EXPLORATION OF ANALGESIC POTENTIALS OF BENZOFURAN PYRAZOLE HETEROCYCLE AND AZOSALICYCLIC ACID THROUGH MOLECULAR DOCKING, PHARMACOKINETICS AND DFT STUDIES

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ABSTRACT

Various diseases and injuries are always presented with pains. These are considered as symptoms associated with various pathological processes in the body. Drugs that are used to alleviate pains such as non-steroidal anti-inflammatory drugs exhibit adverse effects for example cardiac abnormalities, peptic ulcers, liver toxicity and kidney failure. The analgesic activities were compared to ibuprofen the (standard drug). The molecular docking was performed on 20 benzofuranpyrazoleheterocycle and 5 azosalicyclic acid derivatives as COX-2 receptor using molecular visual Docker, ADMET evaluation, and density functional theory (DFT). Five top-ranked compounds (14,16,17,18 and 20) in benzofuranpyrazoleheterocycle with remarkable docking scores, compared to the standard drug IBUPROFEN, were selected -186.169kcal/mol,-186.700kcal/mol,-178.893kcal/mol,-188.798kcal/mol,and -182.233kcal/mol have higher sore than the ibuprofen -111.683kcal/mol and in the azosalicyclic (1,2,3,4 and 5) -126.584kcal/mol, -137.214kcal/mol, -134.701kcal/mol, -130.809kcal/mol and-135.671kcal/mol they also have high docking score than the standard drug. The formation of Hbonds and hydrophobic interactions with CYCLOOXGENASE SHOWS Conventional hydrogen bonds was formed with ASN34 with a bond length of 1.87492Å and GLN461 with a bond length of 1.67137Å, and hydrophobic π-alkyl interaction was formed with PRO153, PRO153, PRO154 and ALA156 residues. Subsequently, the compounds were screened by analyzing their drug-likeness and ADMET properties. The compounds possess safety agents and effective combination therapy as pharmaceutical drugs. The highest occupied molecular (HOMO) orbital, lowest unoccupied molecular orbital (LUMO), and energy gap values were calculated using the DFT. The molecular electrostatic potential (MEP) was analyzed to illustrate the charge density distributions that could be associated with the biological activity. Therefore, compound 18 having good potential may serve as a new potential drug.

TABLE OF CONTENTS

Title page………………………………………………………………………………………I

Declaration………………………………………………………………….………………..II

Certification………………………………………………………………….……………….III

Dedication……………………………………………………………………………………IV

Acknowledgements……………………………………………………………………….……V

Table of contents………………………………………………………………………….…..VI

List of tables……………………………………………………………………………………X

Abstract………………………………………………………………………………………..XI

CHAPTER ONE

1.0Introduction…………………………………………………………………………………..1

• Background of study…………………………………………………………………………1
• Statement of Research problem……………………………………………………………..2
• Justification of the study…………………………………………………………………….3

1.4 Aim and objectives…………………………………………………………………………..3

CHAPTER TWO

2.0 Literature Review……………………………………………………………………………5

2.1 Biochemical and physiological Basis of pain………………………………………………..5

• Models for pain………………………………………………………………………………6

• History of Analgesic use……………………………………………………………………..7

• Definition of Analgesic………………………………………………………………………8

• Non-steroidal anti-inflammatory drugs………………………………………………………9

• Opioids………………………………………………………………………………………10

• Effectiveness and efficacy of analgesics……………………………………………………..10

• Risks of analgesic use………………………………………………………………………..11

• Overview of some analgesic drug result in computational studies…………………………..12

• Molecular docking and interaction result of similar work on analgesic drugs……………12

• Pharmacokinetics and drug-likeness of some similar work on analgesic drugs……………..13

• Density function theory DFT of some similar work on analgesic drugs ………………14

CHAPTER THREE

• Materials and method………………………………………………………………………..16

3.1Materials……………………………………………………………………………………..16

3.2Geometry optimization /DFT method………………………………………………………..16

3.3Molecular Docking method………………………………………………………………….17

• Pharmacokinetics and Drug-likeness method………………………………………………..18
• 2D structures of compounds in benzofuran…………………………………………………..19
• 2D structures of compounds in azosalicyclic acid……………………………………………22

CHAPTER FOUR

4.0 Result and discussion…………………………………………………………………………23

• Docking results of ligands in benzofuranpyrazoleheterocycle………………………………23
• Molecular interaction of five best docked ligands in benzofuranpyrazoleheterocycle………24
• Predicted Drug-likeness properties of ligands in benzofuranpyrazoleheterocycle…………..28
• Evaluation of ADMET properties of ligands in benzofuranpyrazoleheterocycle…………..29
• DFT evaluation results of benzofuranpyrazoleheterocycle…………………………………33
• Docking results of ligands inazosalicyclic acid……………………………………………..34
• Molecular interaction of ligands inazosalicyclic acid……………………………………….35
• Predicted Drug-likeness properties of ligands inazosalicyclic acid…………………………37
• Evaluation of ADMET properties of ligands inazosalicyclic acid…………………………..38
• DFT evaluation result inazosalicyclic acid………………………………………………40

4.11 Molecular electrostatic potential…………………………………………………………….42

CHAPTER FIVE

5.1 Conclusion…………………………………………………………………………..45

5.2 Recommendations…………………………………………………………………..46

References…………………………………………………………………………..47

CHAPTER ONE

1.0INTRODUCTION

1.1 Background of the Study

Pain is defined as multidimensional, subjective and unpleasant experience that is allied to tissue damage comprising sensory experiences that include; time, intensity, space, emotion, cognition and motivation (Kremer et al., 2021). Pain contains both sensory and psychological mechanisms. However, pain is beyond sensation, it comprises of perception and subjective interpretation of the discomfort(Kremer et al., 2021). Major mediators of pain include; Bradykinin, histamine, serotonin and prostaglandins. Pain in its real sense lack a way to define it, but in general term, occurs whenever the body tissues are damaged (Aromeet al., 2016). Sensation of pain is a sign that something in the body is wrong. Pain plays an important role in drawing attention to tissue injury from harmful stimuli and reflexes are elicited to protect the injured part of the body (Aromeet al., 2016). Damage caused by mechanical, thermal, chemical and electrical stimuli through peripheral receptors triggers pain sensation to nociceptors in an organism (Gianòet al.,2023). Perception of pain is a normal physiological response that is mediated by nervous system and is used for diagnosing various diseases such as diabetes, arthritis and cancer that are normally associated with chronic pain (Clauwetal., 2019).

Pain, are beneficial to the immune system. However, they cause a lot of suffering and discomfort to the victims lowering the quality of life and therefore need to be managed. Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used to manage pain (Kołeckaet al., 2022). Opioid analgesics are choice drugs for severe or chronic malignant pain (Bertinet al., 2021). Their mechanism of action involves inhibition of cyclooxygenase (COX) enzyme which results in disruption of prostaglandins synthesis (Johnson et al., 2020). However, non-steroidal anti-inflammatory drugs and opioid analgesics that are normally used to treat pain manifest a great number of adverse effects (Huanget al., 2020). Despite numerous progress in medical science and in the production of new synthetic conventional drugs for management of pain, there is still need for development of more cost-effective and improved remedies with lesser side effects. Recent studies by world health organization (WHO) indicate that these compounds/drugs used in the management of pain, manifest a lot of side effects after long term use that include gastric irritation, ulceration, prolonged bleeding, renal failure, interstitial corrosion, and pruritis (Huanget al., 2020). Reduction in ligament formation, tendon, cartilage healing and delay in muscle regeneration in many studies has been associated with NSAIDs (Roffinoet al., 2021). Conventional drugs used to manage pain, only provide asymptomatic relief and the greatest disadvantage lies in their toxicity to the liver, kidney and reappearance of symptoms after discontinuation (Carrariniet al., 2019). In this regard, herbal medicines have been employed in complementary and alternative medicine (CAM) for treatment of pain, as well as diseases related to these conditions. In general, natural products and in particular, medicinal plants, are believed to be an important source of novel chemical substances with potential therapeutic capabilities. Considering that most of anti-inflammatory, analgesic, anti-malarial and antipyretic synthetic drugs such as aspirin, morphine chloroquine and artemisinin were derived from plant products, the search for plant species with anti-inflammatory, antipyretic and analgesic properties should be viewed as a fruitful strategy in search of new drugs (Tatiyaet al., 2017).

1.2 Statement of Research Problem

Recently, there has been a remarkable development in medical science. Pain cause suffering and discomfort among the victims (Levkovich, et al., 2020). Recent studies by WHO indicates that the NSAIDs used in management of these condition manifest a lot of side effects (Huanget al., 2020). However, treatment and management of many serious indicators of ill health is still a problematic and complex (Rodgers et al., 2018).Therefore, a challenge to the research sector to find alternative approaches of managing pain as well as reduce the dangers associated with experimental screening efforts set.Computational studies offers a method for identifying and optimizing potentials compounds with increased activity for curing of pains. Hence, there is need for chemists to suggest new potentials drugs which are more effective within a short period of time.

• Justification of the Study

Therefore, there should be provision of alternative drugs thathas more cost-effectiveness and improved remedies with lesser side effectsto web lab drug discovery and to of Benefit to researchers in field of pharmaceutical and academia chemistry

• Aim and objectives

The aim of the research is to explore the analgesic potentials of benzofuranpyrazoleheterocycle and azosalicyclic acid through molecular docking, pharmacokinetics and DFT studies.

Through the following objectives to;

• Drawing of the 2D structures of compounds retrieved using chem draw software then converting the 2D to 3D Using Spartan 14 software
• Conduct geometry optimization of compounds and SD using DFT/B3LYP approach and 6-311G basis set
• Conduct molecular docking in the active site of the retrieved receptor and compounds using Molegro virtual Docker.
• Predict drug likeness and pharmacokinetics properties of compounds and SD drug and identifying the leading compound.

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