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. 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 onthe drugs biological activity.

It helps to find consistent relationship between biological activity and molecular properties, so that these “rules” can be used to evaluate the activity of new compounds. It helps in understanding QSAR regarding electronic effects, steric effects and lipophilicity^1–3. It allows to modify the chemical structure of the lead compound to retain or to reinforce the desirable pharmacologic effect while minimizing unwanted pharmacological and physical and chemical properties, which may result in a superior therapeutic agent. It allows to use target analogs as pharmacological probes to gain better insight into the pharmacology of the lead molecule and perhaps to reveal new knowledge of basic biology. 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^4–7.

Classification:

Corticosteroids are classified into glucocorticoids, mineralocorticoids, androgens, anabolic steroids, antiandrogens, 5α-reductase.

Mechanism of action:

A: Glucocorticoids:

Glucocorticoids inhibit neutrophil apoptosis and demargination; they inhibit phospholipase A2, which decreases the formation of arachidonic acid derivatives; they inhibit NF-Kappa B and other inflammatory transcription factors; they promote anti-inflammatory genes like interleukin-10.

B: Androgens:

The androgen receptor exists in the cytoplasm bound to the heat shock proteins HSP90, HSP70, and other chaperones. After binding to an androgen, the androgen receptor dissociates from HSP90 and undergoes a conformational change to slow the rate of dissociation from the androgen receptor. The androgen-receptor complex is transported into the nucleus where it binds to DNA and recruits other transcriptional regulators to form a pre-initiation complex and eventually induce expression of specific genes.

Testosterone and its active metabolite dihydrotestosterone (DHT) antagonize the androgen receptor to develop masculine sex organs including the prostate, seminal vesicles, penis, and scrotum.

Antagonism of the androgen receptor is also responsible for the development of secondary sexual characteristics including facial and body hair, enlargement of the larynx, thickening of the vocal cords, and changes in muscle and fat distribution^8–10.

Triamcinolone:

Triamcinolone is a medication used to manage and treat various conditions such as atopic dermatitis, contact dermatitis (e.g., poison ivy), eczema, bullous dermatitis, herpetiform psoriasis, lichen planus, lichen sclerosis, subacute cutaneous lupus erythematosus, dermatomyositis, and seasonal or allergic rhinitis. It is in the corticosteroid drug class—specifically, a glucocorticoid. This activity reviews the indications, mechanism of action, and contraindications for triamcinolone as a valuable agent in treating and managing various diseases. This activity will highlight the mechanism of action, adverse effects, and other key factors such as dosing, pharmacodynamics, pharmacokinetics, monitoring, and relevant interactions pertinent for interprofessional team members in treating and caring for patients with skin-related conditions.

Triamcinolone is an FDA approved synthetic corticosteroid drug used in the treatment of various skin conditions, including atopic dermatitis, contact dermatitis (e.g., poison ivy), eczema, bullous dermatitis herpetiformis, psoriasis, lichen planus, lichen sclerosis, subacute cutaneous lupus erythematosus, dermatomyositis, seasonal or allergic rhinitis, and numerous others. Triamcinolone may also be used to provide symptomatic rheumatoid arthritis, gouty arthritis, and osteoarthritis. It was previously used in the USA in an inhaler formulation to treat the symptoms of chronic asthma and chronic obstructive pulmonary disease in high-risk patients but was phased out in the purging of CFC-containing products.

Methyl testosterone:

Methyltestosterone is a methylated synthetic androgen receptor agonist with anabolic effects. Methyltestosterone, mimicking testosterone, binds to cytosolic androgen receptors, and the subsequent nuclear transfer of the ligand-receptor complex induces transcription initiation of androgen responsive genes. The gene products are responsible for normal growth and development of male sex organs and secondary sex characteristics. The agent also causes retention of nitrogen, sodium, potassium, phosphorus, as well as calcium.

Methyltestosterone is a 17beta-hydroxy steroid that is testosterone bearing a methyl group at the 17alpha position. It has a role as an antineoplastic agent, an anabolic agent and an androgen. It is a 3-oxo-Delta(4) steroid, a 17beta-hydroxy steroid and an enone. It is functionally related to a testosterone.

QSAR study of triamcinolone derivative:

1: OH group removed from C-21, then it decrease the mineralocorticoid activity. Compound is designed with chemdraw software^11–14. The docking result of modified triamcinolone produce binding affinity -6.8 kcal/mol. The molecule were tested for structure ananlysis by visualisation tool. The entire compound protein ligand complex showed van der walls i.e. GLN A:33, PRO A:28, TYA A:20.

Fig 1: Interaction of compound 1 with PDB:1CCD

2: OH group removed from C-17 then, Glucocorticoid activity decreased. Compound is designed with chemdraw software^15–18. The docking result of modified triamcinolone produce binding affinity -6.9 kcal/mol.The molecule were tested for structure ananlysis by visualisation tool. The entire compound protein ligand complex showed van der waals i.e. ALA A:33, GLY A:36, TYR A:20, VAL A:10.

Fig 2: Interaction of compound 2 with PDB:1CCD

3: OH group removed from C-16 then, Mineralocorticoid activity decreased. . Compound is designed with chemdraw software. The docking result of modified triamcinolone produce binding affinity -7.0 kcal/mol. The molecule were tested for structure ananlysis by visualisation tool. The entire compound protein ligand complex showed van der waals i.e. ALA A:35, GLY A:36, TYR A:20, VAL A:10, PRO A:28.

Fig 3: Interaction of compound 3 with PDB:1CCD

4: OH group removed from C-11 then, Mineralocorticoid activity decreased. . Compound is designed with chemdraw software. The docking result of modified triamcinolone produce binding affinity -6.9 kcal/mol. The molecule were tested for structure ananlysis by visualisation tool. The entire compound protein ligand complex showed van der waals and conventional hydrogen bond i.e. ALA A:35, GLY A:36, TYR A:20, VAL A:10, PRO A:28, LEU A:32.

Fig 4: Interaction of compound 4 with PDB:1CCD

5:Keto group removed from C-3 then, both gluco- and mineralocorticoid activity decreased. . Compound is designed with chemdraw software. The docking result of modified triamcinolone produce binding affinity -6.9 kcal/mol.The molecule were tested for structure ananlysis by visualisation tool.The entire compound protein ligand complex showed Alkyl and Pi-alkyl i.e. VAL A:10, PHE A:26

Fig 5: Interaction of compound 5 with PDB:1CCD

6: Double bond removed between C-3 and C-4 then, both gluco- and mineralocorticoid activity decreased. . Compound is designed with chemdraw software. The docking result of modified triamcinolone produce binding affinity -6.8 kcal/mol. The molecule were tested for structure ananlysis by visualisation tool. The entire compound protein ligand complex showed van der waals i.e. ALA A:35, GLY A:36, TYR A:20, VAL A:10, PRO A:28.

Fig 6: Interaction of compound 6 with PDB:1CCD

7: Double bond removed between C-1 and C-2 then, glucocorticoid activity decreased. . Compound is designed with chemdraw software. The docking result of modified triamcinolone produce binding affinity -6.7 kcal/mol. The molecule were tested for structure analysis by visualisation tool. The entire compound protein ligand complex showed van der waals i.e. ALA A:35, GLY A:36, TYR A:20, VAL A:10, PRO A:28, LLU A:39.

Fig 7: Interaction of compound 7 with PDB:1CCD

QSAR study of methyl testosterone Derivative:

1:Keto group removed from C-3 then, androgenic activity decreased. . Compound is designed with chemdraw software. The docking result of modified methyl testosterone produce binding affinity -7.3 kcal/mol^19–21.The molecule were tested for structure ananlysis by visualisation tool. The entire compound protein ligand complex showed van der waals, Alkyl, Pi-alkyl i.e. VAL A:16, GLY A:15, GLU A:13, PHE A:129, PRO A:126, ARG A:77, TRP A:76.

Fig 8: Interaction of Desoxymethyltestosterone with PDB:1E3G

2:OH group removed from C-3 then, androgenic activity decreased. Compound is designed with chemdraw software. The docking result of modified methyl testosterone produce binding affinity -7.5 kcal/mol. The molecule were tested for structure ananlysis by visualisation tool. The entire compound protein ligand complex showed van der waals, Alkyl, Pi-alkyl i.e. VAL A:16, GLY A:15, GLU A:13, PHE A:129, PRO A:126, ARG A:77, TRP A:76.

Fig 2: Interaction of compound 2 with PDB:1E3G

3:OH group added at the position of keto group then, activity decreased. Compound is designed with chemdraw software. The docking result of modified methyl testosterone produce binding affinity -7.6 kcal/mol. The molecule were tested for structure ananlysis by visualisation tool.The entire compound protein ligand complex showed van der waals, Alkyl, Pi-alkyl i.e. VAL A:16, GLY A:15, GLU A:13, PHE A:129, PRO A:126, ARG A:77, TRP A:76, LEU A:130.

Fig 3: Interaction of compound 3 with PDB:1E3G

4: Replacement of C-2 by O then, androgenic activity decreased. Compound is designed with chemdraw software. The docking result of modified methyl testosterone produce binding affinity -7.8 kcal/mol. The molecule were tested for structure ananlysis by visualisation tool. The entire compound protein ligand complex showed van der waals, Alkyl, Pi-alkyl i.e. VAL A:16, GLY A:15, GLU A:13, PHE A:129, PRO A:126, ARG A:77, TRP A:76.

Fig 4: Interaction of compound 4 with PDB:1E3G

5:Introduction of heterocyclic system into a steroid nucleus in ring A improve the anabolic activity. Compound is designed with chemdraw software. The docking result of modified methyl testosterone produce binding affinity -6.9 kcal/mol. The molecules were tested for structure ananlysis by visualisation tool. The entire compound protein ligand complex showed van der waals, Alkyl, Conventional hydrogen bond i.e. VAL A:16, GLY A:15, GLU A:13, PHE A:129, PRO A:126, ARG A:77, TRP A:76, GLN A:127

Fig 5: Interaction of compound 5 with PDB:1E3G

6: Replacement of methyl group at C-18 by H atom then, activity decreased. Compound is designed with chemdraw software. The docking result of modified methyl testosterone produce binding affinity -10.6 kcal/mol.. The molecules were tested for structure ananlysis by visualisation tool. The entire compound protein ligand complex showed van der waals, Alkyl, Conventional hydrogen bond i.e. VAL A:16, GLY A:15, GLU A:13, PHE A:129, PRO A:126, ARG A:77, TRP A:76, MET A:105, MET A:70

Fig 6: Interaction of compound 6 with PDB:1E3G.

7: Replacement of methyl group by hydroxy group at C-18 then, anabolic activity decreased. Compound is designed with chemdraw software. The docking result of modified methyl testosterone produce binding affinity -7.3 kcal/mol. The molecule were tested for structure ananlysis by visualisation tool. The entire compound protein ligand complex showed van der waals, Alkyl, Pi-alkyl i.e. VAL A:16, GLY A:15, GLU A:13, PHE A:129, PRO A:126, ARG A:77, TRP A:76.

Fig 7: Interaction of compound 7 with PDB:1E3G

CONCLUSION:

Molecular Docking has become an important component of the drug discovery process. In this research Molecular Docking of triamcinolone, substitution of R group at C21 position has reduced mineralocorticoid activity, substitution of hydroxy group at C17 position has reduced glucocorticoid activity, substitution of keto group at C3 position has reduced gluco- and mineralocorticoid activity, removal of double bond between C3 and C4 position has reduced gluco- and mineralocorticoid activity, removal of hydroxy group has reduced mineralocorticoid activity, addition of benzene ring gave slightly reduced activity. Removal of hydroxy group at position C-16, it gives least activity. While addition of hydroxy group at C17 position has enhance the mineralocorticoid activity, it gives best activity.

In methyl testosterone introduction of heterocyclic system into steroid nucleus in ring A it gives best anabolic activity. Replacement of C-2 by O group, it gives least activity. Removal of hydroxy group at C-3 has moderately decreased activity. Removal of keto group at C-3 position it also gives least androgenic activity. Addition of hydroxy group at C-18 position, it gives best anabolic activity.

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Received on 18.05.2023 Modified on 12.07.2023

Asian J. Pharm. Tech. 2023; 13(4):250-256.

DOI: 10.52711/2231-5713.2023.00045