Int J Pharm Pharm Sci, Vol 7, Issue 12, 277-282Original Article

DESIGN, IN-SILICO DOCKING AND PREDICTIVE ADME PROPERTIES OF NOVEL PYRAZOLINE DERIVATIVES WITH SELECTIVE HUMAN MAO INHIBITORY ACTIVITY

VISHNU NAYAK BADAVATH*, BARIJ NAYAN SINHA, VENKATESAN JAYAPRAKASH

Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi 835215, Jharkhand, India
Email: vishnu.niper@gmail.com

 Received: 25 Sep 2015 Revised and Accepted: 02 Nov 2015

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ABSTRACT

Objectives: Curcumin, a known hMAO-A (human Monoamine oxidase-A) inhibitor from Curcuma longa has never been recognized for this property due to its poor permeability and extensive metabolism. Thus, the main objective of this study is to incorporate structural features of Curcumin in the pyrazoline scaffold as an attempt to get potent, selective hMAO-isoform inhibitors with improved permeability.

Methods: A series of twelve novel 4, 4'-(4, 5-dihydro-1H-pyrazole-3,5-diyl)bis(2-methoxyphenol) derivatives (1-12) were designed based on the structure of Curcumin. All the designed compounds were evaluated for their hMAO inhibitory activity by in-silico docking studies (Autodock4.20). The both isomers (R-and S-isomer) are considered for simulation approach to understand the effect of chirality and other structural features that determine the potency and selectivity. In order to judge the pharmacokinetic behavior, all the derivatives were evaluated for their in-silico ADME properties by using Qik Prop v 3.0.

Results: The results of the present study showed that all the designed compounds were found to be potent and selective hMAO-isoform inhibitors, and exhibited lead like properties from the calculated ADME parameters. Curcumin was taken as a standard for comparison to judge any improvement in permeability.

Conclusion: The design strategy adopted has predicted improved potency, selective towards hMAO-isoform and permeability characteristics in comparison with Curcumin.

Keywords: Pyrazoline, hMAO inhibitors, Molecular docking simulation, Autodock4.20, Pharmacokinetic parameters, Schrodinger LLC, Structure-activity relationship.

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© 2016 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)

INTRODUCTION

Monoamine oxidases are FAD (Flavin adenine dinucleotide) containing enzymes located on the mitochondrial outer membrane exists in two different isoforms, MAO-A and MAO-B. They metabolize dietary amines, neurotransmitters, are identified by the difference in their specificity towards their substrate and their selective inhibitors [1, 2]. Serotonin, adrenaline, and noradrenaline are preferably metabolized by MAO-A [3], while β-phenylethylamine and benzylamine by MAO-B [4]. Tyramine, dopamine, and some other important amines are common substrates for both the MAO-isoforms [5]. MAO-inhibitors introduced earlier were abandoned from clinical practice mainly due to their adverse effects; these adverse effects were mainly attributed to non-selective inhibition of isoforms. In the past decade, the interest in MAO inhibitors got renewed due to the fact that isoform-selective inhibitors, that are reversible, are showing potential therapeutic utility in the treatment of depression (MAO-A selective) and neurodegenerative disorders (MAO-B selective) [6–8].

Earlier few researcher synthesized pyrazoline derivatives and stated that the calculated (Ki value) obtained from the molecular docking studies (by AutoDock) concerning the hMAO inhibitory activities of the compounds were found to be in a good agreement with the experimental Ki value [9,10]. Thus, the present study in-silico docking has been performed to understand the interactions of Curcumin-based pyrazoline derivatives (1-12), which are crucial for their hMAO-isoform inhibitory activity. In-silico ADME parameters have also been performed by QikProp v 3.0.

Rationale of designing potent and selective hMAO-isoform inhibitors

Curcumin, a natural compound with proven MAO inhibitory and antidepressant activity [11–16]. As curcumin was having poor bioavailability [17], it is never recognized as a good antidepressant due to its poor permeability and bioavailability. The half-life (t_1/2) of Curcumin in phosphate buffered saline (PBS) at pH 7.2 was less than 10 min due to extensive metabolism [18]. In humans, Moclobemide (MOC) is rapidly and almost completely absorbed and totally metabolized by the liver [19], about 44 percent of the drug is lost due to the first pass effect through the liver [20]. The elimination half-life is around 2 h [21]. Selegiline (SEL) has a low oral bioavailability, which increases to moderate when ingested together with a high-fat meal, the molecule being fat soluble [22]. Selegiline oral bioavailability is drastically increased in females taking oral contraceptives (10-to 20-fold) [23]. This could lead to lose of MAO-B selectivity in favor of an MAO-A selectivity, which in turn would make patients susceptible to the usual risks of non-selective hMAO-inhibitors such as tyramine-induced hypertensive [23].

The novel pyrazoline derivatives (1-12) have been designed by utilizing the structural features in Curcumin. We design chalcone that resembles aryl-α,β-unsaturated carbonyl portion of Curcumin but by reversing the position of the double bond and the carbonyl group, then chalcone was cyclized to provide a series of novel pyrazoline derivatives (1-12) table 1, fig. 1.

Table 1: Structure of designed novel pyrazolines (1-12)

Compound	R	Compound	R
1	H	7
2		8
3		9
4		10
5		11
6		12

MATERIALS AND METHODS

Molecular docking studies were carried on RHEL-5.0 Operating system installed on Dell Precision workstation with Intel core 2 quad processor and 8 GB RAM by using AutoDock4.2 (The Sripps Research Institute) [24].

Molecular docking simulation procedures

In order to understand the interaction at the molecular level, compounds 1-12 were docked with X-ray crystal structure of hMAO-A (PDB: 2BXR) and hMAO-B (PDB: 2BYB) using AutoDock4.2 docking protocol reported earlier [25-30].

Ligand preparation

Ligand structures were drawn using build panel and prepared using Ligprep module implemented Maestro-8.4 (Schrodinger LLC). Energy minimization is carried out using OPLS 2005 force field. Structures were saved in PDB format for AutoDock compatibility. MGL Tools-1.5.6 (The Sripps Research Institute) was used to convert ligand. pdb files to the ligand. PDB qt files.

Protein preparation

X-ray crystal structure of hMAO-A (PDB ID: 2BXR) and hMAO-B (PDB ID: 2BYB) were downloaded from protein data bank (www. rcsb. org). Protein preparation wizard Maestro-8.4 (Schrodinger LLC) was used to prepare protein. Water molecules were removed from the protein, FAD was reconstructed, side chains were optimized for hydrogen bonding and finally energy minimized using OPLS 2001 force field. The protein was then saved in the PDB format. Using MGL Tools-1.5.6 nonpolar hydrogens were merged, assigned AD4.2 type, Gasteiger charges and finally saved in protein. PDB qt format.

Docking protocol

For docking, grid parameter file (. gpf) and docking parameter files (. dpf) were written using MGL Tools-1.5.6. Receptor grids were generated using 60×60×60 Grid points in xyz with a grid spacing of 0.375Å. Grid box was centered on N5 atom of FAD. Map types were generated using Autogrid 4.2. Docking was carried out with following parameters with a number of runs: 50, population size: 150, the number of evaluations: 2,500,000 and number of generations: 27,000, using Autodock 4.2.

Autodock run

Both protein and ligand were selected as a. PDB qt file from “docking”. Autodock was run for each ligand. Docking output was obtained as a. dlg format. Analysis of docking results was done using MGL Tools-1.5.6. A Top scoring molecule in the largest cluster was analyzed for its interaction with the protein.

ADME parameters prediction

ADME parameters were calculated using QikProp v 3.0 tools of Schrodinger software [31]. Qik Prop provides ranges for comparing an exact molecule’s properties with those of 95% of known drugs. QikProp also flags 30 types of reactive functional groups that may cause false positives in high throughput screening assays. It also evaluates the suitability of derivatives based on Lipinski’s rule of five [32-35], which is essential to ensure drug-like pharmacokinetic profile while using rational drug design. All the analogs were neutralized before being used by Qik Prop v3.0.

RESULTS AND DISCUSSION

Molecular docking simulation

Molecular docking simulation was carried out to understand the effect of chirality and other structural features that determine the potency and selectivity of designed novel pyrazoline derivatives (1-12). The 5C carbon of pyrazoline is chiral in nature and two isomers are possible. In the presented work, we considered both the R-and S-isomer to check the effect of chirality on potency and selectivity towards hMAO-isoforms. From the simulation results it seems the substituent’s at 1Nposition of pyrazoline has some effect in determining the potency of the isomers (R-isomer and S-isomer). Except compound 1 was found to be hMAO-B selective, when there is no substitution at 1N position of pyrazoline, while other compounds (2-12) having substituent’s at 1N position of pyrazoline increase in bulkiness and shifts selectivity towards MAO-A isoform with increase in potency too according to the Inhibitory constant (Ki) values obtained by docking analysis. Ki values are represented in table 2. According to the calculated Ki values, compound 8 exhibited the highest hMAO-A inhibitory activity, with higher SI than the standard drug Moclobemide SI. R-isomers of compounds (2, 6-8 and 10-12) were found to perform better than S-isomer, while in case of compounds (3, 5 and 9) S-isomer were found to perform better than R-isomer. Compound 4 R-and S-isomers were found to be equipotent towards hMAO-isoforms. For comparison ki value obtained by Autodock studies, the averages of R-and S-isomers were calculated for each isoform, and their isomer potency and selectivity index were calculated for better understanding. SI was calculated as K_i (MAO-A)/Ki(MAO-B). Selectivity towards MAO-A increases as the corresponding SI decreases while selectivity towards MAO-B isoform increases as the corresponding SI increases. Curcumin, SEL and MOC selectivity index was considered instead of selectivity MAO-A_rac/MAO-B_rac. (table 2). In order to understand the factors that contribute towards the selectivity and potency of the docked complexes of potent compounds (R-and S-isomers) were studied for their orientation and interactions in active site cavity of hMAO-isoforms were discussed below which sheds a light on the key structural features responsible for their potency and selectivity.

Orientation of compounds (1-12) in active site of hMAO-A

R-isomers compound 10 ring A at 3^rd position of pyrazoline towards pocket 2 (lined by Ile180, Ile335, Leu337, Met350 and Phe352). Ring B at the 5^th position of pyrazoline orient towards pocket 3 (lined by Gly74, Arg206, Ile207, Phe208, Glu216 and Trp441) and 1N-substitution of pyrazoline towards pocket 1 (aromatic cage lined by FAD, Tyr407, and Tyr444). All other compounds ring B towards the aromatic cage, ring A towards pocket 3, 1N-substituent’s towards pocket 2.

Orientation of compounds (1-12) in active site of hMAO-A

S-isomers Compound 1 orient in such a way that ring A towards pocket 3, ring B towards pocket 2, this will keep the aromatic cage empty. Compound (2-6 and 9-12) having 1N substituents fills the aromatic cage while rings A and ring B orient same as compound 1. Compound 7 and 8 having similar orientation ring A towards pocket 3 (same as compound 1-6 and 9-12) but ring B towards pocket 1 and 1N-substituents towards pocket 2, and these may be the reason that 1N-substituted pyrazolines exhibit selectivity towards hMAO-A isoform. Compound 8 having the bulkier substitution at 1N position than compound 7 these may be the reason why compound 8 having better Ki value than compound 7.

Interaction of compound (3) with hMAO-A

S-isomer Phenyl ring (Ring A) at 3^rd position of pyrazoline towards pocket 3, ring A establishes π-π interaction with Trp441 and with FAD, moreover ring A hydroxy oxygen forms a hydrogen bond with the oxygen of Pro72. Phenyl ring (Ring B) at the 5^th position of pyrazoline occupy pocket 2, and establishes π-π interaction with Tyr69. This places the substitution at 1N position to orient towards pocket 1, establishes π-π interaction with Tyr69, this may be the reason that S-isomer shows better (Ki value), potency and selectivity than R-isomer fig. 2.

Interaction of compound (3) with hMAO-A

R-isomer Phenyl ring (Ring A) at 3^rd position of pyrazoline occupy pocket 3, and ring A establishes π-π interaction with Trp441. Phenyl ring (Ring B) at the 5^th position of pyrazoline occupy pocket 1. The substitution at 1N position of pyrazoline orient towards pocket 2 fig. 3.

Interaction of compound (8) with hMAO-A

R-isomer Phenyl ring (Ring A) at 3^rd position of pyrazoline occupy pocket 3, and establishes π-π interaction with Trp441and Phe352. Phenyl ring (Ring B) at the 5^th position of pyrazoline towards pocket 1 and establishes π-π interaction with Phe352, moreover ring B-hydroxy oxygen forms a hydrogen bond with the oxygen of Tyr407. The substitution at 1N position of pyrazoline orient towards pocket 2 fig. 4.

Orientation of compounds (1-12) in active site of hMAO-B

R-isomers compound 11 ring A towards aromatic cage (formed by FAD, Tyr435, and Tyr398). Ring B and 1N-substituents of pyrazolines towards hydrophobic pocket (characterized by LEU171, TYR326, PHE168, ILE198, and ILE199). All other compounds ring B and 1N-substitution towards the aromatic cage, while ring A towards the hydrophobic cage.

Orientation of compounds (1-12) in active site of hMAO-B

S-isomers compound 8 ring A and ring B towards aromatic cage (formed by FAD, Tyr435, and Tyr398), and 1N-substitutituents towards the hydrophobic pocket, all other compounds ring B and 1N-substitution towards aromatic cage and ring A towards the hydrophobic cage.

Interaction of compound (1) with hMAO-B

R-isomer Phenyl ring (Ring B) at the 5^rd position of pyrazoline orient towards the aromatic cage, the hydroxy group of ring B established H-bonding interaction with 5N of FAD, this interaction is mainly stabilized by the strongπ-π interaction between Bring of the compound 1and the FAD. Phenyl ring (Ring A) at the 3^th position of pyrazoline keeps in the hydrophobic pocket and anchoring from their face of FAD with a distance of 3.564 Å, moreover establishes π-π interaction with Tyr435 fig. 5.

Table 2: Calculated K_i values corresponding to the inhibition of hMAO-isoforms by novel pyrazoline derivatives 1-12

Compound	MAO-A Calc. Ki (µM)		Isomer potency (R/S)	Racemic potency MAO-Arac =[(R+S)/2]	MAO-B Calc. Ki (µM)		Isomer potency (R/S)	Racemic potency MAO-Brac =[(R+S)/2]	Selectivity MAO-Arac/MAO-Brac	MAO Selectivity
	R	S			R	S
1	2.20	5.36	0.41	3.78	0.296	0.493	0.600406	0.789	4.79	MAO-B
2	1.87	4.83	0.38	3.35	247.51	3.32	74.5512	250.83	0.01	MAO-A
3	61.66	0.035	1761.71	30.84	-	258.92	-	-	-	MAO-A
4	0.151	0.151	1	0.15	35350	-	-	-	-	MAO-A
5	0.376	0.196	1.91	0.28	203310	-	-	-	-	MAO-A
6	0.090	0.192	0.46	0.14	266.12	143000	0.001	143266.1	9x10-7	MAO-A
7	0.750	2.85	0.263	1.8	9220	3.09	2983.81	9223.09	0.000195	MAO-A
8	0.281	0.483	0.58	0.38	-	-	-	-	-	MAO-A
9	0.441	0.238	1.85	0.33	9910	44.09	224.76	9954.09	0.00003	MAO-A
10	0.423	1.20	0.35	0.81	6.89	0.925	7.44	7.815	0.10	MAO-A
11	1.71	6.72	0.25	4.21	216.73	10.65	20.35	227.38	0.01	MAO-A
12	9.13	20.27	0.45	14.7	72910	186.57	390.79	73096.57	0.000201	MAO-A
Curcumin	0.602		-	-	16.40		-	-	0.036	MAO-A
MOC	7.91		-	-	12.13		-	-	0.652	MAO-A
SEL	78.26		-	-	93.62		-	-	0.835	MAO-B

Fig. 2: Interaction of S-enantiomer of Compound (3) with hMAO-A (PDB: 2BXR) active site, H-bonds are shown as green dots and π-π interaction as yellow cylinders

Fig. 3: Interaction of R-enantiomer of Compound (3) with hMAO-A (PDB: 2BXR) active site, H-bonds are shown as green dots and π-π interaction as yellow cylinders

Fig. 4: Interaction of R-enantiomer of Compound (8) with hMAO-A (PDB: 2BXR) active site, H-bonds are shown as green dots and π-π interaction as yellow cylinders

Fig. 5: Interaction of R-enantiomer of Compound (1) with hMAO-B (PDB: 2BYB) active site, H-bonds are shown as green dots and π-π interaction as yellow cylinders

Table 3: Predicted ADME parameters of novel designed pyrazoline derivative using QikProp

Compound	Mol. Formula	Mol. Weight	Log Po/w	Log S	Log BB	PMDCK	Human oral absorption (%)	Lipinski’s violations
1 (R)	C17H18N2O4	314.34	2.467	-4.166	-0.931	263.777	90.564	0
1 (S)			2.477	-4.238	-0.958	255.304	90.387	0
2 (R)	C19H20N2O5	356.37	2.669	-4.694	-1.065	204.091	89.899	0
2 (S)			2.669	-4.694	-1.065	203.993	89.894	0
3 (R)	C24H22N2O5	418.44	3.832	-5.476	-1.044	247.981	100	0
3 (S)			3.83	-5.471	-1.044	247.944	100	0
4 (R)	C23H22N2O6S	454.50	3.374	-5.279	-1.309	169.404	92.62	0
4 (S)			2.789	-4.182	-1.218	142.414	87.882	0
5 (R)	C24H24N2O6S	468.52	3.666	-5.814	-1.354	169.137	94.319	0
5 (S)			3.059	-4.52	-1.222	145.353	89.606	0
6 (R)	C24H22N2O6	434.44	4.048	-6.078	-1.092	274.421	100	0
6 (S)			4.049	-6.08	-1.091	274.542	100	0
7 (R)	C20H22N2O6	386.40	3.27	-5.38	-1.179	205.149	93.455	0
7 (S)			3.27	-5.382	-1.18	204.793	93.445	0
8 (R)	C24H23N3O4S	449.52	4.733	-6.648	-0.629	1172.325	100	0
8 (S)			4.678	-6.428	-0.592	1201.794	100	0
9 (R)	C23H22N2O4	390.43	4.879	-6.379	-0.617	653.791	100	0
9 (S)			4.88	-6.379	-0.617	653.51	100	0
10 (R)	C18H19N3O4S	373.43	2.699	-4.91	-0.847	575.814	91.096	0
10 (S)			2.699	-4.91	-0.848	575.465	91.093	0
11 (R)	C18H19N3O5	357.36	1.415	-3.063	-1.526	67.614	68.59	0
11 (S)			1.416	-3.065	-1.527	67.571	68.591	0
12 (R)	C18H20N4O4	356.38	2.042	-4.069	-1.673	61.088	77.555	0
12 (S)			2.042	-4.068	-1.672	61.086	77.555	0
Curcumin	C21H20O6	368.38	2.96	-4.349	-1.897	128.192	88.259	0
MOC	C13H17ClN2O2	268.739	1.829	-2.233	0.378	978.137	89.028	0
SEL	C13H17N	187.281	3.093	-2.09	0.646	1396.996	100	0

ADME parameterss

All the designed pyrazoline derivatives (1-12) R-and S-isomer were subjected for their predictive ADME parameters with their R and S-isomers, for physical descriptors and pharmaceutically significant properties of pyrazoline derivatives using QikProp v3.0 tool of Schrodinger software, among which major descriptors reported here are required for predicting the drug-like properties of molecules.

These properties are:

1. Molecular weight (Mol. Wt.) (150-650)

2. Octanol/water partition coefficient (Log Po/w) (-2-6.5)

3. Aqueous solubility (QPlogS) (−6.5-0.5)

4. Apparent Madin–Darby canine kidney (MDCK) cell permeability (QPPMDCK) (<25 poor,>500 great)

5. Brain/blood partition coefficient (QPlogBB) (−3.0-1.2)

6. Percent human oral absorption (≥80% is high, ≤25% is poor).

All the novel designed pyrazoline derivatives (1-12) (R-and S-isomers) showed significant drug-like characteristics based on Lipinski’s rule of 5. table 3. The designed pyrazoline derivatives follow the three properties of Lipinski rule of five (Mol. Wt.)<650, (logPo/w) between −2 to 6.5 and (QPlogS)>−7. (QPlogBB) parameter indicated the ability of the drug to pass through the blood-brain barrier which is mandatory for selective hMAO-B inhibition. The QPPMDCK predicted apparent MDCK cell permeability in nm/s. MDCK cells are considered to be a good mimic for the blood-brain barrier and higher the value of QPPMDCK, higher the cell permeability. All designed compounds showed ADME parameters in an acceptable range.

CONCLUSION

All the designed pyrazoline derivatives (1-12) were found to be potent and selective hMAO-isoform inhibitory activity than Curcumin. The results obtained by docking studies could be utilized for the development of novel pyrazoline derivatives with potent and selective hMAO-isoform inhibitory activity. The result of ADME parameters showed that all the designed pyrazolines exhibit lead like properties. The design strategy adopted has significantly improved the permeability characteristics in comparison with Curcumin.

ACKNOWLEDGEMENT

Author acknowledge to Birla Institute of Technology for providing financial support as a prestigious Institute Fellowship.

CONFLICT OF INTERESTS

Declared None

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