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

Research Article

Austin J Pharmacol Ther. 2024; 12(1): 1183.

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

Kamakia Faith*; Ouma Stephen; Richard Kagia

Department of Pharmacology and Pharmacognosy, Kabarak University School of Pharmacy, Kenya

*Corresponding author: Faith Muthoni Department of Pharmacology and Pharmacognosy, Kabarak University School of Pharmacy, Kenya. Email: wfaithmuthoni578@gmail.com

Received: November 27, 2023 Accepted: January 05, 2024 Published: January 12, 2024

Abstract

Introduction: Pain alleviation is the primary intervention in promoting quality of life. Among the compounds used in management of pain are opioids. Codeine is mostly used as antitussive and is commonly present in cough syrups. Tramadol and Morphine are used as analgesics based on severity of pain. Although these drugs provide instant pain relief, they are associated with many side effects and the most worrying once are addiction, respiratory depression and tolerance.

Methods: Codeine, Tramadol, and Morphine were used as query compounds to generate similar compounds using SwissSimilarity. Similar compounds were docked to mu, kappa, and delta receptors and those that showed better docking scores to mu receptor and lower scores to kappa and delta were analyzed for toxicity profiles using ProTox II and pharmacokinetics profiles using SwissADME.

Results: ZINC13831510; 0.992, ZINC03629718; 0. 995; ZINC03870350; 0.993; ZINC28256912; 0.992; and ZINC71774151; 0.977 showed highest binding score to mu receptors and lower to both kappa and delta. All compounds were predicted to inhibit CYP2D6 enzyme. All compounds permeated Blood Brain Barrier with the exceptions of ZINC04102208; 0.992; and ZINC13831510; 0.992. Tramadol, its zinc compounds and ZINC03629718; 0.995. were not substrates for P-glycoprotein. Tramadol and ZINC03639132; 0.976; were predicted immunoactive. All compounds conformed to Lipinski rule of five.

Conclusion: In conclusion, ZINC13831510; 0.992; showed the highest binding score to morphine. ZINC02509756; 0.986; and ZINC26259212; 0.995; were considered the safest as compared to Tramadol and Codeine and their zinc compounds respectively. Further invitro studies are recommended for the following promising compounds ZINC13831510; 0.992, ZINC03629718; 0. 995; ZINC03870350; 0.993; ZINC28256912; 0.992; and ZINC71774151; 0.977 ZINC02509756; 0.986; and ZINC26259212; 0.995;.

Keywords: Codeine; Tramadol, Morphine, docking score, SwissADME, Protox II, toxicity

Abbreviations: BBB: Blood Brain Barrier; AhR: Aryl hydrocarbon Receptor; A: Active; I: Inactive; GIT: Gastrointestinal Tract

Introduction

Opioids are majorly used to alleviate severe pain which is mediated through the mu receptor agonism in the brain [3]. Opioid use has however, been associated with abuse causing addiction leading to deaths of people due to respiratory depressant effects of opioids. Deaths related to synthetically manufactured opioids in United States in 2017, was 47,600, which was three quarter the number of total drug related deaths [18]. Opioids has become great concern in modern management of diseases. Physicians and Pharmacists are in dilemma in provision of patient centered care while maximizing benefits in pharmaceutical interventions and minimizing side effects of those interventions.

Major mechanism of action of opioids involves binding to their mu, delta and kappa receptors [16] on the presynaptic space of afferent sensory axon causing release of calcium channels that lead to loss of mitochondrion function of the cells and decreased in release of substance P. Opioids also bind postsynaptically to their respective receptors causing opening of potassium channels that hyperpolarize the cells increasing action potential required to generate pain impulse transmission.

Opioids are the mainstay in alleviating Pain and according to the WHO ladder of Pain, weak opioids such as tramadol are involved in the second step in pain management. The third step involves use of strong opioids such as morphine. Due to side effects, genetic polymorphism and abuse, there is a need to screen for new opioid analogues with improved metabolism, pharmacokinetics as well as pharmacodynamic properties.