Obsessive-compulsive disorder (OCD) is a heterogeneous disorder driven by multifactorial path-mechanism. Which are characterized by a complex influx of recurrent sensations, unwanted thoughts (obsessions) that can frequently antagonize for a short time frame (compulsion). The appearance of obsessive thoughts and recurrent compulsive actions OCD often includes anxiety symptoms because OCD disorders contribute to anxiety symptoms and characteristics, co-morbidity, course, and the treatment response of patients, which revealed close similarity¹ to neuro-biology.

Although, this is commonly related to a surprising degree of anxiety that happens sequentially that underline the event as “that (anxiety)-induced obsession and same (anxiety)-relieving compulsion”. However, based on analogous psychology, phenomenology and treatment of OCD, DSM-V (diagnostic and statistical manual of mental disorders-5) and ICD-11 (international classification of diseases-11) create a new category of OCD is OCD spectrum² disorder and OCRD (Obsessive-compulsive and related disorder).

Drug promiscuity³ implies a drug that can work on multiple molecular targets⁴, showing related or unrelated pharmacological impacts. Drugs may associate with undesired targets, directing to anti-target (off-target) effects (one of the principal causes concerning side effects). Therefore, interruption to stop off-target^5,6 consequences in the initial drug discovery platforms could decrease the chance of malfunction. The conversion within target and anti-target results are relevant to drug repurposing.

Drug repurposing policies could lower investigation and development expenses. This article details the growth in the rational reinforcement of drug promiscuity to the discovery of multi-target drugs, drug repurposing⁷ and promoting druggability in natural products or medicinal chemistry⁸.

Reasonably we are starting an interesting latest phase inside the story of pharmaceutical and natural product chemistry that needs a significant shift apart from a magic bullet or ‘one-drug-one-target’ mind-inclination. An important expanding representation regarding statements that define magic shotgun⁹ could recommend a continuous re-evaluation of the magic bullet or ‘one-drug-one-disease-one-receptor’ model that possesses overlooked studying inside the pharmaceutical sector toward the earlier few years. Although the possibility of shifting back to a pre-clinical approach is minimum, this is presently widely admitted that high-specificity for a particular target strength does not ever address the requisite efficacy versus side effect characterization. If such is the case, substantial hurdles lie progressing for the chemist, prominently balancing in vitro and in vivo actions according to optimizing the PK and safety characterizations. Therefore, in such conditions, in this article, we testify a multi-targeted (promiscuous or dirty drug) in silico druggability¹⁰ testing approach following its simultaneous investigation of in vivo studies in such regard. However, in our previous study, other researchers and we have also found it valid to a great extent. We are envisaging here to understand and explain its other aspect by investigating it in a new way.

Broad-spectrum symptomatology and complex neuronal network origin of OCD. Its close parallelism neurobiology and pathophysiology, among other CNS disorders. Only SSRIs is a better option till now than others group of CNS related medication. However, selectivity by properties of selective serotonin receptors has limited hit the all-targeted receptor that exacerbates various symptoms due to OCD and related disorders. Furthermore, SSRIs are very limited to the 5HT receptor pathways; in fact, OCD is well established and reported pathophysiology linked with 5HT, but we never ignore its links with cognitive behavior, NMDA receptor, and biogenic amines. In this situation, SSRIs and their use for OCD is limited coverage therapeutic boundary with interindividual variability, resistance from the currently available drug. Only SSRIs is a better¹¹ option till now.

Propranolol is a non-cardioselective β-blocker¹². It appears not to own ISA (intrinsic sympathomimetic activity), but it has membrane-stabilizing properties. It also controls hypertension, MI (myocardial infarction), pheochromocytoma, angina pectoris, cardiomyopathy and cardiac arrhythmias. It is also re-indicated¹³ and manages the aetiology and prophylaxis of migraine, hyperthyroidism, tremor, and sympathetic overactivity in managing anxiety disorders.

Prognostication of druggability, if a drug has previously has identified for a target, that target is by description druggable. If none identified drugs molecule binds to a target, then druggability¹⁴ is designated or prognosticated utilising various ways that rely on evolutionary connections.

Curcumin (Curcuma longa)^14–18 and propranolol display a plethora¹³ of pharmacological activity¹⁹ linked with²⁰ and druggable nature designated as a promiscuous or dirty drug (magic shotgun) that hit ‘on-target as well as ‘off-target’ (anti-target).

On another side, hardly 2% of human proteins combine among currently licensed drugs. Moreover, it is to estimate that merely 10-15% of human proteins remain disease-modifying while hardly 10-15% remain druggable (there is no similarity between the two), indicating²¹ that simply connecting 1-2.25% of disease-modifying proteins act expected to be druggable. Therefore, that seems that the number of distinct undiscovered drug targets is minimal. The "targephilic" strategy²² has proven to be more effective than clinically relevant drugs in discovering target-specific ligands.

Given the high incidence rate, slow rate of drug discovery, clearance of CDER (Centre for Drug Evaluation and Research), clinical trials, high cost, dosage form design and development, following "old" drugs to the therapy of both well-known and rare conditions remains a frequently winning resolution since that requires the application concerning more innoxious compounds. Potentially with less total development cost and shorter development time, defined pharmacokinetics (ADME, AUC, Cmax, Tmax), pharmacodynamics profile, proven formulations (solid-tablet, capsule, liquid-syrup, emulsions, parenteral) and margin of safety. So that, repurposing^7,23–25 of a drug is de-risked and well-qualified option²⁶ in this regard.

The current study provides an overview of multifunctional drugs that target receptors for CNS disorders. It emphasizes that multifunctional drug candidates can develop a quintet to provide both paregoric and disease-modifying effects. One component promotes specific drug properties of the therapeutic element. It acts on targets that produce additive or synergistic therapeutic responses²⁷. At the same time, it makes a therapeutic response at the desired target, inhibits unwanted responses mediated by alternative targets. Extends the duration of efficacy of a compound by contributing to another pharmacodynamic effect. The examples noted to offer a perception of the remarkable ability of drug discovery while new molecules that act on more than one target developed. This approach can improve drug efficacy, improve dosing regimens and reduce side effect profiles.

2. MATERIAL AND METHODS:

Drug likeness and in-silico ADMET analysis of curcumin:

The analysis of curcumin drug-ADMET similarity did evaluate using²⁸ the SwissADME^14,25 algorithm (http://www.swissadme.ch). Similarities²⁹ between curcumin and the drug predicted by Lipinski's rule³⁰ 5. The Law of 5 includes promising drug candidates for <5 Log P (CLog P), <5 H-binding donors, <10 H-binding acceptors, and <500 Da (molecular weight) drug candidates.

2.1 Animals:

Swiss albino mice (male 25 to 30gram) were divided into different groups like control and treated (n=6-9) housed (polypropylene cages) and put under standard laboratory conditions of temperature and relative humidity (25±2°C, 55±5%) sequentially, simultaneously with 12 h light/dark period. Mice administered with standard rodent chow, including water ad-libitum. Mice were accustomed to lab requirements for one week earlier to do the experiments. Though, All the experiments did conduct in a noise-free chamber between 09:00 and 15:00 h. The entire protocols for animal experiments did approve by the Institutional Animal Ethics Committee (IAEC-1337/PO/Re/S/10/CPCSEA) of the CPCSEA (Committee for the Purpose of Control and Supervision of Experiments on Animals), Animal Welfare Board-Ministry of Environment., Forests and Climate Change, Government of India.

2.2 Collection and extraction of rhizome of Curcuma longa extract:

Purchased the rhizomes of Curcuma longa³¹ from a local former of Kushinagar district, U.P India, and dried the same was in the sun for three days, cut into small pieces moreover again dried. Eliminated the uppermost bark of the rhizome to get the fresh rhizomes. The preserved rhizome³² was then grinded (electrical grinder-Havells momentum)) to get a fine rhizome powder. This powder was re-dried and was ready to use. This (1000 g) grinded rhizomes^33,34 powder was extracted with 900ml of anhydrous ethanol or dehydrated ethanol (C₂H₆O) by Soxhlation³⁵ for three days (72h). The obtained rhizome extract of Curcuma longa did concentrate at a temperature <50°C. The residue was freeze-dried. The curcumin in the EERCL did determine by using standard curcumin (Sigma Aldrich, USA), which was 86.48%. The substance of curcumin in the concentrate³⁶ was 89.35%. Further, EERCL did subject to phytochemical analysis³⁷ (including spectrophotometry and HPLC). The extract did employ for the investigation of pharmacological activity.

2.3 Drug and chemical:

Fluoxetine (Abbot India) and propranolol (Cipla India) samples were received as a gift and curcumin purchased from Sigma Aldrich, USA. The standard Ascorbic acid did obtain from the (Himalaya Drug Company, India). We have used other chemicals for experimental purposes from the research lab at our institute. All the solvents used were of analytical grade. All drugs, along with EERCL, were dissolved in 0.9% saline for pharmacological evaluations.

2.4 Treatments Protocol and Evaluation of Pharmacological and acute toxicity studies:

The initial phase of the hypothesis did base on using an in-silico (SwissADME drug-likeness) study for curcumin's promiscuous³⁸ or dirty drug-related nature, including target identification (druggability) and its repurposing. Finally, the in-vivo study used Swiss albino mice for reconfirming the SwissADME²⁵ target identification and drug-likeness studies outcomes of pre-predicted druggability (drug-receptor-protein interaction).

To assess the OCD related anxiety-like behavior provoked by different periods. It evaluated the withdrawal-induced anxious behavior of propranolol and its reversal or attenuation effect using curcumin or fluoxetine. Propranolol 10mg/kg i.p., did treat mice for seven days, and 24hrs, 7 and 21 days later, drug withdrawal did submit to the elevated plus-maze (EPM) marble-burying behavior (MBB) and the motor activity (MA) tests. In another protocol, EERCL (curcumin, 50 mg/kg) and fluoxetine (20mg/kg, i.p.); was administered once after 24hrs and seven days of restraint from propranolol to assess possible reversal or attenuation from the symptoms induced by propranolol removal. EPM outcomes revealed a decrease in complete parameters after 24hrs and seven days of the last exposure to propranolol, intimating OCD related anxiety-like behavior. In the MBB and MA test, 24hrs and seven days of abstinence revealed increased MBB and MA. However, for the dose reuses our previous acute toxicity studies³⁹ dose.

Overall, the present study evaluated OCD related anxiety-like behavior after different periods of abstinence (24 h, 7 and 21 days) from repeated propranolol administration in mice. In addition, it also examined the action of curcumin and fluoxetine in the attenuation or reversal of anxiety-like symptom behavior after seven days to 24 hours of propranolol withdrawal.

2.5 Elevated plus-maze:

The EPM⁴⁰⁴¹ for rats consisted of two perpendicular open arms (10cm× 50cm) and two closed arms (10cm ×50cm with 40-cm walls) in a vertical position. (5cm× 5 cm) of the central stage is attached by the open and close arms. The lateral walls and the panel of the closed components are composed of the floor of black acrylic and transparent acrylic. The bottom of the maze was 45 cm above. Later in the treatment and abstinence period, mice placed into the centre concerning PM (plus-maze) by its nose into the direction concerning one of the closed arms and observed during 5 min in the durability of the following framework: number concerning entries into the open and closed arms, and the time of durability in all of them. Cleaned all the equipment between one and another test with a 10% ethanol solution. An observer recorded the behaviors. The period of durability covers the time spent by the mice in the open and closed arms. Anxiolytic⁴² compounds decrease the animal’s reluctance to open arms and promote the exploration thereof. Divided the animal into different groups, with seven animals were in each group.

2.6 Assessment of Marble-burying Behavior (MBB):

The marble-burying behavior (MBB) paradigm evaluated the anti-OCD (anti-compulsive) activity, a well-accepted and widely used model for evaluating the anti-compulsive activity in animals (mice). In short, mice freely position in separate plastic cages (21 cm×38 cm×14 cm), including 20 small clean glass marbles (10 mm in diameter) that uniformly distribute on 5 cm profound sawdust bedding. The glass marble of fixed diameter arranges uniformly^43–46 spaced on beds in four rows of five. After thirty min presentation to the glass marbles, mice take out, and unburied marbles were count. A marble was considering ‘covered’ if its two-third size was covering with sawdust. The total number of marbles buried regard as an indicator of OC behaviour.

2.7Assessment Locomotor Activity (MA):

OCD is affected by MA; by utilizing Actophotometer (Biocraft scientific Ltd. India), the same (MA) were evaluate in a different set of mice, provided with a rectangular field and four photocells. The motor activity⁴⁵ was evaluated regarding the absolute number of light beam breaks in 10 min. A securing time of five min was given to each animal before the evaluation of the motor activity.

Clue and predictive legitimacy behind the MBB paradigm alongside an appraisal of motor activity in the current studies are that- a behavioural task (marble-burying behaviour paradigm) assesses mice have both OCD-like and anxiety-related behaviour.

2.8 Total antioxidant potential:

The phosphomolybdenum technique evaluated^47,48 the cumulative antioxidant activity of the extract according to the method as per citation. An aliquot (0.1 ml) of the sample at varying concentrations (20 to 100 μg/ml) was mixed, including 1 ml of reagent solution (and four mM ammonium molybdate, 28 mM sodium phosphate and 0.6 M sulphuric acid). The mixture was covered and incubated at 95°C for 90 min. Next, the mixture was cooled, the absorbance did measure at 695 nm against blank. A typical blank solution included 1 ml of reagent solution and the appropriate volume of the same solvent used for dissolving the sample, and it did incubate under the same conditions. The total antioxidant activity⁴⁹ was expressed as the absorbance value at 695 nm using a spectrometer (Shimadzu UV) against blank. Ascorbic acid did use as the reference standard. Based on the calculated absorbance, the cumulative antioxidant activity was recorded (mg/ml) from the calibration line; the antioxidant activity is denoting the number of equivalents of AscAE (ascorbic acid).

2.9 Statistical analysis:

Utilizing either one-way ANOVA, followed by Newman-Keuls test for multiple comparisons or two-way ANOVA accompanied by Bonferroni test for multiple comparisons, whenever required. All data expresses as mean ±SEM (standard error of the mean). p<0.05 was considered significant in every case for the effect of EECLR on MBB and MA test.

RESULTS AND DISCUSSION:

Curcumin has met the requirement for drug-likeness and good physicochemical properties:

We attended in silico (medicinal chemistry), ADMET (pharmacokinetic) investigations and "drug-likeness" applying Lipinski's rule of five on curcumin (1E,6E)-1,7-bis(4-hydroxy-3-methoxyphenyl) hepta-1,6-diene-3,5-dione) (Figure 2) to discover their activity inside the human body. Newly found the in-silico approach to identify a safe and potential drug candidate and mark the possible molecular mechanism of action (m-MOA) of natural molecules with a giant protein. Our conclusions revealed that curcumin has good physicochemical and bioavailability features (Figure1). The GI (gastrointestinal tract) passively absorbed but had poor permeability of blood-brain barrier (Figure 2). The 'Bioavailability Radar' (Fig.2) did create based³⁰ on the prediction of six physicochemical properties; These wanted ranges are symbolised by the bioavailability radar's pink shaded section. Following all six properties for curcumin are inside the pink spectrum, as per the SwissADME estimations, it is fit to continue to get accepted as a drug. Furthermore, it did predict to have a high GI (gastrointestinal) absorbance and zero violations (no violations) of rules defining drug-likeness. It has synthetic availability (2.97%) and good H₂O solubility (Logs=-3.94). The consequences of ADME and drug-likeness features and the bioavailability scores intimate that curcumin has good drug-likeness features and thus have a good potential to be developed into an oral drug for therapeutic use.

TAA (Total antioxidant activity):

The antioxidant action of the curcumin did evaluate the phosphomolybdenum process, accompanied by comparing by the standard solution of ascorbic acid equivalents. The standard curve of ascorbic acid did do with applying ascorbic acid concentrations varying from 20 to 100 μg/ml. The resulting equation showed the absorbance of ascorbic acid standard solution as use of concentration:

Y = 0.5814x + 0.0342, R2 =0.9978

Where x is the absorbance and Y is the ascorbic acid⁵⁰ equivalent (mg/g). Curcumin showed an increase in antioxidant capacity with a rise in dose. The TAC (total antioxidant capacity) of EERCL (Curcumin) did found to be 33.48 ± 3.16 μg ascorbic acid equivalents at 100 μg/ml curcumin concentration. That concludes the TAC. The phosphomolybdenum method did found at the reduction of Mo (VI) to Mo (V) by the sample analyte and the following form of green phosphate Mo (V) complex with maximum absorption at 695 nm. The extract reduced molybdenum VI to a green coloured phosphomolybdenum V complex. This good antioxidant activity may attribute to the presence of high amounts of polyphenols in these extracts.

Fluoxetine (BBB) Propranolol (BBB) Curcumin (GIT)

Fig-3 (a) Target with target class and probability score (b) NCBI, KAAS-KEEG42,43 study result for OCD shows- Related pathway hsa04726 Serotonergic synapse and Gene- HTR2A (promoter polymorphism) [HSA:3356] [KO: K04157] other OCD related protein (Sodium-dependent serotonin transporter) and gene-SLC6A4 Annotation score five out of five via UniProt and further structure is given below (#164230) (b) Boiled EGG model for Curcumin, Fluoxetine and Propranolol.

Table-1 TAC (Total antioxidant capacity) of EERCL (Curcumin).

S.No.	Sample	TAC (mg AscAE/g)
1	EERCL(Curcumin)	327.45±2.32
2	Vit C (Ascorbic acid)	-

Data are shown as mean (SD)

Table-2 shows a meaningful reduction in the parameters investigated in the EPM^41,42 test after a 24 h withdrawal period from repeated propranolol treatment EOA – entries in open arms: p < 0.01; TDOA – time of durability in open arms: p < 0.05; %TOA

Table-2

S. No.	PMT	Ppl 24 hrs	Ppl 7 days	Ppl 21 days
1.	EOA	F_{(1, 13)}=4.12^##	F_{(1, 13)}=3.29^##	F_{(1, 13)}=0.214
2.	TDOA	F_{(1, 13)}=3.10^##	F_{(1, 13)}=2.93^##	F_{(1, 13)}=0.116
3.	%TOA	F_{(1, 13)}=5.11^#	F_{(1, 13)}=3.56^#	F_{(1, 13)}=2.017

Table-3

S.No.	24 Hrs	EERCL	Ppl+Curcumin	7 Days	EERCL	Ppl + EERCL
1.	EOA	F_{(2, 18)} = 6.14#	F_{(3, 24)} = 4.15#	EOA	F_{(2, 18)}= 0.58	F_{(3, 24)} = 5.15^#
2.	TDOA	F_(2,18)=23.29###	F_{(3, 24)} = 26.16###	TDOA	F_{(2, 18)} = 5.17#	F_{(3, 24)} = 10.52^##
3.	%TOA	F_{(2, 18)} = 4.19##	F_{(3, 24)} = 21.26##	%TOA	F_{(2, 18)} = 9.98#	F_{(3, 24)} = 20.21^###

Table-4

S.No.	24 Hrs	FLX	Ppl + FLX	7 Days	FLX	Ppl + FLX
1.	EOA	F_{(2, 18)} = 5.03^##	F_{(3, 24)} = 10.07^#	EOA	F_{(3, 24)} = 0.89^##	F_{(3, 24)} = 5.14^##
2.	TDOA	F_{(2, 18)} = 6.12^##	F_{(3, 24)} = 19.47^##	TDOA	F_{(3, 24)} = 3.14^###	F_{(3, 24)} = 10.98^###
3.	%TOA	F_{(2, 18)} = 5.11^##	F_{(3, 24)} = 48.98^###	%TOA	F_{(3, 24)} = 0.74^#	F_{(3, 24)} = 4.15^#

Table 2-4, Events of plus-maze test subsequently 24 hrs, seven days and 21 days withdrawal Propranolol (A). Results of treatment with Curcumin (B), Fluoxetine (C) subsequent withdrawal Propranolol 24 hrs and seven days. For data analysis, ANOVA accompanied by Student–Newman–Keuls analysis as post hoc was practised. Significant consequences #p < 0.05 versus propranolol, ##p < 0.01 versus Propranolol, ###p < 0.001 versus Propranolol.

EOA = entries in open arms (Expressed in number) (N), TDOA = time of durability in open arms, %TOA = percentage of time in open arms, Ppl=Propranolol, EERCL=ethanolic extract of rhizome of Curcuma longa (Curcumin) Flx=fluoxetine PMT=Plus maze test– percentage of time in the open arms:p < 0.01), that continued for 7 days (EOA: p < 0.01; TDOA: p < 0.01; %TOA: p < 0.05) when compared to their corresponding controls (24 h and 7 d). No statistical difference did see after 21 days of abstinence compared to the control (Table-2). The influence of drugs used to reverse anxiety 24 h after the propranolol treatment in the EMP tests shown in the table-2. Treatment with curcumin (EERCL) after 24 h of abstinence was able to reverse all parameters evaluated in the EMP test (EOA: p < 0.05; TDOA: p < 0.001; %TOA: p < 0.001). Likewise to EERCL (curcumin), fluoxetine administered after 24 h of abstinence shifted the propranolol-induced anxiogenic impact (EOA: p < 0.001; TDOA: p < 0.001; %TOA:p < 0.001). The table-3 exhibits the effects of drugs applied to reverse anxiety observed seven days after propranolol withdrawal in the EMP experiment. EERCL administered seven days after propranolol withdrawal significantly diminished the anxiogenic effect caused by propranolol abstinence (EOA: p < 0.05; TDOA: p < 0.01; %TOA: p < 0.001), however, EERCL administered alone alter these parameters. Administration of fluoxetine 7 days after propranolol withdrawal reduced the anxiety (EOA: p < 0.05; TDOA: p < 0.01; %TOA: p < 0.05), while fluoxetine administered alone did not alter the parameters in the EMP vs control (normal saline). Recommending propranolol withdrawal induce anxiety effect in the animals (EOA: p < 0.001; TDOA: p < 0.001; %TOA: p < 0.001).

Table 5 Effect Ppl withdrawal on MBB and MA test.

Treatment Group	MBB	MA
Control 24 h	11.98±0.84	311.57±14.46
Propranolol 10 mg/kg (24 h)	15± 1.58^**	417.86±12.21^**
Control 7 days	9.74±1.95	376.12±8.65
Propranolol 10 mg/kg (7 days)	10.21±2.74^*	407.25±6.99^*
Control 21 days	12.14±0.96	377.47±7.45
Propranolol 10 mg/kg (21 days)	7.89±1.08^#	389.76±10.64^#

The values are expressed as the mean ± SEM, (n=6). P<0.05 when compared to control

Table-6 Effect of Curcumin (EERCL), Fluoxetine administered after Propranolol withdrawal 24 h on MBB and MA (motor activity)

Treatment Group	MBB	MA
Control	12.81±0.74	335.57±12.12
Propranolol 10 mg/kg	14.47±2.01^***	405.42±11.28^**
EERCL 50 mg/kg	1.12±1.67^**	305.46±6.18
Ppl+EERCL	2.41±0.76	291.98±5.89**
Fluoxetine 20	0.45±0.04^***	315.56±8.12***
Ppl+Flx	1.18±0.18^#	356.45±6.19^#

The data are expressed as the mean ± SEM, (n=6). P<0.01 when compared to control

Table-7 Effect of EERCL and Fluoxetine administered after Propranolol withdrawal 7 d on MBB and MA.

Treatment Group	MBB	MA
Control	10.81±1.79	354.16±12.41
Propranolol 10 mg/kg	7.74±4.84^*	429.56±14.21^*
EERCL 50 mg/kg	0.48±0.15^**	341.14±4.65^**
Ppl+EERCL	1.25±1.89	398.97±9.67^#
Fluoxetine 20	0.42±1.25^**	318.45±6.45^**
Ppl+Flx	1.80±2.24^#	297.12±9.14^#

The data are expressed as the mean ± SEM, (n=6). P<0.001 when compared to control

Effect Ppl withdrawal on MBB and MA test. (A) Control (saline), Propranolol (10 mg/kg) were administered i.p for seven days, and MBB motor activity was registered after 24 hr, seven days and 21 days of propranolol withdrawal. (B) Effect of Curcumin (EERCL), Fluoxetine administered after Propranolol withdrawal 24 h on MBB and MA (motor activity). (C) Effect of EERCL and Fluoxetine administered after Propranolol withdrawal 7 d on MBB and MA. The results did express as mean ±SEM number of MB in 30 minutes and the light beam breaks in 10 minutes. For statistical analysis, ANOVA followed by Student–Newman Keuls or two-way ANOVA followed by post hoc test (A2 and A3) did use. EERCL, e = p < 0.05 versus Fluoxetine, f = p < 0.05 versus Ppl + EERCL. Ppl = propranolol, Flx=Fluoxetine

In table-5., it is noted that propranolol abstinence at 24 h MBB and locomotor activity (p< 0.05), (p < 0.05) respectively and seven days (p<0.05), (p < 0.01) significantly increased MBB and MA of animals concerning the control group. However, 21 d of abstinence does not change parameters compared to the control group. The table -5 shows that treatment with curcumin reduced MBB (p<0.01) and MA of animals after 24 h abstinence compared to the propranolol-exposed control group (p < 0.05), and the group treated only with curcumin reduced the MBB (p<0.01) and MA (p < 0.05) compared the control. On the other hand, treatment of propranolol exposed group with fluoxetine reduced the locomotion (p < 0.001) while animals given only fluoxetine presented no significant change in MA; however, MB did diminish. Considering the seventh day of propranolol abstinence, treatment with curcumin reduced the MBB and MA (reduced but insignificant reduction in MA) of animals (p < 0.05) vs control.

However, such effects (EPM, MBB and MA) persist more significantly only for 24–48 h, with a significant⁴³ decrease after 48 h and disappearing entirely after 21 days. The interruption of motor activity and attenuation in MBB during the treatment of EERCL (p<0.01) and fluoxetine (p<0.001), after propranolol withdrawal (24 h), successively and continuing chronic treatment 24h and 7 d after the propranolol withdrawal attenuation in MBB and MA, but reduced MA is insignificant, i.e. overall MA is statistically unaffected (with chronic treatment only). Such results lead to a standard treatment option for OCD (defined as a dose at which MB decreases, but MA is unaffected) related anxiety. As previously reported, which was induced by PCPA instead of propranolol. Resulting in treatment a reduction in MB and MA (however, the reduction in MA was statistically insignificant). As mentioned earlier, there is a reduction in MB only, but MA is unaffected. But it is not like, for example, that it happens in benzodiazepines and others drugs, which have attenuated MB but affect MA. It is against the standard treatment of OCD, i.e. even if there is a reduction in MB, there is no effect in MA. This situation clarifies the same^46,51, and if the drug has the property of anti-OCD (anti-compulsive), it shows on chronic treatment with outcomes of attenuation of MB without affected the MA.

Propranolol is adopted globally for quick response in CNS disorders like panic or anxiety cases. However, its withdrawal from prolonger uses causes relapse, which is one of the challenges faced by propranolol users. In most cases, users may manifest signs such as anxiety or panic situations according to the duration of abstinence. However, withdrawal-induced symptoms are also significantly correlated with comorbidity in OCD.

Previously reported, the anti-compulsive fluoxetine, an SSRI (selective serotonin reuptake inhibitors) — act via inhibiting the reuptake of the neurotransmitter 5HT in presynaptic neurons. But the computational technique well anticipated that SSRIs, including fluoxetine, also serve as beta-blockers like propranolol, anticipation established in vitro. The outcome advises that a few of these side effects happen if sufferers discontinue using SSRI anti-compulsive might be affected by a rebound to β-adrenergic signalling⁵².

Since 5HT and β-adrenergic receptors bind through chemically related, naturally occurring ligands, the beta-blocker activity of SSRIs might not be too unexpected. A much more formidable challenge is to predict a compound's multifunctional activity for drug targets that share no fundamental similarity in terms of protein structure or endogenous ligands. Further, the technique comes up with the confirmed SEA (similarity ensemble approach) prediction³.

Identifying an active drug and its mechanism of action to determining therapeutic potential only after identifying drug-like compounds that interact with a target site. Although the emphasis on target identification, or “targephilia,” has yielded novel drugs²², overall, it appears to have slowed the drug discovery process, especially for compounds used in treating central nervous system (CNS) disorders. This is because the “targephilic” approach requires a good understanding of target physiology and its integration with the target organ, with a hierarchical integration from in vitro cellular and functional tissue studies to animal models that reasonably predict human responses. Because the majority of CNS drugs were discovered empirically, drug discovery in this area appears less amenable to target-based approaches^7,22 than it seems for other types of therapeutics. Improving the success rate in CNS drug discovery requires a more pharmacometrics-based approach, with a renewed emphasis on defining basic CNS function in intact animals and a more systematic in vivo screening of novel structures. Efforts must also be directed toward defining the sites of action of existing CNS drugs to aid in the design of second-generation agents²² with improved efficacy and safety.

In earlier studies, it has stood shown that the antioxidant activity of fluoxetine⁵³ did an effect similar to curcumin. However, this study has done repurposed against the selective nature of fluoxetine, with the wanted effect of magic shotguns (scattergun effect), i.e., curcumin^9,27,39,54, which effectively solves the complex nature of OCD. And on the other hand, it has also done showed that fluoxetine has anti-compulsive activity. Therefore, in this entire study, research is playing a leading role in the direction of curcumin to act like fluoxetine.

In the end, the result is telling us the same. However, comparing the selective action of fluoxetine with the magic shotgun properties of curcumin may be a research question. We have already discussed this speculation regarding multifunctional draggability and their repurposing, but the act of fluoxetine on the serotonin receptor is also not very selective. Because the serotonin receptor also has many (more than14) receptors, research has also seen this^11,55–57. A sudden cessation of propranolol^58,59 is causing withdrawal symptoms. In some patients, this beta-blocker withdrawal-induces - is also causing beta Blocker syndrome. Overall, the antioxidant effect of curcumin similar to that of fluoxetine and the withdrawal of propranolol are producing anti-OCD, and OCD related anxiety-induced syndrome, respectively.

Earlier investigations have shown that the anti-compulsive effect of curcumin did contribute by antioxidants, neuromodulators, and the 5HT1a receptor⁵³.

The main reason for using propranolol in this study was that its lipophilic⁵² and multifunctional properties quickly used in anxiety. Although this effect wears off very quickly, there a quick response is the first choice.

Animal studies in the present research also found that this (propranolol) is valid to a great extent because, in the same way it is giving quick response in the EPM and MBB model test, it is causing the withdrawal-induced syndrome by stopping it suddenly. We also found in this study that the propranolol withdrawal induces model did significantly more meaningful than PCPA generates OCD. However, this needs to be optimised once again as an induction model only because the propranolol-induced model has a higher human or clinical correlation than that of PCPA⁶⁰ (p-chlorophenylalanine).

The anti-compulsive activity of curcumin, a FRAC in curcumin and ascorbic acid in traces, was also found according to phytochemical screening and in silico study support the previous study⁶¹. Apart from EPM, this is important for checking MBB and MA; at present, the investigation of MBB and MA has shown more predictive validity than EPM and open field studies. Another reason for using MBB and MA is that the behavioral task (marble-burying behavior paradigm) assesses mice with both OCD-like and anxiety-related behavior simultaneously than another model.

Drug-likeness, target identification and ADME²⁵ did identify using SwissADME, which (Fig 1-2) did observe to have drug-likeness³⁰ properties (no violation of observation regarding Lipinski's rule of 5). However, target identification resulting give 1oo target classes (including enzyme, ion channel, receptor, target protein and histone protein etc.) shown in (fig. 3-b) in which MAO-A (monoamine oxidase A) have a high probability score among all target classes. And it has good absorption from GIT, which remains set on the Boiled egg model^14,30.

The study of the KAAS-KEGG⁶² (KEGG Automatic Annotation Server, where KEGG, i.e., Kyoto Encyclopedia of Genes and Genomes) model describes the previously acquired target, receptor, KO (KEGG orthology) and receptor/target network of OCD and curcumin. That identifies as ortholog assignment of KO, i.e., bidirectional best-hit (BBH) method using FASTA, is an extra sequence alignment tool utilised to search for similarities among sequences of DNA including proteins. FASTA⁶³ is for "FastA" or fast-all". In other words, FASTA is a fine tool for similarity searches. The primary database similarity hunt tool was developed, introducing the development of BLAST (a basic local alignment search tool).

Moreover, a meaningful research question in the bioavailability^14,64,65 of curcumin still raises here, i.e. Insufficiently absorbed after administration. However, the results of these in silico studies (SwissADME study) suggest it to be primarily absorbed in GIT (BoilEDEgg model). Many research papers have been published on the absorption story (poorly absorbed) and have also been practiced piperine. This movement remained throughout the research. Due to which did monitor every activity during the entire investigation. Although, various studies did show that even a low degree of physiologically achievable concentrations of curcumin is probably sufficient for its chemotherapeutic and chemo-preventive activity.

To some extent, it came out that this is true. Because, in CNS related previous studies and current research, it has done and seen that the effect of concentrations is limited only to acute treatment but not to chronic therapy or more. As revealed by target identification (SwissADME target identification), MAO-A has the highest probability score^25,66–68 in the target class shown in (fig. 1-2). And in earlier studies, MAO activity has also been found that curcumin inhibits it and affects the concentrations in the synaptic cleft. If there is any possibility of this, then it is that, and curcumin is acting like MAO enzyme inhibitors, which may be acting as an Irreversible mode of action, like⁶⁹ "suicidal inhibitors" or "hit and run" drugs⁷⁰. Although we did not investigate this in the present study, it is the first reported possibility in published research to date. It will likely be a new research question in this perspective rather than more and more research on poor absorption.

CONCLUSION:

Conclusive investigation of the overall notion of a multifunctional approach reveals that uniform modulation of diverse targets provides better therapeutic outcome and side effect profiles than activity for a selective ligand. And this model is the only rational strategy that suggests that structural features mixed with selective ligands create multiple ligands spanning a wide variety of targets and target classes. A principal challenge in multiple ligands is achieving an equitable activity at every target of interest while concurrently achieving a complete selectivity and an excellent pharmacokinetic profile. And they were based on pre-clinical (in vivo) after in silico studies. And as a responsible researcher, you won't hesitate to say that animal studies are compelling only after in silico or HTS, drug-likeness and target prediction studies. Instead, direct animal studies using only hypotheses and literature review as a basis (i.e., SwissADME). That too, when in silico research results are pointing to animal studies. This model may be good from a druggability testing point of view and animal welfare point of view.

These results showed that the multifunctional nature of propranolol might, to a great extent, expose to withdrawal-induced obsessed anxiety, and curcumin could efficiently treat propranolol dependent obsessed mice. Moreover, curcumin anti-compulsive competency extensively revealed promising benefits besides the “one drug-one receptor-one disease” approach or “magic bullet”.

ACKNOWLEDGEMENT:

The authors want to thanks BioRender.com for creating images to illustrate graphical abstracts.

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Received on 10.07.2021 Modified on 15.12.2021

Research J. Pharm. and Tech. 2022; 15(7):2898-2908.

DOI: 10.52711/0974-360X.2022.00484