AZT),
(
)-oxetanocin A, and ()-carbovir. Such correlations involving EPS
data and anti-HIV activity were also found with many other active
nucleosides. Conversely, inactive compounds had EPS
different from those of compounds in the same series that were active.
For example, apio-ddNs, which are inactive against HIV,
exhibit clear differences in electrostatic potential and 3-D electron
density shape from isoddNs that are active against HIV. Additionally,
the inactivity of (S,S)-isoddC and (S,S)-isoddT can be correlated convincingly with a combination of their EPS data and
their conformational energy maps. The electrostatic potential distributions of active nucleoside triphosphates show remarkable correlations. For example, (S,S)-isoddATP, AZT triphosphate
(AZTTP), and oxetanocin A TP have similar 3-D electron density surface patterns and similar high and low regions of electrostatic potential, which may suggest that these compounds proceed through related mechanisms in their interactions with, and inhibition of, HIV reverse
transcriptase (RT). Docking of AZTTP, (S,S)-isoddATP, and
other active triphosphates into the active site of HIV RT and
calculation of the EPS of both the nucleotide and the active site show
that there is excellent matching between inhibitor and enzyme
binding site EPS data. The structure-activity profile discovered has contributed to the development of a first predictive
quantitative structure-activity relationship analysis in the area.
| |
INTRODUCTION |
Correlation of anti-human
immunodeficiency virus (HIV) activity with specific structural
characteristics of nucleoside inhibitors is of considerable
significance in contributing to the understanding of the bioactivation
and mechanism of action of these compounds. Additionally, such
investigations may provide predictive information on the structural
characteristics most likely to elicit activity. In the case of
nucleosides active against HIV, quantitative structure-activity relationship (QSAR) correlations have not been proposed. An
approach with limited success is the correlation of activity with
conformation (i.e., glycosidic torsional angle, orientation of the
5'-OH, and sugar ring puckering) (1, 4, 25, 38). For
anti-HIV-active nucleosides targeted at HIV reverse transcriptase
(RT), phosphorylation to the triphosphate is a requirement for
inhibition. However, molecular recognition studies with the
phosphorylating kinases are complicated by the fact that the crystal
structures of some of these enzymes have not been determined. However,
examination of electrostatic potential surfaces (EPS) has suggested
that if molecules have similar electrostatic potentials, along with
some other key properties such as conformation, hydrophobicity, and hydrogen-bonding sites, then it is more probable that their molecular recognition by enzymes and receptors would be similar (2, 8, 28,
33). Thus, by using electrostatic potential, fundamental structural properties can be examined for qualitative and
quantitative correlations. Areas of high,
neutral, and low electrostatic potential can be determined for active
nucleosides and nucleotides. The binding sites within relevant enzymes
would then be expected to have opposite areas of electrostatic potential.
We have recently investigated the synthesis and anti-HIV activity of
isomeric dideoxynucleosides (isoddNs), i.e.,
dideoxynucleosides (ddNs) with transposed base moieties or
transposed -CH2OH groups (30). One of these
isomeric nucleosides, (S,S)-isodideoxyadenosine [(S,S)-isoddA], has potent activity against HIV type
1 (HIV-1) and HIV-2 (31). Its triphosphate is one of the
most powerful inhibitors of HIV RT known (Ki = 16 nM) (31). The enantiomer of this compound also shows some
activity against HIV (14, 15). In comparison, none of
the other isomeric nucleosides of the (S,S), (R,R), or apio families were found to have significant
anti-HIV activity (30). The antiviral data for these
compounds provided a unique opportunity to investigate the
usefulness of electrostatic potential and conformational analysis for
the correlation of the anti-HIV activities of normal ddNs and isoddNs.
To facilitate this study, a method for the examination of these active
nucleoside derivatives was investigated. This method involved
small-molecule manipulation with respect to electron densities and
electrostatic potentials. The analysis led to some interesting
qualitative relationships between the nucleoside derivatives. One such
relationship is the existence of similar electrostatic potential
distributions for 3'-azido-3'-deoxythymidine (AZT), (S,S)-isoddA, ()-carbovir, and oxetanocin A, all of which
are active against HIV (27). This relationship was
strengthened further by the examination of related but inactive
compounds that were found to have different EPS patterns. Extensive
development of this initial qualitative correlation led to more
relationships among the active nucleoside derivatives and also to the
development of the first predictive QSAR analysis in this area. In
addition, electrostatic potential data were utilized to produce a model of the active site of HIV-1 RT docked with a variety of competitive triphosphate inhibitors. This paper describes the first comprehensive application of EPS data in the anti-HIV field.
(A preliminary account of some aspects of this work, has appeared
previously [27]).
| |
MATERIALS AND METHODS |
Molecular modeling of the nucleoside derivatives was
carried out on a Silicon Graphics IRIS 4000/5000 system using the SYBYL program (version 6.4; Tripos Associates, St. Louis, Mo.). The structures were first fully minimized to their lowest energy by the
Powell method, and charges were considered by using the
Gasteiger-Huckel charge calculation. The Gasteiger-Huckel charge
calculation can give more accurate results in nucleosides where
hydrogen bonding between 5'-OH and O-2 can take place. To construct the
EPS, the partial charges were calculated using the Gasteiger-Marsili
method. Then the electron density was calculated by using a resolution of 7, followed by the mapping of electrostatic potential on the surface
of the electron density. Surfaces were then compared by using their
fully minimized structures. For the conformational analysis, a total of
1,369 conformations (372; 0° and 360° were confirmed by
recalculation) were generated and their energies were fully minimized
by using GRID search. Both 
and 
were defined and searched
through a full 360° range, with 10° increments. Each conformation
gave an energy value, and these values were graphed in terms of
and by using the TABLE and GRAPH options in SYBYL. For
QSAR results, the torsion angles and of each
molecule in each group were set to those of the representative molecule
for each set, e.g., -D-ddC for the 2', 3'-dideoxycytidine (ddC) group and
()-2',3'-dideoxy-3'-thiacytidine [()-3TC] for
the oxythiolane group. Then, by using the ALIGN DATABASE command, each
group was aligned to give the best overlap of carbon atoms.
Realignments and recalculations were necessary in some instances due to
poor structural overlap. With a good overlap, a molecular spread sheet
(MSS) was created and the comparative molecular field analysis (CoMFA;
Tripos Inc.) for each molecule was calculated. Then a partial
least-squares (PLS) analysis was performed using the log
1/IC50 (where IC50 is the 50% inhibitory concentration) and the CoMFA data. Bioactivities were calculated by
using the VIEW CoMFA command in the QSAR dialog box.
To calculate the electrostatic potential for the active site of HIV RT,
the X-ray crystal structure for HIV RT was modified from the structure
originally obtained (13, 21) to include Mg2+
ions and the appropriate ddN triphosphate. Also, the active site was
extracted from the X-ray structure to minimize unnecessary calculations. Charges were then calculated by using the
Gasteiger-Marsili method. Connolly surfaces were generated in the
Molcad module of SYBYL with a probe radius of 1.4 Å and a dot density
of 5.0 points/area to reduce the calculation time. Docking was
performed by using the dock feature, and the energy was minimized.
| |
RESULTS AND DISCUSSION |
Qualitative structure-activity relationship: EPS maps of
nucleosides.
While the pathway for the mechanism of action of
anti-HIV nucleosides is complex, we have developed a method to
"group" active and inactive molecules by their EPS. This method
involves examining the pattern of high (positive, red-orange), neutral,
and low (negative, purple-blue) electrostatic potentials located on the
surfaces of the electron densities for a correlation. Molecules with
similar patterns of EPS can be grouped together and compared with
structurally related molecules that are active or inactive. All of the
molecules examined and their anti-HIV activities are shown in
Table 1 and Fig.
1.
Examination of the electrostatic potential of (
S,S)-isoddA
(compound 1) and various other ddNs shows some remarkable correlations.
For example, comparison of (
S,S)-isoddA (compound 1)
and (
R,S)-
or
-
D-AZT (compound 3) shows
that both molecules, in addition
to having similar overall
three-dimensional (3-D) electron density
shapes in their most stable
conformations, also exhibit similar
regions of high (red-orange,
positive) and low (purple-blue, negative)
electrostatic potential (Fig.
2). For purposes of comparison and
correlation, we have examined only the key regions on the surface
map
and have allowed for small deviations resulting from rotational
freedom
about the glycosidic bond.
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FIG. 2.
EPS of (S,S)-isoddA (top) and AZT
(bottom).
FIG. 3.
EPS of (S,S)-isoddA (top) and
(R,R)-isoddA (bottom).
FIG. 4.
EPS of (S,S)-isoddA (top) and
(R,S)-apio-isoddA (bottom).
FIG. 5.
EPS of (S,S)-isoddA (top) and ()-carbovir
(bottom).
FIG. 6.
EPS of (S,S)-isoddA (top) and oxetanocin A
(bottom).
FIG. 7.
Electrostatic potentials of ddC (top, both panels), 5-F-ddC
(bottom, left), and 5-Et-ddC (bottom, right).
FIG. 8.
Electrostatic potentials of (+)-dOTC (top) and ()-dOTC
(bottom).
FIG. 9.
Electrostatic potentials of ()-3TC (top) and (+)-3TC
(bottom).
FIG. 10.
Electrostatic potentials of L-d4A (top left),
L-d4FC (top right), L-d4G (bottom left), and
L-FddC (bottom right).
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|
This initial observation that two nucleosides that
are active against HIV may show similar EPS prompted us to
analyze some
active and inactive compounds. As expected,
(
S,S)-isoddA (compound
1) and its less active enantiomer,
(
R,R)-isoddA (compound 2),
exhibited different 3-D
electron density shapes and different
electrostatic
potentials (Fig.
3). Neither the
electrostatic potential
distribution nor the conformational map of
(
R,R)-isoddA correlated
with that of AZT. Comparisons
between (
S,S)-isoddA and the isoddNs
that were
inactive against HIV were also of significance. For
example, the anti-HIV-inactive
D- and
L-related apio-series of
isoddA (
30) exhibited
different electron density shapes and
different electrostatic
potentials from (
S,S)-isoddA (Fig.
4).
Differences in EPS were also apparent within the
(
S,S)-isoddN group, which was consistent with the anti-HIV
data that showed
that none of the compounds with bases other than
adenine had activity
(
30). Interestingly, a detailed
comparison of (
S,S)-isoddA (compound
1) with
(
S,S)-isoddC (compound 7) and (
S,S)-isoddT
(compound 8)
showed that they all had similar 3-D shapes and similar
electrostatic
potentials with the exception of the base region.
Conformational
data (see below) aided further in providing a possible
explanation
for the inactivity of (
S,S)-isoddC and
(
S,S)-isoddT. Interestingly,
the anti-HIV-active carbocyclic
nucleoside (
)-carbovir (compound
9) (
39), exhibited an
electrostatic potential distribution similar
to that of
(
S,S)-isoddA (Fig.
5). The
anti-HIV-active (
)-oxetanocin
A (compound 10) (
36)
also had an electrostatic potential map
similar to those of
(
S,S)-isoddA, AZT, and (
)-carbovir (Fig.
6).
Other active molecules have also been examined. Several different
patterns have emerged which show remarkable correlations
within their
respective groupings. One such group includes the
anti-HIV-active
molecule
-
D-ddC (compound 11) and several of
its
structurally related derivatives, including
5-fluoro-
-
D-ddC
(5-F-
-
D-ddC) (compound
12) and 5-ethyl-
-
D-ddC (compound 13)
(
7,
16,
29; D. Baker, C. K. Chu, and K. Agrawal, presented
at
the Workshop on Nucleosides in HIV Chemotherapy, Developmental
Therapeutics Branch AIDS Program, National Institute of Allergy
and
Infectious Diseases, 1988). All of these molecules show the
same
pattern of high and low electrostatic potentials (Fig.
7).
Also, other active, structurally
related molecules such as 3'
F-
-
D-ddC
(compound 14)
(
3,
11,
12,
22,
37) show similar patterns
with only minor
differences. However, inactive derivatives, such
as
3'
F-
-
D-ddC and 2'
F-
-
D-ddC
(
26), exhibit completely different
patterns.
Another group of active molecules that was investigated was related to
(
)-3TC (compound 15) and the active oxathiolane compounds
(
9,
24,
35). The molecules (+)-2'-deoxy-3'-oxo-4'-thiocytidine
[(+)-dOTC] (compound 16) and (+)-dOTFC (compound 17) had closely
related electrostatic patterns along with their mirror images
(
)-dOTC
(compound 18) and (
)-dOTFC (compound 19) (Fig.
8). Also,
(
)-2',3'-dideoxy-5-fluoro-3'-thiacytidine [(
)-FTC] (compound
20)
and (
)-3TC (compound 15) showed the same pattern of electrostatic
potential within their set and had the same general pattern as
their
counterparts, the oxathiolane compounds. Additionally, the
active
compound (
)-
-dioxolane G [(
)-DXG] (compound 21)
(
17)
showed EPS data similar to those of (
)-FTC (compound
20) and
(
)-3TC (compound 15). Differences were found between the
electrostatic
potentials of the potently anti-HIV active compound
(
)-3TC and
its less active enantiomer, (+)-3TC (Fig.
9).
The third series of active molecules examined comprised the
L-isomers of the d4N series (compounds 22 to 25) and the
-
L-isomer
of 5FddC (compound 26) (
5,
10,
23).
Remarkably, all molecules
investigated, regardless of their base
moiety, had the same pattern
of high and low electrostatic potentials
(Fig.
10).
Correlations with conformational maps of nucleosides.
In cases
where compelling correlations, particularly for inactivity, were not
available from the EPS data of nucleosides, we resorted to
supporting conformational explanations. Examination of the
conformational maps of the anti-HIV-inactive
(S,S)-isoddC (compound 7) and the anti-HIV-active
-D-ddC (compound 11) demonstrated that they are clearly
different (Fig. 11 and
12).
Among the major differences are the relatively larger number of less
favorable conformations in (S,S)-isoddC versus
-D-ddC and their corresponding locations. Also,
(S,S)-isoddC shows, within a local minimum region, several
conformations with relatively small distances from 5'-OH to O-2, which
would suggest the presence of hydrogen bonding (34) (Fig.
13; Table
2).
Finally, the anti-HIV-inactive (R,S)- and (S,R)-apio-isoddAs (compounds 4 and 5) demonstrated little
correlation with (S,S)-isoddA (compound 1) with respect to
conformational energy maps, in contrast to the similarity of these maps
for (S,S)-isoddA and other anti-HIV-active ddNs such as
-D-ddC (compound 11).
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FIG. 11.
Conformational maps of -D-ddC (left) and
(S,S)-isoddC (right).
FIG. 12.
Right-hand views of conformational maps for
-D-ddC (left) and (S,S)-isoddC (right).
Energies range from 4 to 22 kcal/mol for the -D-ddC
graph and from 6 to 18 kcal/mol for the (S,S)-isoddC graph.
FIG. 13.
Minimized structure of (S,S)-isoddC showing
hydrogen bonding between the 5'-OH and O-2 of the cytosine moiety.
FIG. 14.
EPS of (S,S)-isoddATP and AZTTP (far left),
(S,S)-isoddATP and oxetanocin triphosphate (middle left),
ddCTP and 5FddCTP (middle right), and ddATP and 2CF3ddATP
(far right).
|
|
Correlations of EPS data of nucleoside triphosphate inhibitors and
their binding to the active site of HIV RT.
It should be carefully
pointed out that the correlations described for nucleosides do not give
any information on the efficiency with which these compounds are
phosphorylated by kinases to their triphosphates, the actual cellular
inhibitors of HIV RT. Thus, a compound may have excellent EPS
correlations with other anti-HIV nucleosides but may not have
significant anti-HIV activity because of poor phosphorylation by
kinases. For this reason, we also examined the electron density and EPS
data of both active and inactive nucleoside triphosphates. The
correlations were remarkable. We discovered that AZTTP and
(S,S)-isoddATP have similar 3-D electron density surface
patterns and similar high and low regions of electrostatic potential
distribution (Fig. 14). The
triphosphate of the anti-HIV-active carbocyclic nucleoside,
()-carbovir (compound 9), also exhibited an electrostatic potential
distribution similar to that of (S,S)-isoddATP. Figure 14
shows the similarity of the EPS of the triphosphates of oxetanocin A
and (S,S)-isoddA. Correlations were also found with a number
of other active triphosphates such as -D-ddCTP and
5F--D-ddCTP. However, there was a clear difference
between the EPS data for the anti-HIV-active compound
-D-ddATP and the data for its inactive 2-trifluoromethyl
derivative (Fig. 14).
To further examine the binding relationship between the active site of
HIV-1 RT (
32) and triphosphate inhibitors, an EPS
of the
active site was then created. For Fig.
15, AZTTP was docked
into the active
site to show the interactions that occur with
Mg
2+ ions,
the amino acid residues Tyr115, Asp110, Asp185, and Asp186,
and the
growing viral DNA chain. As can be seen, each residue
of importance in
the active site has an electrostatic potential
that matches (is
opposite in electrostatic potential) with the
corresponding region in
the triphosphate. For Fig.
16,
(
S,S)-isoddATP
was docked into the active site of HIV RT and
the electrostatic
potential was calculated. The EPS matching between
inhibitor and
active site is clearly apparent. Other anti-HIV-active
nucleoside
triphosphates were also investigated, with similar results.
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FIG. 15.
Active-site model of HIV RT showing AZTTP binding
within the active site. Electrostatic potentials are shown for both the
ligand and the active site. Magnesium ions are behind the triphosphate
group.
FIG. 16.
Model of the active site of HIV RT with
(S,S)-isoddATP docked inside.
FIG. 17.
QSAR graphs showing the relationship between the actual and
the predicted biological activity (log 1/IC50). The ddC
series (left) and the 3TC series (right) are shown.
FIG. 18.
Bioactivities calculated from the QSAR analysis of each
series' CoMFA. Each series is shown with a molecule docked inside the
bioactivity measurement. In the D-ddC series (right),
-D-ddC is shown; in the 3TC series (left), ()-3TC is
shown.
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|
QSARs.
To further strengthen the nucleoside groupings that
have been highlighted thus far, QSARs were prepared for two
representative sets, D-ddC and 3TC. In this case QSAR
analysis was attempted in order to further illustrate the relationship
between electrostatic potential and anti-HIV activity. A QSAR set with
all examined molecules was attempted and found to have no defined
relationship. With this in mind, the groupings were developed to
perform the analysis. To accomplish this task, molecules were
structurally aligned, an MSS was created, and the CoMFA of each
molecule was calculated. CoMFA is a quantitative calculation of the
electrostatic potential and steric interactions of each molecule. The
use of CoMFA in QSAR is well documented (19, 20).
In these analyses, only CoMFA and the log 1/IC
50 values
were subjected to PLS analysis to ascertain the relationship between
each active nucleoside derivative and its corresponding electronic
structure. Due to the methods used for testing active nucleosides,
more
than one cell line and one set of published data were used
to
construct the QSAR analysis. This allowed confirmation of a
statistical
relationship between structure and activity but not
the determination
of specific activities of unknown sets. However,
the analysis
leads to a qualitative prediction of possible modifications
that
enhance activity. The groupings of molecules used and the
data
collected (cross-validated
q2,
r2, and
F values) are
summarized in Table
3, and the residual
values
for each molecule are shown in Table
4. The QSAR for the ddC
series
demonstrates the complexity of generating an accurate QSAR
with
predictive abilities. First, the cross-validated
q2 value is slightly lower than most
q2 values for other systems, but the
r2 and the
F values indicate
that there is a clear relationship
being produced. Graphical
representations of each QSAR are shown
in Fig.
17. In the oxathiolane series of
molecules, the
q2 was slightly lower than in the
ddC series, but the other data
suggest a more defined
relationship.
The data collected for the relative contributions of steric
interactions (0.601 for
D-ddC and 0.395 for 3TC) and
electrostatic
potential (0.399 for
D-ddC and 0.605 for 3TC)
also show that the
qualitative relationships that were examined
previously are adequate
for examining electrostatic potential except
perhaps in the case
of the
D-ddC series. In this case, an
additional analysis of the
respective volumes may be needed for a more
accurate qualitative
indicator of activity. The other series show that
electrostatic
potential is a slightly more important factor in activity
than
steric interactions with regard to a PLS analysis of CoMFA data
for each
series.
With the ability to generate a correlation among the active
nucleosides, the next step was to use this information to
generate
a predictive profile for the enhancement of antiviral
activity.
One method for accomplishing this is to use the QSAR
data to generate
a bioactivity representation of the electron density
and EPS.
Each series could then be examined for possible modifications,
and a log 1/IC
50 could be
predicted.
In this study, two representative series were examined, and the
predictions of changes to enhance their anti-HIV activities
are shown
in Fig.
18. Each qualitative
representation has different
colors to show the possible
modifications that could improve activity.
Steric bulk is represented
by yellow and green. Yellow is used
to show a region where a decrease
in steric bulk would improve
activity, while green represents a
region where an increase in
steric bulk would lead to improved
activity. Electrostatic potential
is represented by red and blue. Red
shows a region where a modification
in the electronic structure to a
more negative species would improve
activity, while blue shows a region
where a more positive charge
would improve activity. Ideally,
modifications in a number of
areas would be required to lead to a
highly active compound for
each series. A summary of the results of the
QSAR studies is shown
in Table
5.
In conclusion, examination of the anti-HIV data of some normal ddNs and
isoddNs, their 3-D electron density patterns, their
EPS, and their
conformational data reveals some interesting correlations.
The EPS of
(
S,S)-isoddA shows regions of high and low electrostatic
potential remarkably similar to those of
-
D-AZT,
(
)-oxetanocin
A, and (
)-carbovir. Correlations involving EPS data
and anti-HIV
activity were also found with many other active
nucleosides such
as those exhibiting EPS similarities with
-
D-ddC, (
)-3TC, or
L-d4A. Conversely,
inactive compounds had EPS different from those
of compounds in the
same series that were active. For example,
the anti-HIV-inactive
apio-ddNs exhibit clear differences in electrostatic
potential, 3-D
electron density shape, and conformational maps
from to the
anti-HIV-active isoddNs. The electrostatic potential
distributions of
active nucleoside triphosphates show remarkable
correlations. For
example, (
S,S)-isoddATP, AZTTP, and oxetanocin
A
triphosphate have similar 3-D electron density surface patterns
and
similar high and low regions of electrostatic potential, which
may
suggest that these compounds proceed through related mechanisms
in their interactions with, and inhibition of, HIV RT. Docking
of
AZTTP, (
S,S)-isoddATP, and other nucleoside
triphosphates into
the active site of HIV RT and calculation of the EPS
of both the
nucleotide and the active site show that there is excellent
matching
between the EPS data for the inhibitor and that for the enzyme
binding site. The structure-activity profile discovered has significant
ramifications and has contributed to the development of a first
predictive QSAR analysis in this area. This is also the first
comprehensive application of EPS data in the anti-HIV
field.
| |
ACKNOWLEDGMENT |
We thank the National Institutes of Health for support of this
research investigation (AI 32851).
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Department of
Chemistry, Room 415 CB, The University of Iowa, Iowa City, IA 52242. Phone: (319) 335-1364. Fax: (319) 353-2621. E-mail:
vasu-nair{at}uiowa.edu.
| |
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Antimicrobial Agents and Chemotherapy, November 2000, p. 2939-2947, Vol. 44, No. 11
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
