INTRODUCTION:

QSAR: Quantitative structure-activity relationships (QSAR) have been applied for years in the development of relationships between physicochemical properties of chemical substances and their biological activities to obtain a reliable statistical model for prediction of the activities of new chemical entities^1,2.

A quantitative structure-activity relationship (QSAR) is a mathematical relationship which correlates measurable or calculable molecular properties to some specific biological activity in terms of an equation. QSAR attempts to identify and quantify the physicochemical properties of a drug and to see whether any of these properties have an effect on the drugs biological activity^3,4.

In 3D QSAR, 3D properties of a molecule are considered as whole rather than considering individual substituent. This method involves the analysis of the quantitative relationship between the biological activity of a set of compounds and their three-dimensional properties using statistical correlation methods.

It revolves around the important features of a molecule, its overall size and shape, and its electronic properties.

A psychoactive drug that slows brain and body reactions is called a depressant. Depressants slow body functions by decreasing heart and breathing rates and lowering blood pressure. The broad classification of CNS depressants includes sedative-hypnotics, general an aesthetics, analgesics, opioid and nonopioid analgesics, anticonvulsants, antipsychotics, and antidepressants^5–7.

A CNS depressant is a sedative that slows the activity of the central nervous system (CNS). This class of drugs used to be called tranquilizers Slow nerve activity, relax muscle tension, lower alertness, and cause drowsiness. Doctors may prescribe CNS depressants to treat anxiety, sleep disorders, muscle spasms, and convulsions. Long-Term Abuse: blood and liver disease.

Classification of CNS Depressant:

CNS Depressant can be classified into- Sedative hypnotics, Anxiolytic drug, CNS Depressants with skeletal muscle relaxant properties, Anticonvulsants, Antipsychotic.

Mechanism of action of CNS Depressant:

Alcohol was believed to produce CNS depression by a generalized membrane action altering the state of membrane lipids. However, lately specific effect on multiple receptors operated and voltage gated ion channels/ other critical proteins has been demonstrated at concentrations attained during moderate drinking. Thus, several neurohumoral systems are concurrently affected producing a complex pattern of action quite different from that produced by other depressants like barbiturates and benzodiazepines, which predominantly facilitate GABAA receptor mediated Cl¯channel opening. Alcohol has been shown to enhance GABA release at GABAA sites in the brain. It also inhibits NMDA and kainate type of excitatory amino acid receptors (operating through cation channels) Mechanism of Action of Antipsychotic Drugs Dopaminergic Pathways Goals: Presynaptic Dopaminergic Neuron. To quiet hyperactive DA neurons that mediate psychosis. To trigger underactive DA neurons that mediate Antipsychotic drug negative and cognitive symptoms Postsynaptic receptor. To preserve physiologic function in DA neurons that regulate movement and Postsynaptic neuron prolactin secretion^8,9.

QSAR Study of Phenothiazine Derivatives:

1. Phenothiazine The molecular docking of ligand checked against PDB: 6CM4 for antipsychotic activity^10–12. The docking result of phenothiazine is -8.6kcal/mol. The entire compound protein ligand complex shows the conventional hydrogen bond with active site residue GLY96.and pi -pi stacked that is PHE41, pi -sigma that is ILE95, also pi-alkyl bond that is VAL65, ILE122. Benzene ring interact with pi-pi stacked, pi-sigma, pi-alkyl bonds.

Fig. 1: The interaction between phenothiazine and PDB: 6CM4

2. Substitution of SCH3 at C-2 will decrease activity. The molecular docking of ligand checked against PDB: 6CM4 for antipsychotic activity. Substitution of SCH3at C2 position Leads to decrease activity. The docking result of modified Substitution of SCH3at C2 position phenothiazine is -1.2kcal/mol. The entire compound protein ligand complex shows the conventional hydrogen bond with active site residue TYR416.and pi -suffer that is PHE189, PHE389, HIS393, PHE110, pi -sigma that isTHR412, also pi-alkyl bond that is TRP100. Benzene ring interact with pi-pi stacked, pi-sigma, pi-alkyl bonds.

Fig. 2: The interaction between Scandium trihydride phenothiazine derivative with PDB:6CM4

3. Oxidation of Sulphur at C-5 position will decrease the activity. The molecular docking of ligand checked against PDB: 6CM4 for antipsychotic activity. Oxidation of Sulphur at C-5 position will ring leads to decrease activity. Oxidation of Sulphur at C-5 position will the docking result of modified phenothiazine is -8.5kcal/mol. The entire compound protein ligand complex shows the conventional hydrogen bond with active site residue ASP114.and pi -pi stacked that is PHE, pi -Anion that is ASP114, also pi-alkyl bond that is ALA122, CYS118.Benzene ring interact with pi-pi stacked, pi-alkyl bonds.

Fig. 3: The interaction between Sulphur phenothiazine derivative with PDB:6CM4

4. Addition of electron donating group like nitro at C-2 position will decreases activity. The molecular docking of ligand checked against PDB: 6CM4 for antipsychotic activity. Addition of donating at C-2 position will leads to decreases activity. The docking result of modified phenothiazine is -7.2kcal/mol. The entire compound protein ligand complex shows the conventional hydrogen bond with active site residue GLY96.and pi -pi stacked that is PHE41, pi -sigma that is ILE95, also pi-alkyl bond that is VAL65, ILE122. Benzene ring interact with pi-pi stacked, pi-sigma, pi-alkyl bonds.

Fig. 4: The interaction between Nitrogen Dioxide phenothiazine derivative with PDB:6CM4

5. Substitution of any aromatic ring will be decreasing activity. The molecular docking of ligand checked against PDB: 6CM4 for antipsychotic activity. Substitution of any aromatic ring will be decreasing activity leads to decrease activity. The modification is occurred in Phenothiazine ring the docking result of modified phenothiazine ring is-8.5kcal/mol. The entire compound protein ligand complex shows the and pi -pi T stacked that is PHE239, pi - sigma that is THR412 ILE134, also pi-alkyl bond that is VAL65. Benzene ring interact with pi-pi stacked, pi-sigma, pi-alkyl bonds.

Fig. 5: The interaction between aromatic ring of phenothiazine derivative with PDB:6CM4

6. Substitution at C-4 of any group for example CF3 will decrease the activity of the drug. The molecular docking of ligand checked against PDB: 6CM4 for antipsychotic activity. Substitution at C-4 of any group will lead to decreases in activity. The modification is occurred in phenothiazine ring with CF3. the docking result of modified phenothiazine is - 7.6kcal/mol. The entire compound protein ligand complex shows the conventional hydrogen bond with active site residue TRP.41 and pi -pi stacked that is TYR408, TRP100 pi -sigma that is LEU94, VAL91 also Pi Hydrogen bond is THR412. Benzene ring interact with pi-pi stacked, pi-sigma, pi-alkyl bonds.

Fig. 6: The interaction between Trifluoromethyl phenothiazine derivative with PDB:6CM4

7. Addition of the any electron withdrawing group at C-2 position the activity of group will Increase. e.g., CF3. The molecular docking of ligand checked against PDB: 6CM4 for antipsychotic activity. Addition of the any electron withdrawing group at C-2 position the activity of group will leads to increase in the activity. The modification is occurred in phenothiazine ring with CF3 the docking result of modified phenothiazine is -10.6kcal/mol. The entire compound protein ligand complex shows the Halogen with active site residue ASP114.and pi -pi stacked that is TRP386, pi -Sulphur is 390, also pi-alkyl bond that is CYS118, VAL115, PHE389. Benzene ring interact with pi-pi stacked, pi-sigma, pi-alkyl bonds.

Fig. 7: The interaction between Trifluoromethyl phenothiazine derivative at C2 with PDB:6CM4

8. The nitrogen of the phenothiazine ring will be replace or remove the activity will decrease. The molecular docking of ligand checked against PDB: 6CM4 for antipsychotic activity The nitrogen of the phenothiazine ring will be replace or remove it will lead to decrease activity. The modification is occurred in phenothiazine. the docking result of modified phenothiazine is -4.9kcal/mol. The entire compound protein ligand complex shows pi -pi stacked that is ALA1073, pi -sigma that isALA1074, also pi-alkyl bond that is ALA1073. Benzene ring interact with pi-pi stacked, pi-sigma, pi-alkyl bonds.

Fig. 8: The interaction between Nitrogen phenothiazine derivative with PDB:6CM4

QSAR Study of Barbiturate Derivatives:

1. Barbiturate. The docking result of modified Barbiturate is -7.1kcal/mol. The molecular docking of ligand checked against PDB: 6K41 for CNS depressant activity^13,14. The entire compound protein ligand complex shows the Pi hydrogen bond with active site residue TRP386andPi Alkyl that isPHE390, PHE198, also alkyl bond that is CYS118, VAL115. Benzene ring interact with pi-pi stacked, pi-sigma, pi-alkyl bonds.

Fig. 9: The interaction between Barbiturate derivative at C2 with PDB:6K41

2. Addition of the Ethyl group at 5 positions increase the activity. The molecular docking of ligand checked against PDB: 6K41 for CNS depressant activity. Addition of the Ethyl group at 5 position leads to increase activity. The modification is occurred in Barbiturate ring with ethyl group the docking result of modified Barbiturate is -7.2kcal/mol. The entire compound protein ligand complex shows the conventional hydrogen bond with active site residue TRP413and Pi Alkyl is THR412

Fig. 10: The interaction between Ethyl Barbiturate derivative at C5with PDB:6K41

3. Addition of the Methyl group by removing the hydrogen the activity will increase. The molecular docking of ligand checked against PDB: 6K41 for CNS depressant activity. Addition of the Methyl group by removing the hydrogen the activity will leads to increase activity. The modification is occurred in Barbiturate ring by removing the hydrogen. The docking result of modified Barbiturate is -9.2kcal/mol. The entire compound protein ligand complex shows the conventional hydrogen bond with active site residue TRP100. and pi - Hydrogen TYR9681, LEL90

Fig. 11: The interaction between Methyl l Barbiturate derivative with PDB:6K41

4. Removal of the carbonyl group at 2,4,6 position decrease activity. The molecular docking of ligand checked against PDB: 6K41 for CNS depressant activity. Removal of the carbonyl group at 2,4,6 position leads to decrease activity. The modification is occurred in Barbiturate by carbonyl ring the docking result of modified barbiturate is -4.1kcal/mol. The entire compound protein ligand complex shows the conventional hydrogen bond with active site residueASP10706.and Alkyl that is PHE 1103, also pi-alkyl bond that is ALA1074.

Fig. 12: The interaction between Carbonyl Barbiturate derivative with PDB:6K41

5. Removal of the one NH group will decrease activity. The molecular docking of ligand checked against PDB: 6K41 for CNS depressant activity. Removal of the one NH group will lead to decrease activity. The modification is occurred in Barbiturate ring with NH group the docking result of modified barbiturate is -1.2kcal/mol. The entire compound protein ligand complex shows the conventional hydrogen bond with active site residue THR412, SER405. and, also pi-alkyl bond that is VAL51, LUE54. Alkyl is TRP100. Benzene ring interact with pi-alkyl bonds.

Fig. 13: The interaction between Carbonyl Barbiturate derivative with PDB:6K41

6. Addition of the any aromatic ring for example benzene ring will decrease activity. The molecular docking of ligand checked against PDB: 6K41 for CNS depressant activity. Addition of the any aromatic ring will leads to decrease activity. The modification is occurred in Barbiturate ring with benzene ring. the docking result of modified Barbiturate is - 1.2kcal/mol. The entire compound protein ligand complex shows the conventional hydrogen bond with active site residue GLU368, THR67, ASN70.andpi -sigma that is ILE95, also pi- alkyl bond that is ALA317and Pi donor Hydrogen bond is ASN430. Benzene ring interact with pi-pi stacked, pi-sigma, pi-alkyl bonds.

Fig. 14: The interaction between Aromatic ring of Barbiturate derivative at with PDB:6K41

CONCLUSION:

Molecular Docking has become an important component of the drug discovery process. In this research Molecular Docking of phenothiazine, substitution of Scandium trihydride at C2 position gave extremely reduced activity, oxidation of sulphur at C5 position gave slightly reduced activity, Nitrogen dioxide at C2 position gave moderately reduced activity, addition of Trifluoromethyl at C4 position gave moderately reduced activity, removal of nitro group gave extremely reduced activity, addition of benzene ring gave slightly reduced activity. On addition of Trifluoromethyl at C2 position gave extremely enhance the activity. The result was analysed and it was concluded that on the basis of binding affinity, In Phenothiazine at C2 Position formed to be the best as it gives best activity In Barbiturate addition of ethyl group at C5 position gave slightly enhanced activity, addition of methyl group at gave moderately extremely activity. On removal of carbonyl group at 2,4,6 position gave moderately reduced activity, Removal of amine group at 1,3 positions gave extremely reduced activity, addition of benzene ring will extremely reduce activity. The result were analysed and it was concluded that on the basis of binding affinity, In Barbiturate at 2,4,6 position formed to be best as it gives best activity.

REFERENCES:

1. Yadav T, Rohane S. Acute Toxicity study of Synthesized drug and Herbal Product. 2021; 11(4): 251-256. doi:10.52711/2231-5691.2021.00044

2. Yadav P, Rohane S, Velhal A. Adverse Drug Reactions and Comorbidities in Patient Treated for. 2021; 14(December): 416-419. doi:10.52711/0974-4150.2021.00073

3. Bagal A, Borkar T, Ghige T, et al. Molecular Docking – Useful Tool in Drug Discovery. 2022; 15(April): 129-132. doi:10.52711/0974-4150.2022.00020

4. Aware D, Rohane S. Review Article. A Role of Herbal Drug as an Immunity Booster during Covid-19 Pandemic. 2021; 11(3): 206-211. doi:10.52711/2231- 5691.2021.00037

5. Rohane SH, Chauhan AJ, Kumar N. Synthesis and in vitro antimycobacterial potential of novel hydrazones of eugenol. Arab J Chem. 2020; 13(2): 4495-4504. doi: 10.1016/j.arabjc.2019.09.004

6. Pawar SS, Rohane SH. Review on Discovery Studio: An important Tool for Molecular Docking. 2021; 14(February):86-88. doi:10.5958/0974-4150.2021.00014.6

7. Galande AK, Rohane SH. Insilico Molecular docking analysis in Maestro Software. 2021; 14(February): 97-100. doi:10.5958/0974-4150.2021.00017.1

8. Nangare SA, Rohane SH. Review on Guassion, the General Purpose in Computational Chemistry for Medicinal Chemistry. 2021; 14(February): 89-91. doi:10.5958/0974- 4150.2021.00015.8

9. Patil NS, Rohane SH. Organization of Swiss Dock: In study of Computational and Molecular Docking Study. 2021; 14(April): 145-148. doi:10.5958/0974- 4150.2021.00027.4

10. Jejurikar BL, Rohane SH. Drug Designing in Discovery Studio. 2021;14(April):135- 138. doi:10.5958/0974-4150.2021.00025.0

11. Pawar RP, Rohane SH. Role of Autodock vina in PyRx Molecular Docking. 2021; 14(April): 132-134. doi:10.5958/0974-4150.2021.00024.9

12. Rohane SH, Makwana AG. In silico study for the prediction of multiple pharmacological activities of novel hydrazone derivatives. Indian J Chem -Section B. 2019; 58(03): 387-402.

13. Rohane SH, Makwana AG. A Review on Hydrazone, the fascinating field of investigation in medicinal chemistry. Asian J Res Chem. 2017; 10(4): 417. doi:10.5958/0974-4150.2017.00070.0

14. Satpute UM, Rohane SH. Efficiency of AUTODOCK: Insilico study of Pharmaceutical Drug Molecules. Asian J Res Chem. 2021; 14(1): 1-5. doi:10.5958/0974- 4150.2021.00016.x

Received on 09.04.2024 Modified on 10.06.2024

Asian J. Research Chem. 2024; 17(4):203-208.

DOI: 10.52711/0974-4150.2024.00037