ISSUE 2

Abstract:
Gout is a common metabolic disorder characterized by hyperuricemia and the deposition of monosodium urate crystals in joints and soft tissues, leading to episodes of acute inflammation and chronic joint damage. It manifests initially as acute gouty arthritis with sudden, severe joint pain and can progress to chronic tophaceous gout and renal complications if left untreated. The pathogenesis involves disruptions in uric acid metabolism, crystal formation, and an intense inflammatory response mediated by the NLRP3 inflammasome and pro-inflammatory cytokines. Diagnosis is based on clinical features, laboratory tests, and imaging modalities. Effective management combines acute symptomatic treatment, long-term urate-lowering therapy, and lifestyle modifications. Early intervention is critical to prevent irreversible joint damage and associated comorbidities, improving patient outcomes and quality of life.

Keywords: 

Clogged pores, inflammation, synthetic & herbal treatments, bacterial infection.

Introduction:

Gout is a metabolic disorder where levels of uric acid in the blood are elevated (hyperuricemia), permitting monosodium urate crystals to form and deposit within joints and soft tissues[1]. Usually, this elicits very sudden and severe bouts of joint inflammation and pain, with the affliction of podagra (big toe), although other joints can also be affected [2].

Types of Gout:

Acute Gout: It is an acute attack with sudden pain, swelling, redness, and warm sensation in a single joint, usually the great toe [3]. It is thus called podagra. It commonly happens at night, and can be precipitated by alcohol, trauma, surgery, or excessive consumption of high-purine foods [4]. Intense inflammation occurs because of the immune response to urate crystal deposition in the joint [5]. Without treatment, these attacks can last from several days to weeks and can recur [6].

Chronic Gout: Chronic gout occurs over a while with recurrent acute attacks in the presence of prolonged hyperuricemia [7]. It consists of persistent inflammation of the joints, which may be  polyarticular, like knees, elbows, wrists. Chronic gout can produce joint deformity, quite

limiting mobility, and damaging to cartilage and bone. Undoing treatment, this disorder would turn out to be a very disabling one severely affecting the quality of life achievable [8].

Tophaceous Gout: These commonly Tophaceous gout is an advanced form of gout characterized by the formation of tophi, which are large, visible deposits of monosodium urate crystals in soft tissues [9]. develop in the ears, fingers, toes, and around joints. Tophi can become painful,

inflamed, and even ulcerated, sometimes releasing a chalky white substance. This type usually appears after years of uncontrolled gout and signals long-standing, poorly managed hyperuricemia [10].

2. Etiology and Risk Factors of Gout

Primary and Secondary Causes: In the onset of gout, hyperuricemia takes the stage; the serum uric acid level goes above its solubility limit, setting an environment for monosodium urate crystals to stay affixed to joints and tissues [11]. Depending on the cause behind it, gout might be classified as either of two: primary or secondary.

Primary Causes:
Primary gout is caused by inherited or idiopathic abnormalities in purine metabolism [12]. The condition is usually linked to excess production or reduced excretion of uric acid in the absence of any underlying disease [13]. Most cases of primary gout are secondary to renal under-excretion of uric acid [14]. The major etiological factor is inheritance in that it most often runs in families [15]. Defects in relevant enzymes such as HGPRT deficiency in some cases of Lesch-Nyhan syndrome may also be associated with primary hyperuricemia. It

mainly affects adult males and females after menopause [16]. Further, in case there's a sudden increase in serum urate concentration or saturation level in the plasma, tissue, or extracellular fluid, gout nephropathy, another form of renal damage resulting from uric acid crystallization, develops from primary gout [17].

Secondary Causes:
Secondary gout occurs whenever it develops secondary to any disease or by medications that alter the metabolism of uric acid [18]. Chronic kidney disease is a common etiology as it limits the excretion of uric acid by the body [19]. Other secondary etiologies are

hematological malignancies (such as leukemia), psoriasis, or treatments that induce rapid cell turnover resulting in accelerated purine breakdown[20]. Acceptable medications include thiazide-type diuretics, low-dose aspirin, cyclosporine, and chemotherapy agents that

precipitate gout by inhibiting uric acid excretion [21].

Risk Factors:

Genetic Factors:

In other words, a strong genetic predisposition plays a huge role in acquiring gout [22]. Gene variants in SLC2A9, ABCG2, URAT1, and others modify the efficiency of urate transport and kidney functions, thereby causing hyperuricemia [23]. Since genes determine abnormalities in uric acid handling, gout is more common in individuals whose parents suffer from gout [24].

Lifestyle Factors:

The various lifestyle activities greatly determine the onset of gout. Alcohol consumption, especially beer and hard liquor, increases the production of uric acid and decreases its elimination [25]. Being obese gives rise to insulin resistance and decreases kidney function,

both of which contribute to lower levels of uric acid elimination [26]. Lesser physical activity and dehydration on a chronic basis further deteriorate the condition by limiting the kidneys & 39; capacity to eliminate urates [27].

Dietary Factors:

Diet plays a major role in increasing uric acid levels [28]. Foods rich in purines, such as red meat, liver, kidney, shellfish, and anchovies, may cause uric acid to be set at high levels in the blood after digestion [29]. High-fructose corn syrup in soft drinks and processed foods also significantly leads to its elevation [30]. Hence, less consumption of dairy, fruits, and vitamin C are said to be associated with higher risk, as they can drop serum uric acid [31].

Comorbid Conditions:

Several health conditions predispose individuals to gout. Hypertension, type 2 diabetes  mellitus, obesity, dyslipidemia, and chronic kidney disease are some of the conditions [32]. These comorbidities may make the kidneys incapable of excreting uric acid efficiently or stimulate the overproduction of uric acid [33]. Metabolic syndrome formation in which some of these conditions coexist is strongly associated with an increase in the risk for gout [34].

Abstract:
Cholestatic liver disease (CLD) encompasses a spectrum of hepatobiliary disorders characterized by impaired bile formation and accumulation of toxic bile acids, leading to hepatic injury, fibrosis, and progressive liver dysfunction. The Farnesoid X Receptor (FXR), a bile acid–activated nuclear receptor, serves as a crucial regulator of bile acid homeostasis, lipid metabolism, and inflammation. Pharmacological modulation of FXR has emerged as a promising therapeutic approach; however, existing agonists such as Obeticholic acid exhibit dose-limiting adverse effects.

In this study, Morgan fingerprint–based virtual screening was conducted using Obeticholic acid as the lead molecule to identify structurally similar analogs from the DrugBank database. The shortlisted candidates were subjected to molecular docking against FXR (PDB ID: 5Y1J) to evaluate their binding affinities and interaction profiles. Among 20 screened compounds, Calcifediol (25-hydroxyvitamin D₃) demonstrated the most favorable docking energy (–8.7 kcal/mol), surpassing the reference compound Obeticholic acid (–7.6 kcal/mol). Validation of the FXR model through PDB-REDO refinement confirmed enhanced stereochemical quality, with improved R-free values, Ramachandran plot normality, and bond geometry metrics.

Physicochemical and pharmacokinetic evaluation revealed that Calcifediol possesses a balanced lipophilic–hydrophilic profile, high gastrointestinal absorption, blood–brain barrier permeability, and compliance with major drug-likeness filters, indicating excellent pharmacological potential.

Overall, the computational findings highlight Calcifediol as a promising secosteroidal Vitamin D analog capable of modulating FXR activity. The results suggest a novel therapeutic avenue linking vitamin D metabolism with bile acid regulation, warranting further in vitro and in vivo validation for its potential use in cholestatic liver disease management.

Keywords: 

Farnesoid X Receptor (FXR),Cholestatic Liver Disease, Calcifediol, Morgan Fingerprint Screening, Molecular Docking

Introduction:

Cholestatic liver disease (CLD) represents a diverse group of hepatobiliary disorders characterized by impaired bile formation and flow, resulting in accumulation of toxic bile acids, hepatocellular injury, and progressive fibrosis leading to cirrhosis or liver failure1. The condition can be intrahepatic, as seen in primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), or extrahepatic, involving bile duct obstruction2. Chronic cholestasis disrupts bile acid homeostasis, induces oxidative stress, and triggers inflammatory and fibrotic cascades that compromise hepatic architecture and function3.

Despite notable advances in hepatology, current therapeutic options remain limited. Ursodeoxycholic acid (UDCA) remains the first-line therapy for PBC; however, many patients exhibit incomplete biochemical or clinical response4. Obeticholic acid (OCA), a semi-synthetic bile acid derivative and potent Farnesoid X Receptor (FXR) agonist, represents a significant milestone as a second-line agent. Yet, its long-term administration is often associated with pruritus, dyslipidemia, and potential hepatotoxicity, emphasizing the need for safer and more effective FXR modulators5.

The Farnesoid X Receptor (FXR) (PDB ID: 5Y1J), a ligand-activated nuclear receptor, is predominantly expressed in the liver, intestine, and kidneys, where it plays a central role in bile acid synthesis, lipid metabolism, glucose regulation, and inflammation control 6. Activation of FXR induces expression of small heterodimer partner (SHP) and suppresses CYP7A1, the rate-limiting enzyme in bile acid synthesis, thereby maintaining bile acid homeostasis. Dysregulation of FXR signaling has been directly implicated in cholestasis, steatosis, and hepatic inflammation, making it a promising therapeutic target for restoring metabolic balance and reducing hepatocellular damage7.

In this context, computational drug repurposing represents an efficient strategy for discovering new FXR modulators from existing drug libraries, thereby reducing cost, time, and toxicity risks associated with traditional drug discovery. Modern cheminformatics techniques, such as Morgan fingerprinting, allow identification of structural analogs with potential pharmacophoric similarity to known active compounds.

In the present study, Morgan fingerprint–based virtual screening was performed using Obeticholic acid as the lead molecule against the DrugBank database, followed by molecular docking analysis of the shortlisted candidates against the FXR receptor. Among the screened compounds, Calcifediol (25-hydroxyvitamin D₃), a hydroxylated secosteroidal analog of Vitamin D, displayed the most favorable binding energy (–8.7 kcal/mol), outperforming Obeticholic acid (–7.6 kcal/mol). Owing to its known immunomodulatory, anti-inflammatory, and metabolic-regulatory effects, Calcifediol emerges as a promising repurposed candidate for FXR modulation in cholestatic liver disease.

This investigation highlights the potential of Vitamin D derivatives as novel nuclear receptor modulators, suggesting an unexplored mechanistic link between vitamin D metabolism and hepatic bile acid regulation. Such findings pave the way for future in vitro and in vivo validation to substantiate Calcifediol’s therapeutic role in managing cholestatic liver disorders.

Abstract:
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons, leading to motor and non-motor dysfunctions. Levodopa, the gold-standard therapy, often results in diminished efficacy and motor fluctuations with long-term use, highlighting the need for alternative treatments. This study employed computational drug repurposing to identify potential therapeutic candidates for PD, focusing on the Dopamine D₂ receptor, a key target in PD pathophysiology. Using Morgan fingerprint-based virtual screening and molecular docking, 19 structurally similar compounds to Levodopa were identified. Carbidopa, a DOPA decarboxylase inhibitor, exhibited the highest binding affinity (–6.4 kcal/mol) and was identified as a promising repurposing candidate. The results underscore the potential of Carbidopa as an adjunctive or alternative treatment for PD, offering enhanced therapeutic efficacy with its favorable interaction profile. The study demonstrates the utility of computational methods in drug discovery, enabling the identification of existing drugs with new therapeutic roles.

Keywords: 

Parkinson's Disease, Drug Repurposing, Dopamine D₂ Receptor, Molecular Docking, Carbidopa.

Introduction:

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the selective loss of dopaminergic neurons in the substantia nigra pars compacta, leading to dopamine deficiency in the striatum and resulting in classical motor symptoms such as bradykinesia, rigidity, resting tremor, and postural instability¹. In addition to motor dysfunction, PD is often associated with non-motor manifestations including cognitive impairment, mood disorders, and autonomic dysfunction, reflecting widespread neurochemical alterations².

Despite extensive research, current pharmacotherapeutic strategies for PD remain primarily symptomatic. Levodopa, a dopamine precursor, continues to serve as the gold-standard treatment due to its ability to replenish striatal dopamine levels. However, long-term Levodopa therapy is associated with motor fluctuations, dyskinesias, and diminished efficacy over time. Adjunctive therapies such as dopamine agonists and monoamine oxidase-B (MAO-B) inhibitors offer temporary benefits but fail to halt disease progression3. Consequently, the identification of alternative or adjunctive agents with enhanced efficacy and safety profiles remains an urgent therapeutic priority.

The Dopamine D₂ receptor (PDB ID: 1I1R), a G protein–coupled receptor (GPCR), plays a pivotal role in regulating dopaminergic neurotransmission, motor control, and neuroplasticity4. Dysregulation of D₂ receptor signaling has been implicated in the pathophysiology of PD, making it an attractive molecular target for drug discovery.

In this context, computational drug repurposing has emerged as a powerful approach to accelerate the identification of novel therapeutic candidates from existing drug libraries. By integrating cheminformatics and molecular docking, this strategy minimizes cost, time, and clinical risk compared to traditional de novo drug discovery. Among various methods, Morgan fingerprint–based virtual screening enables recognition of structural and pharmacophoric similarities between known drugs and potential analogs5.

In the present study, Morgan fingerprint–based virtual screening was conducted using Levodopa as the lead compound against a comprehensive drug database, followed by molecular docking analysis against the Dopamine D₂ receptor. The screening identified 19 structurally similar compounds, among which Carbidopa, a well-known DOPA decarboxylase inhibitor, exhibited the highest binding affinity (–6.4 kcal/mol) compared to Levodopa (–5.8 kcal/mol). Carbidopa’s favorable interaction profile and pharmacodynamic synergy with Levodopa suggest its potential as an effective alternative or adjunctive therapeutic candidate for PD management.

This investigation underscores the utility of computational drug repurposing in uncovering novel therapeutic roles of existing drugs. The findings highlight Carbidopa’s strong binding affinity and target specificity toward the Dopamine D₂ receptor, paving the way for further in vitro and in vivo validation to substantiate its role as a potential alternative treatment in Parkinson’s disease.