Criblage Virtuel POM des Acides Boswelliques comme agents

Transcription

428
Criblage Virtuel POM des Acides
Boswelliques comme agents
antitumoraux et Analogues des
Arganines A-K de l’Argania spinosa
Ben Hadda T.1*, Gharby S.2, Charrouf Z. 2, Al Afeefy A.3, Kabouche Z.5
& Masand V.4
1 - Prof. au Laboratoire Chimie des Matériaux, Faculté des Sciences d’Oujda, Université
Mohammed Premier, Oujda-60000, Morocco. E-mail: [email protected]
2 - Prof. Charrouf et Doct. Gharby au Laboratoire de Chimie des Plantes et de Synthèse
Organique et Bioorganique, Faculté des Sciences, B.P. 1014 RP, Rabat, Morocco. E-mails:
[email protected]; [email protected]
3 - Prof. au Department of Pharmaceutical Chemistry, College of Pharmacy, Alkharj
University, Alkharj, 11451, P.O. Box 2457, Saudi Arabia. E-mail: [email protected]
4 - Prof. au Department of Chemistry, Vidya Bharati College, Amravati, Maharashtra, India.
E-mail: [email protected]
5 - Prof. A la Faculté des Sciences, Laboratoire d’Obtention de Substances Thérapeutiques
(LOST), Université Mentouri-Constantine, Constantine 25000, Algeria. E-mail:
[email protected]
Résumé
Plusieurs analogues des saponines naturelles (Arganines A-K) ont été préparées par semi-synthèse,[1] en
modifiant les substituants à différentes positions du squelette carboné; ces auteurs ont élucidé le rôle structural des groupements fonctionnalisés; cétoniques, et hydroxyls et ester sur l’activité biologique de ces saponines.
Pour notre part, en utilisant le criblage virtuel (POM), nous avons confronté nos résultats bioinformatiques
aux résultats expérimentaux ci dessus, en étudiant les propriétés physico-chimiques, pharmaceutiques et les
effets toxiques possibles de ces saponines. Les résultats révèlent que la modification de la molécule originale,
à ces groupes fonctionnalisés change de façon significative l’activité biologique de la molécule mère.
Mots clés : Bioinformatique, criblage virtuel (POM), sites pharmacophores, saponines, Argania spinosa,
Acides boswelliques naturels.
Actes du Premier Congrès International de l’ Arganier, Agadir 15 - 17 Décembre 2011
429
Virtual POM Screening of Boswellic Acids as Analogues
of Arganines A-K extracted from Argania spinosa
Abstract
Several analogues of natural saponins (Arganines A-K) have been semi-synthesized [1] by modifying
the substituents at different positions of the carbon skeleton; in order to elucidate the structural role of this
drug’s ketonic/ester/alcohol functionalized groups. By using a virtual screening, we studied the physicochemical and pharmaceutical properties and the toxic effects of these molecules. In present work, we have
amalgamated three programs Petra/Osiris/Molinspiration (POM) for theoretical prediction studies of the
anti-Cancer activity. The results reveal that the modification of the original molecule (Arganine) at those
functionalized groups change significantly the biologicalA activity of the molecule.
Keywords: Bioinformatics, virtual screening, pharmacophore sites, saponins, Argania spinosa, Natural Boswellic acids.
Introduction
Pharmacologically, saponins family is the most important class of organic compounds that has been
extracted from Argania spinosa L. tree of Agadir at Morocco. Unfortunately, it received less interest than
it deserves. In this communication, we will compare with similar patented saponins derivatives (Natural
Boswellic acids).
The present investigation relates to pharmaceutical evaluation of compounds of general formula 1
with anticancerous activity.
H3C
H3C
CH3
CH3
O R3
O R3
CH3
HO
CH3
O
CH3
HO
R4
CH3
O
CH3
R4
O
O
R2
CH3
H3C
R1 O
Arganines
(A)-(K)
R2
H3C
R1 O
Arganines
(A)-(K)
Figure 1. General structure of some semi-synthetic Boswellic acids (a)-(f) [1] and some saponins
extractred from Argania spinosa; the natural Arganines (A)-(K) [4-8].
Results and discussion
Antitumoral screening of Boswellic acids
All boswellic acids (A)-(F) are derived semi-synthetically from natural triterpenoic acids known as
boswellic acids by the induction of apoptosis there of cytotoxicity and anti-cancer activity displayed by
semi-synthetic analogues of natural triterpenes, known as Boswellic acids [1]. These compounds may be
used for the treatment of cancer of colon, prostrate, liver, breast, central nervous system (CNS), leukemia
(Tables 1 & 2) and malignancy of other tissues, including ascites and solid tumors [1].
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Table 1. Preliminary bioactivity of boswellic acids as cytotoxic agent related anti-cancer agents [1].
Compd.
(A)
(B)
(C)
(D)
(E)
(F)
R1
H
H
H
H
H
H
R2
H
H
H
CH3CO
CH3CO
CH3CO
Substituents
R3
H
H
(O=)
H
H
(O=)
R4
CH3
H
CH3
CH3
H
CH3
Bioactivity [1]
IC50 (mM)
13
14
10
16
12
15
R5
H
CH3
H
H
CH3
H
Table 2. In-vitro cytotoxicity of natural boswellic acids on human cancer cell lines [1].
Compd.
Conc.
(A)
(D)
(E)
5x10-5
5x10-5
5x10-5
HT-29
68
96
91
Colon
SW-620
61
97
91
Colo-205
86
95
89
Hep-2
45
88
62
(Lung)
DU-145
95
0
88
PC-3
100
45
79
Virtual screening and molecular properties calculations
Osiris Calculations:
Structure based design is now fairly routine but many potential drugs fail to reach the clinic because
of ADME-Tox liabilities. One very important class of enzymes, responsible for many ADMET problems,
is the cytochromes P450. Inhibition of these or production of unwanted metabolites can result in many
adverse drug reactions. Of the most important program, Osiris is already available online. With our recent
publication of the drug design combination of various pharmacophore sites [9-15], by using heterocyclic
structure, it is now possible to predict activity and /or inhibition with increasing success in two targets
(bacteria and HIV virus). This is done using a combined electronic/structure docking procedure and
an example will be given here. The remarkably well behaved mutagenicity of divers synthetic molecules
classified in data base of CELERON Company of Switerzland can be used to quantify the role played
by various organic groups in promoting or interfering with the way a drug can associate with DNA.
Toxicity risks (mutagenicity, tumorogenicity, irritation, reproduction) and physicochemical properties
(ClogP, solubility, drug-likness and drug-score) of compounds (A)-(F) are calculated by the methodology
developed by Osiris as a sum of fragment-based contributions and correction factors (Table 3 & Figure 3).
Figure 3. Bioavailability evaluation and toxicity risks determination by using POM suite [2].
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Molinspiration calculations
CLogP (octanol/water partition coefficient) is calculated by the methodology developed by
Molinspiration as a sum of fragment-based contributions and correction factors. The method is very
robust and is able to process practically all organic and most organometallic molecules [9-15]. Molecular
Polar Surface Area TPSA is calculated based on the methodology published by Ertl et al. as a sum of
fragment contributions. O- and N- centered polar fragments are considered. PSA has been shown to be
a very good descriptor characterizing drug absorption, including intestinal absorption, bioavailability,
Caco-2 permeability and blood-brain barrier penetration. Prediction results of compounds and molecular
properties (CLogP, TPSA, GPCR ligand and ICM) are valued (Tables 3 & 4).
Table 3. Osiris calculations of compounds (A)-(F).
Toxicity Risks
Osiris calculations
Compd.
MW
cLogP
S
DL
D-S
456
5.4
-6.11
-2.46
0.19
(B)
456
5.5
-6.13
-2.03
0.2
(C)
470
4.73
-5.76
-1.77
0.23
(D)
498
5.89
-6.52
-2.37
0.16
(E)
498
5.98
-6.54
-1.92
0.16
(F)
512
5.22
-6.17
-1.72
0.19
MUT
(A)
TUMO
IRRI
REP
Lipophilicity (clog P value) and polar surface area (TPSA) values are two important predictors of
per oral bioavailability of drug molecules. Therefore we calculated log P and PSA values for compounds
(A)-(F) using molinspiration software programs and compared them to the values obtained for standard
market available drugs. In contrast to all compounds, for compound (C), the calculated log P value is
lower than 5, which is the upper limit for drugs to be able to penetrate through biomembranes according
to Lipinski’s rules. The polar surface area (PSA) is calculated from the surface areas that are occupied
by oxygen and nitrogen atoms and by hydrogen atoms attached to them. Thus, the PSA is closely related
to the hydrogen bonding potential of a compound. Molecules with PSAs of 140 Å or more are expected to
exhibit poor intestinal absorption.
The toxicity risk predictor locates fragments within a molecule which indicate a potential toxicity
risk. Toxicity risk alerts are an indication that the drawn structure may be harmful concerning the
risk category specified. From the data evaluated in Table 4 indicate that, all structures are supposed
to be mutagenic when run through the mutagenicity assessment system but as far as irritating and
reproductive effects are concerned, all the compounds are at low risk comparable with standard drugs
used. The log P value of a compound, which is the logarithm of its partition coefficient between n-octanol
and water, is a well established measure of the compound’s Hydrophilicity. Low Hydrophilicity and
therefore high log P values may cause poor absorption or permeation. It has been shown for compounds
to have a reasonable probability of being well absorb their log P value must not be greater than 5.0. On
this basis, all the series is having log P values under the acceptable criteria. Along with this, compound
(C) which has shown good antitumoral screening results is having low log p values as compared to other
compounds in the series. The aqueous solubility of a compound significantly affects its absorption and
distribution characteristics. Typically, a low solubility goes along with a bad absorption and therefore the
general aim is to avoid poorly soluble compounds.
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Our estimated log S value is a unit stripped logarithm (base 10) of a compound’s solubility measured
in mol/liter. There are more than 80% of the drugs on the market have an (estimated) log S value greater
than -4. In case of compound (A)-(F), values of log S are low as compared to others published series.
Further, the Table 4 shows drug likeness of compounds (A)-(F) which is not in the comparable zone with
that of standard drugs. The drug score combines drug likeness, clogP, logs, molecular weight and toxicity
risks in one handy value than may be used to judge the compound’s overall potential to qualify for a
drug. The reported compounds (A)-(F) showed moderate to good drug score.
Table 4. Molinspiration calculations of molecular properties and drug-likness of natural Boswellic
acids (A)-(F).
Compd.
Molinspiration calculations [a]
Drug-likeness [b]
MW
cLogP
TPSA
OHNI
NV
Vol
GPCRL
ICM
KI
NRL
(A)
457
6.79
58
2
1
471
-0.81
0.02
-0.44
0.79
(B)
457
6.79
58
2
1
471
0.24
0.01
-0.35
0.67
(C)
471
5.69
75
2
1
474
0.23
0.05
-0.63
0.84
(D)
499
7.493
64
1
1
508
0.06
0.02
-0.49
0.69
(E)
499
7.43
64
1
1
508
0.15
0.04
-0.41
0.58
(F)
513
6.39
81
1
2
510
0.15
0.10
-0.66
0.31
[a]
[b]
TPSA: Total Polar Surface Area; ONI: OH--NH Interraction; NV: Number of Violation, Vol: volume.
GPCRL: GPCR ligand; ICM: Ion Channel Modulator; KI: Kinase Inhibitor; NRL: Nuclear Receptor Ligand.
As recapitulation, we can say that the understanding of this situation of various bioactivities of
saponins of Argania spinosa is easy to interpret for the structural pharmacophore site in right face to
which should added a supplementary pharmacophore site in left face.
Conclusion
The results of present investigation support the suggested antitumoral pharmacophore sites
of boswellic acids. It has been suggested that the combination of two functional groups such as two
carboxylates or a carboxylate with hydroxyl groups present in these compounds are “pharmacophoric”
in nature. On the other hand, the rest of substituents (methyl substituents) increase the hydrophobic
character and liposolubility of the molecules. This in turn, enhances activity of the compounds and
biological absorbance, so as, all the semi-synthesized boswellic acids could be oxidized on double bond
and lead to new series containing more than one pharmacophore site have better pharmaceutical
properties.
Acknoweldgements
Prof. T. Ben Hadda is indepted to Organisators of “Premier Congrès International sur l’Arganier, 1517 décembre, 2011, Agadir, Morocco”, for financial support and transport facilities. He attests her that
it was a real success.
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Criblage Virtuel POM des Acides Boswelliques comme agents

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