In Silico Screening of Compounds Similar to Codeine, Tramadol, and Morphine with Better Pharmacodynamic and Pharmacokinetics Profiles

  

    
Serial no
    
Similarity score
    
Compound
    
Binding score to mu receptor
    
Binding score to delta receptor
    
Binding score to kappa receptor
  
  

    

      
 
    
    

    
Morphine_
    
-6.4
    
-6.8
    
-7.3
  
  

    

      
 
    
    
98.30%
    
ZINC03629718; 0.983;
    
-6.1
    
-7.0
    
-7.1
  
  

    

      
 
    
    
98.80%
    
ZINC03812983; 0.988;
    
-6.5
    
-7.4
    
-7.3
  
  

    

      
 
    
    
982%
    
ZINC03830598; 0.982;
    
-6.0
    
-7.4
    
-7.3
  
  

    

      
 
    
    
98.80%
    
ZINC03831152; 0.988;
    
-5.9
    
-7.3
    
-7.3
  
  

    

      
 
    
    
99.10%
    
ZINC03870349; 0.991;
    
-6.0
    
-7.3
    
-7.1
  
  

    

      
 
    
    
98.80%
    
ZINC03870350; 0.988;
    
-6.2
    
-7.2
    
-7.1
  
  

    

      
 
    
    
99.30%
    
ZINC03875420; 0.993;
    
-6.3
    
-8.0
    
-7.1
  
  

    

      
 
    
    
99.20%
    
ZINC04102208; 0.992;
    
-6.8
    
-7.8
    
-7.3
  
  

    

      
 
    
    
98.80%
    
ZINC04217170; 0.988;
    
-6.4
    
-7.0
    
-7.8
  
  

    

      
 
    
    
99.20%
    
ZINC05599925; 0.992;
    
-6.2
    
-7.1
    
-7.3
  
  

    

      
 
    
    
99.00%
    
ZINC05966734; 0.990;
    
-5.8
    
-6.6
    
-6.7
  
  

    

      
 
    
    
99.20%
    
ZINC13831510; 0.992;
    
-9.2
    
-8.1
    
-7.3
  
  

    

      
 
    
    
99.30%
    
ZINC26259212; 0.993;
    
-6.0
    
-7.5
    
-8.5
  
  

    

      
 
    
    
99.00%
    
ZINC26266464; 0.990;
    
-7.1
    
-9.6
    
-7.3
  
  

    

      
 
    
    
98.80%
    
ZINC27517251; 0.988;
    
-6.4
    
-8.2
    
-6.9
  
  

    

      
 
    
    
99.50%
    
ZINC28256912; 0.995;
    
-6.2
    
-8.3
    
-7.5
  
  

    

      
 
    
    
99.30%
    
ZINC33839041; 0.993;
    
-6.3
    
-8.2
    
-7.9
  
  

    

      
 
    
    
99.80%
    
ZINC33839042; 0.988;
    
-6.3
    
-7.2
    
-7.3
  
  

    

      
 
    
    
99.20%
    
ZINC37250136; 0.992;
    
-6.4
    
-8.5
    
-7
  
  

    

      
 
    
    
99.70%
    
ZINC39949141; 0.997;
    
-6.6
    
-8.3
    
-7.5
  
  

    
Note: From (Pettersen et al., 2004), (Eberhardt et al., 2021) 
  

Table 1: Binding scores of morphine and zinc compounds to mu, delta and kappa receptors.

ZINC13831510; 0.992;(-9.2) had the highest binding score to mu receptor as compared to both the kappa and delta receptor. ZINC13831510; 0.992; was analysed for its pharmacokinetic profile.

Both morphine and ZINC13831510; 0.992 showed high GIT absorption, substrate of P-glycoprotein. They both showed CYP2D6 inhibition. Morphine showed permeation to BBB while ZINC13831510; 0.992 showed lack of BBB permeation. Morphine and ZINC13831510; 0.992 showed lack of CYP1A2, CYP2C9 and CYP2C19 enzyme inhibition. They both complies with Lipinski rule of five.

Tramadol and Zinc compounds docking scores to mu, delta, and kappa receptors: ZINC02509756; 0.986;(-5.7), ZINC02510775; 0.995(5.7), ZINC02525883; 0.995; (5.6), ZINC03639132; 0.976; (5.9), ZINC05958052; 0.979; (-5.6) and ZINC71774151; 0.977; (-7.4) showed better docking score to mu receptor than tramadol (-5.5). These zinc compounds were further analysed for their pharmacokinetic properties and toxicity profiles.

All the zinc compounds shown higher binding scores to delta receptor. Three Zinc Compounds namely ZINC01849532; 0.994; (-6.6), ZINC02525883; 0.995; (-7.4), ZINC03639132; 0.976; (-6.5) and ZINC76734760; 0.977; (-6.8) showed higher binding score to kappa receptor than Tramadol (-6.4). ZINC71774151; 0.977; showed highest binding score to mu receptor than kappa and delta receptors therefore, it was further analysed for its pharmacokinetic properties as well as toxicity profiles.

Both tramadol and ZINC71774151; 0.977 showed high GIT absorption, BBB permeation and inhibition of CYP2D6 enzyme. They, however lack inhibition to CYP1A2, CYP2C9, CYP2C19 and CYP3A4. They are not substrate to P-glycoprotein. They comply with Lipinski rule of five.

Codeine and zinc compounds binding scores to mu, delta and kappa receptors: ZINC03806721; 0.991; (-6.7) and ZINC37250136; 0.997; (-6.4) showed lower docking score to delta receptor than the reference codeine drug (-6.9). The rest of the Zinc compounds showed better docking scores than codeine.

ZINC03870349; 0.993; (-6.8), ZINC03870350; 0.993; (-6.8), ZINC04217170; 0.992; (-7.0), ZINC05599925; 0.997; (-7.0), ZINC27517251; 0.993; (-6.7) and ZINC33839042; 0.992; (-6.9) showed lower docking scores to kappa receptor as compared to reference codeine which showed docking score of (-7.1).

ZINC03629718; 0.995; (-8.3), ZINC03870350; 0.993; (-7.8) and ZINC28256912; 0.992; (-8.9) had the highest binding to mu receptors as compared to delta and kappa receptors. These Zinc compounds were further analysed for their pharmacokinetic profiles through SwissADME tool and toxicity using ProTox II server.

Codeine, ZINC03629718; 0.995; (-8.3), ZINC03870350; 0.993; (-7.8) and ZINC28256912; 0.992; (-8.9) showed high GIT absorption, BBB permeation P-glycoprotein substrates and CYP2D6 inhibition. ZINC03629718; 0.995; (-8.3) is an exception in that it is not a substrate to P-glycoprotein. Codeine and the Zinc compounds showed lack of enzyme inhibition to CYP1A2, CYP2C9, CYP2C19 and CYP3A4.These compounds showed no violation to Lipinski rule of five.

Toxicity Profiles

Oral toxicity: None of the Morphine zinc compounds showed higher LD50 than Morphine, although all compounds belonged to toxicity Class IV with exceptions of ZINC04217170; 0.988;

ZINC27517251; 0.988; and ZINC37250136; 0.992 that belong to Toxicity class III. ZINC26259212; 0.995; was the safest with oral LD50 of 1140 mg/kg belonging to toxicity class IV compared to Codeine 85mg/kg and the rest of the zinc compounds belonging to class III.

Four of Tramadol’s zinc compounds were predicted to be in class IV as compared to Tramadol and other zinc compounds in Class III toxicity. These compounds include, ZINC05958052; 0.979; ZINC03639132; 0.976; ZINC02509756; 0.986 and ZINC71774151; 0.977. The safest compound with highest Oral LD50 was ZINC71774151; 0.977.

According to Drwal et al. (2014), Class I refers to death after swallowing (LD50 = 5); Class II refers to death after swallowing (5< LD50=50); Class III: toxic after swallowing (50< LD50=300); Class IV: harmful after swallowing (300<LD50=2000); Class V: harmful after swallowing (2000<LD50=5000) and Class VI: non-toxic (LD50>5000)

Hepatotoxicity and immunotoxicity: None of Morphine’s, Tramadol’s, and codeine’s zinc compounds were predicted hepatotoxic active. ZINC26266464; 0.990; ZINC26266464; 0.995; were predicted immunotoxic active with probability of 0.64. Tramadol and its zinc compound ZINC03639132; 0.976; were predicted immunoactive with probabilities of 0.87 and 0.81 respectively.

End point toxicities: None of the compounds were predicted active in causing carcinogenicity, mutagenicity and cytogenecity.

Morphine and its zinc compounds ZINC03812983; 0.988; and ZINC39949141; 0.997; were predicted active in nuclear receptor signalling with probability scores of 0.62, 0.62 and 0.66 respectively. Codeine and its zinc compounds namely ZINC28256912; 0.992, ZINC03830598; 0.991; ZINC05599925; 0.997 and ZINC39949141; 0.993 were also predicted active for nuclear receptor signaling with probability scores of 0.8, 0.62, 0.83, 0.93 and 0.62 respectively.

Phamacokinetic Profiles

P-glycoprotein substrates: Morphine and its zinc compounds were all predicted to be P-glycoprotein substrates. All Codeines zinc compounds were predicted substrates of P-glycoprotein with exceptions of ZINC03629718; 0.995. Tramadol and its zinc compounds were not substrates for P-glycoprotein.

1.6.2 BBB penetration

Morphine was predicted to cross BBB while its two zinc compounds were not. These compounds include ZINC04102208; 0.992; and ZINC13831510; 0.992. All other compounds were predicted to permeate BBB.

Enzyme inhibition: None of the compounds were predicted to inhibit CYP 1A2, CYP2C9, CYP2C19, and CYP3A4. All compounds were predicted to inhibit the CYP2D6 enzyme.

Post Docking Analysis

Codeine and zinc compounds 2D-Interactions with mu receptors: ZINC03870350; 0.993; ZINC03629718; 0.995 with -8.3 kcal/mol and -7.8 kcal/mol respectively showed binding to mu receptor with van der waals forces, pi-sigma bonds as well as pi-alkyl bonds. Codeine with -6.1 kcal/mol showed binding to active sites via van der waals forces-sigma-cation, pi-anion as well as pi-pi stacking amongst others.

Tramadol and zinc compound binding to mu receptor visualization [15]: ZINC71774151; 0.977; with binding affinity of -7.4kcal/mol as compared to Tramadol-5.5kcal/mol showed pi-pi stacking of the pharmacophore to mu binding site. Both compounds bonded with van der waals forces as well as pi–alkyl bonds to mu active sites.

Discussion

Opioids are currently used in pain management by acting via mu, kappa, and delta receptors [7]. The side effects of opioid agonists are propelling the urge to seek new analgesics with limited side effects. The effect on mu receptors is respiratory depression due to the binding of the agonists in the amygdala, brain stem, and thalamus (Imam et al., 2018). Through activation of the mu receptors, secretion of substance P and acetylcholine is inhibited leading to constipation [5]. Withdrawal and dependence effects occur on the activation of mu receptors. Kappa receptor activation produces aversion and euphoric effects [9] as well as pruritic effects due to their effects on the release of histamine. Both mu and kappa receptors produce sedation due to their effects on the CNS (Chung et al., 2017). Prior work by [14] showed that hyperalgesia effects of morphine are not attributable to the binding of morphine to peripheral receptors but to central mu receptors. Kappa receptors’ actions in hypothalamus and in the adrenal glands cause diuresis as a side effect [10]. Delta receptor is associated with convulsions due to actions on the thalamo-cortical areas and the hypothalamus [4].

Opioids (morphine, tramadol and codeine) and their zinc compounds were analysed in this study and compounds with better docking scores to mu receptor were highlighted. They produced positive compounds that can be discovered as potent analgesics. Based on results in Table 2, ZINC03812983; 0.988; ZINC04102208; 0.992; ZINC04217170; 0.988; ZINC13831510; 0.992, ZINC26266464; 0.990, ZINC27517251; 0.988; ZINC37250136; 0.992; and ZINC39949141; 0.997 showed better binding energies to mu receptor than morphine. Based on data in Table 3, ZINC02509756; 0.986; ZINC02510775; 0.995, ZINC02525883; 0.995, ZINC03639132; 0.976, ZINC05958052; 0.979; and ZINC71774151; 0.977; showed higher binding energies to mu receptor than tramadol. Table 5, highlights compounds with better docking scores to mu receptor than codeine. These Zinc compounds therefore, gives promising results in discovery of potent analgesic compounds but with serious side effects such as respiratory depression, constipation, vomiting and withdrawal effects.

Table 2: Tramadol and zinc compounds binding scores to mu, delta and kappa receptors.

  

    
Serial no
    
Similarity score
    
Compound
    
Binding score to mu receptor
    
Binding score to delta receptor
    
Binding score to kappa receptor
  
  

    

      
 
    
    

    
Tramadol
    
-5.5
    
-5.7
    
-6.4
  
  

    

      
 
    
    
99.70%
    
ZINC00000853; 0.997;
    
-5.3
    
-6.4
    
-6.3
  
  

    

      
 
    
    
98.10%
    
ZINC00020781; 0.981;
    
-4.8
    
-5.9
    
-6.3
  
  

    

      
 
    
    
99.40%
    
ZINC01849532; 0.994;
    
-5
    
-6.8
    
-6.6
  
  

    

      
 
    
    
99.80%
    
ZINC02015652; 0.998;
    
-5.1
    
-6.9
    
-6.1
  
  

    

      
 
    
    
97.90%
    
ZINC02243733; 0.979;
    
-5.5
    
-6
    
-5.9
  
  

    

      
 
    
    
98.60%
    
ZINC02509756; 0.986;
    
-5.7
    
-6.1
    
-6
  
  

    

      
 
    
    
99.50%
    
ZINC02510775; 0.995;
    
-5.7
    
-6.3
    
-6.1
  
  

    

      
 
    
    
99.50%
    
ZINC02525883; 0.995;
    
-5.6
    
-6.4
    
-7.4
  
  

    

      
 
    
    
97.60%
    
ZINC03639132; 0.976;
    
-5.9
    
-7.1
    
-6.5
  
  

    

      
 
    
    
99.50%
    
ZINC03643419; 0.995;
    
-5.4
    
-6.6
    
-6.2
  
  

    

      
 
    
    
99.50%
    
ZINC03643421; 0.995;
    
-5.5
    
-7.3
    
-6.1
  
  

    

      
 
    
    
97.90%
    
ZINC05958019; 0.979;
    
-5.5
    
-7
    
-5.9
  
  

    

      
 
    
    
97.90%
    
ZINC05958052; 0.979;
    
-5.6
    
-6.7
    
-6.3
  
  

    

      
 
    
    
97.70%
    
ZINC21986241; 0.977;
    
-5.4
    
-6.4
    
-6
  
  

    

      
 
    
    
98.90%
    
ZINC33979435; 0.989;
    
-5.1
    
-6.2
    
-5.3
  
  

    

      
 
    
    
98.80%
    
ZINC33979436; 0.988;
    
-4.8
    
-6.3
    
-6.1
  
  

    

      
 
    
    
99.00%
    
ZINC33979437; 0.990;
    
-5.3
    
-6.4
    
-6.2
  
  

    

      
 
    
    
97.70%
    
ZINC71774151; 0.977;
    
-7.4
    
-6.9
    
-6.4
  
  

    

      
 
    
    
97.70%
    
ZINC76734760; 0.977;
    
-5.5
    
-6.3
    
-6.8
  
  

    
Note: From (Pettersen et    al., 2004), (Eberhardt et al., 2021) 
  

Table 2: Tramadol and zinc compounds binding scores to mu, delta and kappa receptors.

Close

Table 3: Codeine and zinc compounds binding scores to mu, delta and kappa receptors.

  

    
Serial no
    
Similarity score
    
Compound
    
Binding score to mu receptor
    
Binding score to delta receptor
    
Binding score to kappa receptor
  
  

    

      
 
    
    

    
Codeine
    
-6.1
    
-6.9
    
-7.1
  
  

    

      
 
    
    
99.10%
    
ZINC00402777; 0.991;
    
-6.1
    
-7.4
    
-7.3
  
  

    

      
 
    
    
99.10%
    
ZINC00490120; 0.991;
    
-6
    
-7.4
    
-7.1
  
  

    

      
 
    
    
99.10%
    
ZINC02039583; 0.991;
    
-6.4
    
-6.4
    
-7.3
  
  

    

      
 
    
    
99.50%
    
ZINC03629718; 0.995;
    
-8.3
    
-7.8
    
-7.1
  
  

    

      
 
    
    
99.10%
    
ZINC03806721; 0.991;
    
-5.7
    
-6.7
    
-7.8
  
  

    

      
 
    
    
99.10%
    
ZINC03830598; 0.991;
    
-6.3
    
-7.1
    
-7.5
  
  

    

      
 
    
    
99.30%
    
ZINC03870349; 0.993;
    
-6
    
-7.1
    
-6.8
  
  

    

      
 
    
    
99.30%
    
ZINC03870350; 0.993;
    
-7.8
    
-7.2
    
-6.8
  
  

    

      
 
    
    
99.50%
    
ZINC03875420; 0.995;
    
-6
    
-7.6
    
-7.8
  
  

    

      
 
    
    
99.20%
    
ZINC04217170; 0.992;
    
-5.9
    
-7.2
    
-7
  
  

    

      
 
    
    
99.70%
    
ZINC05599925; 0.997;
    
-6.4
    
-6.9
    
-7
  
  

    

      
 
    
    
99.50%
    
ZINC26259212; 0.995;
    
-6.6
    
-7.7
    
-7.2
  
  

    

      
 
    
    
99.50%
    
ZINC26266464; 0.995;
    
-6.5
    
-8.5
    
-7.4
  
  

    

      
 
    
    
99.30%
    
ZINC27517251; 0.993;
    
-6.3
    
-6.9
    
-6.7
  
  

    

      
 
    
    
99.20%
    
ZINC28256912; 0.992;
    
-8.9
    
-8.3
    
-7.5
  
  

    

      
 
    
    
99.50%
    
ZINC33839041; 0.995;
    
-6.3
    
-8.3
    
-7.9
  
  

    

      
 
    
    
99.20%
    
ZINC33839042; 0.992;
    
-6
    
-7.2
    
-6.9
  
  

    

      
 
    
    
99.00%
    
ZINC34275567; 0.990;
    
-6.1
    
-7.8
    
-7.7
  
  

    

      
 
    
    
99.70%
    
ZINC37250136; 0.997;
    
-6.3
    
-6.4
    
-7.1
  
  

    

      
 
    
    
99.30%
    
ZINC39949141; 0.993;
    
-6.2
    
-8.3
    
-7.5
  
  

    
Note: From (Pettersen et    al., 2004), (Eberhardt et al., 2021) 
  

Table 3: Codeine and zinc compounds binding scores to mu, delta and kappa receptors.

Close

Table 4: Codeine and zinc compounds binding scores to mu, delta and kappa receptors.

  

    
Compound name
    
Oral LD50 (mg/kg)
    
Predicted toxicity    class
    
Predicted Accuracy    %
  
  

    
Morphine
    
461
    
IV
    
23
  
  

    
ZINC13831510; 0.992
    
335
    
IV
    
100
  
  

    
ZINC03812983; 0.988;
    
335
    
IV
    
100
  
  

    
ZINC04102208; 0.992;
    
335
    
IV
    
100
  
  

    
ZINC04217170; 0.988;
    
85
    
III
    
100
  
  

    
ZINC26266464; 0.990;
    
335
    
IV
    
100
  
  

    
ZINC27517251; 0.988;
    
85
    
III
    
100
  
  

    
ZINC37250136; 0.992;
    
85
    
III
    
100
  
  

    
ZINC39949141; 0.997;
    
335
    
IV
    
72.9
  
  

    
Codeine
    
85
    
III
    
100
  
  

    
ZINC03629718; 0.995
    
85
    
III
    
100
  
  

    
ZINC02039583; 0.991;
    
85
    
III
    
100
  
  

    
ZINC03870350; 0.993;
    
85
    
III
    
100
  
  

    
ZINC28256912; 0.992
    
335
    
IV
    
100
  
  

    
ZINC03830598; 0.991;
    
85
    
III
    
100
  
  

    
ZINC05599925; 0.997
    
85
    
III
    
100
  
  

    
ZINC26259212; 0.995;
    
1140
    
IV
    
100
  
  

    
ZINC26266464; 0.995;
    
335
    
IV
    
100
  
  

    
ZINC27517251; 0.993;
    
85
    
III
    
100
  
  

    
ZINC33839041; 0.995;
    
85
    
III
    
100
  
  

    
ZINC37250136; 0.997;
    
85
    
III
    
100
  
  

    
ZINC39949141; 0.993
    
N/A
    
N/A
    
0
  
  

    
Tramadol
    
228
    
III
    
100
  
  

    
ZINC71774151; 0.977
    
388
    
IV
    
100
  
  

    
ZINC02509756; 0.986;
    
387
    
IV
    
100
  
  

    
ZINC02510775; 0.995;
    
228
    
III
    
100
  
  

    
ZINC02525883; 0.995;
    
228
    
III
    
100
  
  

    
ZINC03639132; 0.976;
    
318
    
IV
    
100
  
  

    
ZINC05958052; 0.979;
    
387
    
IV
    
100
  
  

    
Note: From; (ProTox-II - Prediction of    TOXicity of Chemicals, 2021). 
  

Table 4: Codeine and zinc compounds binding scores to mu, delta and kappa receptors.

Close

Table 5: Hepatotoxic and immunotoxic profiles of Morphine, Codeine, and Tramadol.

  

    
Compound
    
Hepatotoxicity
    
Probability
    
Immunotoxicity
    
Probability
  
  

    
Morphine
    
I
    
0.99
    
I
    
0.87
  
  

    
ZINC13831510; 0.992
    
I
    
0.89
    
I
    
0.96
  
  

    
ZINC03812983; 0.988;
    
I
    
0.99
    
I
    
0.87
  
  

    
ZINC04102208; 0.992;
    
I
    
0.89
    
I
    
0.96
  
  

    
ZINC04217170; 0.988;
    
I
    
0.9
    
I
    
0.97
  
  

    
ZINC26266464; 0.990;
    
I
    
0.99
    
A
    
0.64
  
  

    
ZINC27517251; 0.988;
    
I
    
0.9
    
I
    
0.97
  
  

    
ZINC37250136; 0.992;
    
I
    
0.99
    
I
    
0.94
  
  

    
ZINC39949141; 0.997;
    
I
    
0.99
    
I
    
0.98
  
  

    
Codeine
    
I
    
0.99
    
I
    
0.94
  
  

    
ZINC03629718; 0.995
    
I
    
0.97
    
I
    
0.94
  
  

    
ZINC02039583; 0.991;
    
I
    
0.99
    
I
    
0.94
  
  

    
ZINC03870350; 0.993;
    
I
    
0.9
    
I
    
0.97
  
  

    
ZINC28256912; 0.992
    
I
    
0.99
    
I
    
0.87
  
  

    
ZINC03830598; 0.991;
    
I
    
0.99
    
I
    
0.94
  
  

    
ZINC05599925; 0.997
    
I
    
0.99
    
I
    
0.94
  
  

    
ZINC26259212; 0.995;
    
I
    
0.98
    
I
    
0.7
  
  

    
ZINC26266464; 0.995;
    
I
    
0.99
    
A
    
0.64
  
  

    
ZINC27517251; 0.993;
    
I
    
0.9
    
I
    
0.97
  
  

    
ZINC33839041; 0.995;
    
I
    
0.9
    
I
    
0.97
  
  

    
ZINC37250136; 0.997;
    
I
    
0.99
    
I
    
0.94
  
  

    
ZINC39949141; 0.993
    
I
    
0.99
    
I
    
0.87
  
  

    
Tramadol
    
I
    
0.92
    
A
    
0.87
  
  

    
ZINC71774151; 0.977
    
I
    
0.84
    
I
    
0.84
  
  

    
ZINC02509756; 0.986;
    
I
    
0.94
    
I
    
0.86
  
  

    
ZINC02510775; 0.995;
    
I
    
0.86
    
I
    
0.7
  
  

    
ZINC02525883; 0.995;
    
I
    
0.86
    
I
    
0.7
  
  

    
ZINC03639132; 0.976;
    
I
    
0.95
    
A
    
0.81
  
  

    
ZINC05958052; 0.979;
    
I
    
0.94
    
I
    
0.86
  
  

    
Key I=Inactive,    A=Active 
  

Table 5: Hepatotoxic and immunotoxic profiles of Morphine, Codeine, and Tramadol.

Close

Zinc compound ZINC05966734; 0.990; showed the lowest docking score to delta receptor than the rest of the zinc compounds and the morphine drug used as the standard. Data in Table 3 shows all the zinc compounds showed higher binding energies to delta receptor than Tramadol. ZINC03806721; 0.991; and ZINC37250136; 0.997; showed lowest docking scores to delta receptor than Codeine based on Table 5. ZINC05966734; 0.990; ZINC03806721; 0.991; and ZINC37250136; 0.997; are promising in developing opioid agonist with least convulsive side effects associated with delta receptor.

In Table 1, ZINC04217170; 0.988, ZINC26259212; 0.993, ZINC33839041; 0.993; and ZINC39949141; 0.997; showed higher docking energies to kappa receptor than morphine. Data on Table 3 showed that these zinc compounds showed higher binding score to kappa receptor than tramadol, ZINC01849532; 0.994, ZINC02525883; 0.995, ZINC03639132; 0.976; and ZINC76734760; 0.977; These zinc compounds therefore, have higher propensity than the rest of the zinc compounds to produce euphoria and diuresis. Table 5 shows that ZINC03870349; 0.993, ZINC03870350; 0.993, ZINC04217170; 0.992; ZINC05599925; 0.997; ZINC27517251; 0.993; and ZINC33839042; 0.992; showed lower binding energies to kappa receptor than codeine and therefore, shows promising results in discovery of opioid agonists with little euphoria side effects.

ZINC13831510; 0.992; showed the highest docking score to mu receptor than Morphine, equal binding energy to kappa receptor as Morphine and higher delta receptor binding than Morphine. ZINC03629718; 0. 995; ZINC03870350; 0.993; and ZINC28256912; 0.992; showed better docking energies to mu receptor than both delta and kappa to codeine as outlined in Table 5. Table 3 indicates that ZINC71774151; 0.977 with the highest binding score to mu than both kappa and delta receptors as compared to Tramadol.

In Tables 10 and 11, Pharmacokinetics profiles of opioids and Zinc compounds were analysed. Opioid analgesics that lack BBB permeation lack the CNS side effects and therefore would lead to better tolerability to the patients and lack of abuse. ZINC13831510; 0.992 and ZINC04102208; 0.992 zinc compounds lack BBB permeation as compared to reference Morphine compound. Codeine, Tramadol and their zinc compounds showed BBB permeation therefore, it is expected that they will have CNS side effects. Table 10 outlines the compounds, which were predicted to be substrates for P-glycoprotein.

Morphine, tramadol, codeine and their zinc compounds showed CYP2D6 inhibition as indicated in Table 11. These compounds also showed absence of CYP1A2, CYP2C19, CYP2C9 and CYP3A4 inhibition. All Zinc compounds analysed for pharmacokinetic profile and their standard drugs complied with Lipinski rule of five, which indicates drug likeness.

In Table 6, ZINC27517251; 0.988;, ZINC37250136; 0.992; and ZINC04217170; 0.988; showed the most toxic compounds having LD50 of 85mg/kg as compared to Morphine which showed LD50 of 461mg/kg.ZINC13831510; 0.992, ZINC03812983; 0.988;, ZINC04102208; 0.992; and ZINC39949141; 0.997 showed LD50 of 335mg/kg. Codeine and these zinc compounds ZINC03629718; 0.995, ZINC03870350; 0.993; and ZINC28256912; 0.992; were the most lethal with LD50 of 85mg/kg. The safest zinc compound was ZINC26259212; 0.995; predicted to have LD50 of 1140mg/kg. Tramadol, ZINC02510775; 0.995 and ZINC02525883; 0.995 were predicted to be the most lethal with LD50 of 228mg/kg.Tramadol was predicted to be toxic when swallowed while ZINC71774151; 0.977 was considered harmful when swallowed. ZINC71774151; 0.977 was predicted to be the safest with LD50 of 387mg/kg followed by ZINC02509756; 0.986; with LD50 of 387mg/kg.

Table 6: Carcinogenicity, mutagenicity and cytogenecity toxicity predictions.

  

    
Compound name
    
Carc
    
P
    
Mut
    
P
    
Cyt
    
P
  
  

    
Morphine
    
I
    
0.74
    
I
    
0.93
    
I
    
0.68
  
  

    
ZINC13831510; 0.992
    
I
    
0.74
    
I
    
0.93
    
I
    
0.68
  
  

    
ZINC03812983; 0.988;
    
I
    
0.63
    
I
    
0.78
    
I
    
0.63
  
  

    
ZINC04102208; 0.992;
    
I
    
0.62
    
I
    
0.78
    
I
    
0.61
  
  

    
ZINC04217170; 0.988;
    
I
    
0.6
    
I
    
0.73
    
I
    
0.58
  
  

    
ZINC26266464; 0.990;
    
I
    
0.62
    
I
    
0.78
    
I
    
0.61
  
  

    
ZINC27517251; 0.988;
    
I
    
0.81
    
I
    
0.93
    
I
    
0.69
  
  

    
ZINC37250136; 0.992;
    
I
    
0.75
    
I
    
0.89
    
I
    
0.69
  
  

    
ZINC39949141; 0.997;
    
I
    
0.81
    
I
    
0.93
    
I
    
0.69
  
  

    
Codeine
    
I
    
0.73
    
I
    
0.85
    
I
    
0.62
  
  

    
ZINC03629718; 0.995
    
I
    
0.73
    
I
    
0.85
    
I
    
0.62
  
  

    
ZINC03870350; 0.993;
    
I
    
0.62
    
I
    
0.78
    
I
    
0.61
  
  

    
ZINC28256912; 0.992
    
I
    
0.74
    
I
    
0.93
    
I
    
0.68
  
  

    
ZINC03830598; 0.991;
    
I
    
0.81
    
I
    
0.93
    
I
    
0.69
  
  

    
ZINC05599925; 0.997
    
I
    
0.81
    
I
    
0.93
    
I
    
0.69
  
  

    
ZINC26259212; 0.995;
    
I
    
0.6
    
I
    
0.81
    
I
    
0.58
  
  

    
ZINC26266464; 0.995;
    
I
    
0.6
    
I
    
0.73
    
I
    
0.58
  
  

    
ZINC27517251; 0.993;
    
I
    
0.62
    
I
    
0.78
    
I
    
0.61
  
  

    
ZINC33839041; 0.995;
    
I
    
0.62
    
I
    
0.78
    
I
    
0.61
  
  

    
ZINC37250136; 0.997;
    
I
    
0.81
    
I
    
0.093
    
I
    
0.69
  
  

    
ZINC39949141; 0.993
    
I
    
0.74
    
I
    
0.93
    
I
    
0.68
  
  

    
Tramadol
    
I
    
0.62
    
I
    
0.8
    
I
    
0.76
  
  

    
ZINC71774151; 0.977
    
I
    
0.69
    
I
    
0.71
    
I
    
0.65
  
  

    
ZINC02509756; 0.986;
    
I
    
0.67
    
I
    
0.8
    
I
    
0.77
  
  

    
ZINC02510775; 0.995;
    
I
    
0.65
    
I
    
0.77
    
I
    
0.97
  
  

    
ZINC02525883; 0.995;
    
I
    
0.65
    
I
    
0.77
    
I
    
0.97
  
  

    
ZINC03639132; 0.976;
    
I
    
0.55
    
I
    
0.8
    
I
    
0.69
  
  

    
ZINC05958052; 0.979;
    
I
    
0.67
    
I
    
0.8
    
I
    
0.77
  
  

    
Key Carc=Carcinogenicity, Mut=Mutagenicity, Cyt=Cytotoxicity,    I=Inactive, A=Active

      Note: From; (ProTox-II - Prediction of    TOXicity of Chemicals, 2021) 
  

Table 6: Carcinogenicity, mutagenicity and cytogenecity toxicity predictions.

Close

Table 7: Nuclear receptor signaling toxicity pathways.

  

    
Compound
    
Ahr
    
p
  
  

    
Morphine
    
A
    
0.62
  
  

    
ZINC03812983; 0.988;
    
A
    
0.62
  
  

    
ZINC39949141; 0.997;
    
A
    
0.66
  
  

    
Codeine
    
A
    
0.8
  
  

    
ZINC28256912; 0.992
    
A
    
0.62
  
  

    
ZINC03830598; 0.991;
    
A
    
0.83
  
  

    
ZINC05599925; 0.997
    
A
    
0.93
  
  

    
ZINC39949141; 0.993
    
A
    
0.62
  
  

    
Key A= Active, AhR=Aryl hydrocarbon    Receptor=probability

      Note: From; (ProTox-II    - Prediction of TOXicity of Chemicals, 2021) 
  

Table 7: Nuclear receptor signaling toxicity pathways.

Close

Table 8: P-glycoprotein substrates predictions.

  

    
Compound
    
P-gp    substrate
    
Compound
  
  

    
Morphine
    
Yes
    
ZINC03870350;    0.993;
    
Yes
  
  

    
ZINC13831510; 0.992
    
Yes
    
ZINC28256912;    0.992
    
Yes
  
  

    
ZINC03812983; 0.988;
    
Yes
    
ZINC03830598;    0.991;
    
Yes
  
  

    
ZINC04102208; 0.992;
    
Yes
    
ZINC05599925;    0.997
    
Yes
  
  

    
ZINC04217170; 0.988;
    
Yes
    
ZINC26259212;    0.995;
    
Yes
  
  

    
ZINC26266464; 0.990;
    
Yes
    
ZINC26266464;    0.995;
    
Yes
  
  

    
ZINC27517251; 0.988;
    
Yes
    
ZINC27517251;    0.993;
    
Yes
  
  

    
ZINC37250136; 0.992;
    
Yes
    
ZINC33839041;    0.995;
    
Yes
  
  

    
ZINC39949141; 0.997;
    
Yes
    
ZINC37250136;    0.997;
    
Yes
  
  

    
Codeine
    
Yes
    
ZINC39949141;    0.993
    
Yes
  
  

    
ZINC02039583; 0.99;
    
Yes
    
 
    
 
  
  

    
Note: From; (SwissADME, 2017) 
  

Table 8: P-glycoprotein substrates predictions.

Close

Table 9: CYP inhibition by opioids.

  

    
Compound
    
CYP2D6    inhibition
    
 
  
  

    
Morphine
    
Yes
    
ZINC03629718;    0.995
    
Yes
  
  

    
ZINC13831510; 0.992
    
Yes
    
ZINC02039583;    0.991;
    
Yes
  
  

    
ZINC03812983; 0.988;
    
Yes
    
ZINC03870350;    0.993;
    
Yes
  
  

    
ZINC04102208; 0.992;
    
Yes
    
ZINC28256912;    0.992
    
Yes
  
  

    
ZINC04217170; 0.988;
    
Yes
    
ZINC03830598;    0.991;
    
Yes
  
  

    
ZINC26266464; 0.990;
    
Yes
    
ZINC05599925;    0.997
    
Yes
  
  

    
ZINC27517251; 0.988;
    
Yes
    
ZINC26259212;    0.995;
    
Yes
  
  

    
ZINC37250136; 0.992;
    
Yes
    
ZINC26266464;    0.995;
    
Yes
  
  

    
ZINC39949141; 0.997;
    
Yes
    
ZINC27517251;    0.993;
    
Yes
  
  

    
Codeine
    
Yes
    
ZINC33839041;    0.995;
    
Yes
  
  

    
ZINC37250136; 0.997;
    
Yes
    
ZINC03639132;    0.976;
    
Yes
  
  

    
ZINC39949141; 0.993
    
Yes
    
ZINC02525883;    0.995;
    
Yes
  
  

    
Tramadol
    
Yes
    
ZINC02510775;    0.995;
    
Yes
  
  

    
ZINC71774151; 0.977;
    
Yes
    
ZINC02509756;    0.986;
    
Yes
  
  

    
ZINC05958052; 0.979;
    
Yes
    
 
    
 
  
  

    
Note: From; (SwissADME, 2017) 
  

Table 9: CYP inhibition by opioids.

Close

Table 10: Codeine and zinc compounds 2D-interactions with receptors (Shaweta et al., 2021).

    

    

    Table 10: Codeine and zinc compounds 2D-interactions with receptors (Shaweta et al., 2021).
    

Close

Table 11: Tramadol and zinc compounds 2D-interactions with receptors.

    

    

    Table 11: Tramadol and zinc compounds 2D-interactions with receptors.
    

Close

Morphine, ZINC03812983; 0.988, ZINC39949141; 0.997, Codeine, ZINC28256912; 0.992 and ZINC03830598; 0.991 were predicted active against AR with probability scores of 0.62,0.62,0.66,0.8,0.62 and 0.83 respectively. ZINC00409844; 0.992; ZINC01651927; 0.991; ZINC01747085; 0.985; ZINC00394165; 0.987; ZINC00406627; 0.980; ZINC01557001; 0.987 and ZINC71451975; 0.975 were predicted active against AhR with probability scores of 0.5,0.5,0.55,0.72,0.81,0.59 and 0.56 respectively. The rest of the compounds were predicted to be inactive in signaling AR-LBD, Aromatase, ER-LBD.

Conclusion

Compounds with the highest docking scores to mu receptor and lower docking scores to both kappa and delta will produce better analgesic effects than rest of the compounds. ZINC13831510; 0.992, ZINC03629718; 0. 995; ZINC03870350; 0.993; ZINC28256912; 0.992; and ZINC71774151; 0.977 showed the highest binding score to mu receptors and lower to both kappa and delta.

All compounds except ZINC04102208; 0.992; and ZINC13831510; 0.992 were predicted to penetrate Blood Brain Barrier. All compounds and reference compounds were predicted to inhibit the CYP2D6 enzyme.

In conclusion, ZINC13831510; 0.992; showed the highest binding score to morphine. ZINC02509756; 0.986; was considered the safest as compared to Tramadol and its zinc compounds. ZINC26259212; 0.995; was considered the safest as compared to the rest of the Codeine’s zinc compounds.

Author Statements

1. ReccommendationsFurther studies such as quantitative structure-activity analysis and ease of synthesizability of ZINC13831510; 0.992, ZINC02509756; 0.986, ZINC26259212; 0.995, ZINC71774151; 0.977, ZINC03629718; 0. 995; ZINC03870350; 0.993; and ZINC28256912; 0.992 should be done.

2. In vitro analysis of ZINC13831510; 0.992, ZINC02509756; 0.986, ZINC26259212; 0.995, ZINC71774151; 0.977, ZINC03629718; 0. 995; ZINC03870350; 0.993; and ZINC28256912; 0.992 should be done.

Funding Sources

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Conflict of Interest Statement

The authors declare that there are no conflicts of interest.

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Citation: Faith K, Stephen O, Kagia R. In Silico Screening of Compounds Similar to Codeine, Tramadol, and Morphine with Better Pharmacodynamic and Pharmacokinetics Profiles. Austin J Pharmacol Ther. 2024; 12(1): 1183.

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