Indian Journal o f Che mi stry
Vol 45A, January 2006, pp. 13-20
Molecular Electrostatic Potential (MESP) studies on the
anti-hyperglycemic agents- 2,5-dihydroxyquinones
D S Patel", P Daga", P V Bharatam"·*, R K Dongareh & S R Gadreh·*
"De partment o f Medicinal C he mi stry, Nati o nal in stitute o f Pharmaceuti ca l Educ ati o n a nd Research (N IPER ).
S. A. S. Nagar ( Moh a li ) 160 062, Punjab. Indi a
Email: p vbh aratam @ niper.ac.in
hDepartme nt of C he mi stry, Uni versity o f Pune, Pun e 4 11 007 , India
Email: gadre@ che m.unipun e .ern et.in
Received 12 December 2004, revised 14 Nove111ber 2005
Th e mappin g of Mo lec ul ar Electrostati c Potential (MESP) has been carri ed o ut o n 2 ,5-dih ydro xyquinon e de ri va ti ves to
brin g out th e commo n set of e lectronic ch aracteri stic s o f mo lecul es th at act as e ffec ti ve in sulin mime tic agent s. A fo rce- fi e ld
based sys te mati c co nformati o nal search has al so been carri ed o ut o n eac h syste m to o btain the least e ne rgy co nfo rme r Th e
geo metry o ptimizati o n o f th e lowest e nergy conformer is carri ed out us in g quantum c he mi cal B3 L YP/3-2 1G meth od o n
eac h syste m to o btain th e wave fun cti o n. Th e MESP isosurface pl ots have bee n ge ne rated and th e c riti ca l po int
ch aracte ri sti cs es timated for th ese mo lecul es. Th e copl anarity o f th e two te rmin a l rin gs attach ed to ce ntra l
2.5-dih yd roxyquin o ne rin g as we ll as the availabilit y o f th e nearb y oxygen lo ne pa ir is see n to play impo rtant rol e in
definin g the anti -di abeti c acti vity of th e mo lecules.
Non-insulin dependent diabetes mellitus (NIDDM) or
type-2 diabetes mellitus (T2DM) is characterized by
an elevated blood glucose level that results from
inadequate in sulin action in insulin-sensitive tissues
and from abnormal insulin secretion . It is estimated
that by 2010, more than 220 mi II ion people
1
worldwide wi II be affected by the disease • Due to the
limitations of current therapy, there is a need for the
2
newer therapy in this area . A quinone derivative,
fungal metabolite Demethylasteriquinone (JMC-1)
from fungus of genus Pseudomassaria was found to
have anti-hyperglycemic activity . This small molecule
mimics the action of insulin by activating the Insulin
Receptor Tyrosine Kinase (lRTK) and shows
promi sing anti-diabetic activit/. The reported lead
compound JMC-1 acts on in sulin receptor with EC 50
of 5 ~tm in contrast to a closely related analog
L-767,827 which is about 100 times less active.
JMC-1
L-767,827
Further, some synthetic 2 ,5-dihydrox yqui no nes
were reported of which JMC-9 (Table l) show s very
high potency at concentration as low as 0. 3 ~un and
other JMC-4 does not show any activity. These data
show that the fungal metabolite JMC-1 is not the o nl y
isolated compound with the anti-diabe tic activit y but
further new ana logs based on thi s model can be
developed with potent anti-diabe tic activity that can
4
be feasible for discovering new therapy for diabetes .
Electrostatics of molecul es provides a hi ghl y
informative means of characterizing the essential
electronic features of drugs and th e ir stereoe lectro ni c
complementarity with the receptor site. Since the
receptor recognizes the stereoel ectronic effects and
not the atoms, studi es of three dime ns ional Mol ec ular
Electrostatic Potential (MESP) and its gradient plots
have
become
popular
for
characte ri zing
pharmacologically active
mol ecules
from
an
electronic point of view 5·6 . As the drug acti o n is a
result of the complementarity of the electroni c surface
of the dru g and the active site, it may be safe ly
assumed that the difference in drug action of a seri es
of molecules is a result of difference in the e lectro ni c
structure or the differences in the charge di stribution
in the molecules . The MESP analysis of several se ri es
of molecules has been reported to show cffec ti ve
correlation with their biological acti v ities 610 .
14
I ND IAN J C HEM . SEC A, JANUA RY 2006
The present study attempts to ex pl ore th e definiti ve
elec troni c ch aracteristi cs, which the 2,5-clihyclroxyqui non e cleri vat ives should possess so as to act
as effect ive in sulin mimetic agents. The coplanarity or
lack of coplanarity between th e rin gs probabl y
controls the activity of the set of molecul es.
Furthermore. th e presence or absence of n electron
di stributi on between the rings is a critical feature in
definin g the bi ologica l activity. In vestigations on th e
MESP topography. which gives a succin ct
interpretation of the weak intermolecular interaction s,
are being reported here.
Com putational Details
The 2,5-clihyclroxyquinone series (Table 1)
repo rted by Liu er a/.4 is employed in thi s study to
perform the conformational search and subsequent
11
geo metry optnmzatton.
SYBYL6.9
package
in stalled on Sili co n Graphics ' Octane 2' workstation
was us-eel to perform sys tematic conformationa l search
and population density calcul ation . The lowes t energy
conformers of all systems und er consideration were
subjected to ab initio density functional (DFT) 13
ca lculati ons employing B3L YP hybrid functiona l 14
with 3-2 1G basis set to ge nerate wave function s using
Gaussian98 package 15 .
The MESP, V( r ) at a point r due to a molecular
system with nu clear charges {ZA} located at a {R" }
and elec tron density p(r) is given by :
T abl e I -
M o l.
I. D.
Structures o r 2.5 di hydro xyquinone series with th eir
1
relati ve act i vit y and th e EC 50 va lues ( fLM )'
Ring B
Rin g e
Rc' l. acti vit y
1.00 (5.0 )
JMC-1
H
N
JMC-2
9i Po
0.71 (7 0 )
H
JMC-3
1(1
0.00 (N A )
JMC-4
JMC-5
611 (0 3)
Qj·~
3. 33 ( 1.5 )
0
JMC-6
Here N is th e total number of nuclei in th e
molecul e, the first term represents the contribution
due to nuclei and the second term ari ses due to the
continuous electronic charge density.
MESP is capab le of revealing subtl e changes
observed in the spatial electronic di stribution du e to
cha nges in the molecul ar framework by locating and
characteri zing th e critical points (CPs) 16· 17 • The
criti cal points are the points where all the three first
partial derivatives of the function under investigation
van ish. i.e. VV(r)=O. The CPs provide valuable
informati on about the structure and the environment
of the molec ule . The nature of a CP is determin ed by.
th e Hess ian matri x evaluated at the CP. The elernents
of Hessian matri x. which is real and sy mmetric (and
hence hermitian ), are given by:
.-.
• ;
l
-. ·' ··' ,1 . :- ..
i
~-
.JMC-7
Qt
5.00 ( I 0)
s
f1
u
>..
o.R:l (11 OJ
0. 16 (300)
.JMC-9
111.117 (03 )
.A- Not A ctive. fi gures in parenth eses indicate th e EC, 0 i. e.
effective co ncentration to achi ev e th e max imal n;spon se (th e
respo nse achi eved by 100 nM o f in sulin ) in at least 50°/c
an i.malsl :·
.i ; · '
PATEL el al.: MESP STUDIES ON 2,5-DIHYDROXYQUINONES
Diago nalization of thi s matri x by an orthogonal
transformation can be carried out in order to obtain
the eigenvalues A. 1, A.2 , A. 3 . If all the eigenvalues are
non-zero , the CP is known as non-degenerate, while a
CP with at least one zero eigenvalue is known as a
degenerate CP. The class ificati o n of non-degenerate
CP is done in terms of the number of non-zero
eigenvalues of the function fat that CP, known as R
(rank) and th e excess of the positi ve eigenvalues over
the negative ones, known as 0 (signature) . Such a CP
is assigned a label of (R, 0). If a ll the ei genvalu es are
positi ve, the CP refe rs to a minimum while if one of
th e eigenvalues is negative th e CP is sa id to be a
saddle. The no n-degenerate maxima and minima are
de noted as (3,-3) and (3,+3). respec ti vely while
18
saddl es are denoted as (3,-1) and (3,+1) .
MESP for all the molecules in their optimi zed
geometry was calculated and res pective topography
19
mapped using INDPROP . Th e MESP was sampled
over the entire accessible surface of a molecule
(conespo ndin g to a van der W aals contact surface) .
This color coded surface provides jnformation about
regions of negati ve valued potential (deep blue color)
susceptible for electrophillic attack and region s of
positive valued potential (red color) likely to be
attacked by nuc leophiles. The geometries and M ESP
isosurfaces were visualized usmg the package
UNIVIS-2000 (Ref. 20).
15
conformers were c hosen and energy minimized us in g
Tripos Force Fields. lt was observed that two rings,
substituted on ce ntral ring may or may not be
coplan ar so th at structure of interes t are stabl e in two
conformation as shown in Fig. I. It was found th at if
two terminal rings are coplanar then th e molecul e is
less stable as compared to the one in which these two
rings are orthogonal.
The most stable conformers were th e n o ptimi zed at
the B3L YP/3-21G level. The final B3LYP/3-2 1G
le vel optimized dihedrals of th e two aryl rings with
the central 2,5-dihydroxyquinone rin g are evaluated
and reported in Table 2. Tn the case of more acti ve
molecul es, ring C shows a planar confo rmation with
respect to the plane of central qui none rin g whil e rin g
B shows slight deviation from this plan arity. If thi s
deviation
exceeds
with
nng
B
becomi ng
perpendicular to the central qui none rin g, the
molecule shows lesser activity. Tn fact, steric reasons
force L-767,827 to be highl y strained and th e two
rings are almost pe rpendicular to ce ntra l ring leading
to lack of biological activity.
Table 2 -Dihedral angles calc ul ated at 8 3LYP/3-2 1G
optimi zed geome li"i es
'·
Results and Discussion
Conformational analysis
Since the bi oactive conformation of the 2,5dihydroxyquinones in the active site of receptor is not
known, the universal approach of approximation that
the bi oactive conformation is the leas t energy
conformer of the mol ec ule was followed. For thi s
purpose, a systematic search of molecule JMC-9 was
carried out around sin gle bonds. From many
conformers thus generated, the least energy
I
H
... , _
'*,1 /
/
I
Conformation I
Less stable
,
Conformation II
More stable
Fig. I - In co nfo rmation I, th e two terl"'linal rings are almost
cop lanar whil e in confo rmati on II, the two terminal rings are
al most orth ogona l in JMC-9.
·
'
Dihedral angle (cleg.)
Mol.
I. D.
Cll- C:~-CrC,
Cu-C,-C 5 -Cr.
JMC-1
22.05
59.5 1
J.MC-2 .
23.64
23.28
JMC-3
22.84
5.92
JMC-4
38.57
4 1. 27
JMC-S
37.59
42.3 8
JMC-6
42.43
9.13
. JMC-7
62. 16
0.07
c:·JMC-8
3.91
7. 09
' J~<::-9
22.48
6.26
INDIAN 1 CHEM, SEC A, JAN UA RY 2006
16
MESP analysis
The MESP topography calculation of the molecules
in Tabl e-! has been canied out to understand their
electrostatic features . MESP isosurfaces of selected
molecules are given in Fig. 2. The following
observations could be made from the MESP analysis:
1. The MESP isosurface (Fig. 2) of the lead
molecule JMC-1 (B and C rings are indole
derivatives), depicts that there is a continuum of
the negative valued MES P from the carbonyl
oxygen 011 towards the negative potential of the
Fig 2 -
2.
ring B, thus making its lone pair partially
The
available
for
weak
interactions.
perpendicular orientation of ring C with that of
the central ring A, leads to non -availability of the
lone pairs of the carbonyl oxygen 012 for weak
interactions.
The MESP isosurfaces of the most active
compounds JMC-3 (B ring is indole deri vative
and ring C is phenyl) and JMC-9 (B rin g is
indole derivative and ring C is phenyl) show
di stinct features (Fig. 2). Simil ar to JMC-1 , in
JMC-1
JMC-3
JMC-4
JMC-6
JMC-8
JMC-9
MESP isosurfaces of value - 12.55 (kca l/mol) of molecules at B3L YP/3-21 G level. Ato mic numberin g sc heme show n above is empl oyed.
17
PATEL et al.: MESP STUDIES ON 2,5-DIHYDROXYQUINONES
3.
case of both JMC-3 and JMC-9, an electronic
continuum is observable from the carbonyl
oxygen 011 towards the negative potential due to
the n: cloud of the indole ring B, which renders
partial availability of its (011) lone pair of
electrons for weak interactions. On the other
hand, ring C is almost planar to the central ring
A, which diminishes the chances of the lone pair
of electrons on 012 to be involved with the
negative potential due to the 1r cloud of the
phenyl ring and thus make them completely
available for any kind of weak intermolecular
interactions with the receptor. These two features
are considered to be favourable conditions for the
higher potency of the molecules.
4.
JMC-4 (B ring is phenyl derivative and ring C is
5.
phenyl) is the inactive molecule in the given
series. From the MESP isosurface of JMC-4
(Fig. 2), it can be seen that the perpendicular
arrangement of nng B induces greater
involvement of the lone pair of 011 to the
negative MESP potential of ring B. This region
also involves the negative potential from the
OCH 3 group. Hence, making 011 lone pairs
unavailable for any intermolecular interactions.
Ring C is also oriented perpendicular to the
central ring and we can observe similar negative
potential continuum from the lone pair of
electrons on both 012 and 09 towards that of the
phenyl ring. Thus in this case, there is complete
non availability of the 011 and 012 carbonyl
oxygen lone pairs to participate in intermolecular
interaction .
Table 3 -
~-naphthalene and
phenyl respectively) is less active molecule in the
series (Fig. 2). The terminal rings B and C are
coplanar with the central ring A, the MESP
isosurface of JMC-8 shows four small isol ated
negative potential regions around the two
carbonyl oxygen atoms and two hydroxyl oxygen
atoms from two larger negative potential over the
rings B and C. This allows the two lone pair of
electrons to be completely available for the
intermolecular interaction. This also appears to
be not the required character because when both
011 and 012 are equally available, specificity of
the interaction and orientation of the ligand with
receptor might reduce.
JMC-6 shows a moderate activity in the series,
the perpendicular orientation of ring B with that
of the central ring A, leads to non-availability of
the lone pairs of the carbonyl oxygen 011 for
weak interactions. However, ring C is slightly
above the plane compared to JMC-3 and JMC-9.
Continuum of the negative valued MESP from
the carbonyl oxygen 012 towards the negat ive
potential of the ring C is not observed, making
available the lone pairs of 012 for interactions.
The value of MESP minima at 012 for JMC-3
and JMC-9 is deeper than that of JMC-6, hence
making
it
slightly
less
available
for
intermolecular interactions with receptor.
JMC-8 (Rings B and C are
Critical point characterization
The MESP critical points were calculated at
B3LYP/3-21G optimized geometries details of which
are given in Table 3 and Fig. 3.
Details ofMESP CPs ca lculated at B3LYP/3-21G optimized geometries (in kcal /mo l)
MESP at (3,+ l) CP
MESP at (3,+3) CP
Molecule
l.D.
Rei.
activity
07
09
Oil
012
Ring A
Ring 8
Rin g C
JMC-1
1.00
-48 .1
-53 .3
-35.4
-47.4
134.4
195.7
196.6
JMC-2
0.16
-47.5
-46.6
-33 .3
-33.7
137.0
199. 3
199.8
JMC-3
16.66
-42.6
-30.2
-29.7
-30.8
142.0
202.8
102.4
JMC-4
N.A. "
-43 .2
-42.7
-46.0
-45.8
135.8
I ! 1.6
106.5
JMC-5
3.33
-41.9
-40.9
-37.2
-43.1
140.1
226.2
108.6
JMC-6
5.00
-41.1
-28.0
-37.4
-28.0
147.2
163. 1
105.4
JMC-7
0.83
-42.9
-25.9
-47.7
-29. 1
143 .9
108.7
103.4
JMC-8
0.16
-25.2
-27.0
-26.4
-27.2
146.5
104.5
105.5
JMC-9
16.67
-43 .5
-3 1.2
-38.2
-31.8
141.0
200.6
I 01.9
" Not active
INDIAN J CHEM, SEC A, JANUARY 2006
18
The fo llowing general features may be noted. In
the lead molecule JMC-1, almost similar higher
negative potential on all oxygens 07, 09, 011 and
012 has been found. The higher potency molecules
(JMC-3 and JMC-9) show much difference in the
negative potential on the oxygen 07 as compared to
that on oxygen atoms 09, 011 and 012. The
reduction in the negative potential on the 09, 011 and
012 has been found because of decrease in continuum
of negative potential on termin al rings with the
negative potential on the oxygen atoms due to their
lone pairs. As the difference in negative potential
among four oxygen atoms gets numerically reduced,
the biological activity also appears to get reduced, for
example, in the inactive molecule JMC-4, the
negative potential on the four oxygen atoms are
almost equal. The comparative electropositive
character at the ring centers of B and C rings also
appears to be informative. For example, in the most
active systems (JMC-3 and JMC-9), positive MESP
JMC-1
JMC-6
potential at ring Cis much smaller than that of ring B
whereas in relatively less active/in active systems
(JMC-4 and JMC-8), the difference in the positive
potentials of rings B and C is very small. The
electropositive character at ring center of ring A does
not seem to contribute significantly towards the
observed differential potencies of molecules since the
values for all the ligands are close. Both the criteria
considered above (i) the difference in the negative
potential on the oxygen 07 and 09, O J l and 012 and
(ii) difference in electropositive potential at th e rin g
ce nters of B and C rings are appear to be important.
For example, in JMC-5 the positive potential of ring
B is higher than ring C but simultaneous ly there is not
much difference between the negative potential on the
oxygen 07 and 09, 011 and 012, which reduce the
binding specificity of the li gand at the receptor site.
From the above discussion, the following
generalization can be made about th e MESP based
pharmacophoric features of title compounds. The
JMC-3
JMC-8
JMC-4
JMC-9
Fig. 3 - M ES P-tex tured van der Waals sur face of a few re presentati ve mo lecules. Red and bl ue co lo urs represe nt positi ve and nega ti ve
MES P respecti ve ly. [The respecti ve CP values (kcal/mo l) of negati ve mini rna are also sho wnj.
PATEL et at.: MESP STUDIES ON 2,5-DIHYDROXYQUINONES
higher activity of the 2,5-dihydroxyquinones can be
correlated to the MESP values on the four oxygen
atoms attached to the dihydroxyquinone ring. When
the negative potential on oxygen atoms due to their
lone pairs is not in continuum with the rr electron
potential of the terminal rings, the oxygen atoms are
freely available for binding with the receptor.
However, the partial delocalization 9f the potential on
one of the oxygen atoms appears to be desirable so as
to increase the specificity of ligand-receptor
interactions. Since our studies are_ carried out on a
small data set of molecules, it is de$irable to extend it
for a larger one and also at a better level of tlieory.
Conclusions
The detailed conformational analysis and the
MESP analysis of the 2,5-dihydroxyquinone series
brings out some significant features which are
seemingly a pre-requisite for the hi~her potency of the
molecule. The evaluation of the dihedrals of the two
aryl rings with the central 2,5-dihyproxyquinone ring
showed that one of the terminal rings should be nearly
planar to the plane of central quinone ting while the
other can be slightly deviated from this planarity. But,
none should be perpendicular · to ·central 2,5dihydroxyquinone ring. From the MESP isosurface
analysis, it is evident that the lone pair of electrons on
carbonyl oxygen 012 should be completely available
and the lone pair of electrons of the carbonyl oxygen
Oll should be partially available for any kind of
weak intermolecular interactions. The marginal
difference in the negative potential MESP value
ranging from -43.2 to -30.2 kcal/mol for the four
different oxygen atoms (07, 09, 011 and 012) and
200.6 kcal/mol MESP value of the ring B is also a
distinct feature for the most active molecule. Our
preliminary results from the B3L YP calculations at a
higher basis-set 6-31G(d) indicate that there are rather
small differences in the above two features noticed at
the lower basis-set. Thus, it may be concluded that
attempts to improve coplanarity between A, B and C
rings should be considered in future design of insulin
mimetics of this class of compounds.
Acknowledgement
RKD acknowledges
(OIB 446).
support
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19
INDPROP
Package,
Department
of
Chemistry,
U ni vers ity of Pune, Pun e, Indi a; see (a) Bapal S V,
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20
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