Murugesan Vanangamudi

Introduction: Tuberculosis (TB) is a transmissible disease caused by Mycobacterium tuberculosis, which continues to be a major public health issue worldwide. The situation has become more alarming with the increasing cases of multidrug-resistant (MDR) strains, which makes treatment difficult. Nitrofurans, a class of heterocyclic compounds known for their antimicrobial potential, have gained renewed attention as scaffolds for anti-TB drug design. This study aimed to investigate the structural features governing the antitubercular activity of 5-nitrofuranyl derivatives using 2D-QSAR modeling and molecular docking analysis and to identify new compounds that inhibit the biosynthesis of the Mycobacterium tuberculosis cell wall. Method: Twenty-eight 5-nitrofuranyl derivatives were studied by means of 2D-QSAR analysis employing descriptors from the Dragon software suite within the framework of CP–MLR methodology. Statistically significant models were selected based on r², Q² (LOO and L5O), and test set predictivity. Molecular docking was performed using AutoDock Vina against Galactofuranosyltransferase 2 (GlfT2), a validated target involved in the cell wall biosynthesis of M. tuberculosis. Result: Robust QSAR models were obtained with up to R² = 0.912 and Q²LOO = 0.839. Key descriptors influencing activity included topological descriptors (IC1, JGI2, JGI5), mass-weighted Burden eigenvalues (BELm2, BELm6), molecular weight (MW), and selected atom-centered fragments such as C-006 and C-031. Docking studies revealed that several compounds (notably 27, 25, and 3) exhibited high binding affinity to GlfT2 (−9 to −6.7 kcal/mol), correlating well with QSAR predictions. Discussion: The obtained QSAR parameters suggested the importance of molecular topology, electronic features, and particular structural fragments in modulating antitubercular activity. Molecular docking to the GlfT2 protein showed that the binding affinity of compounds 27, 25, and 3 was found to be more favorable for their binding in the active site of the enzyme. Moreover, the results from the ADME study demonstrated that compound 3 acquired the best pharmacokinetic properties compared to the other molecules. Conclusion: This integrated QSAR and molecular modeling study highlights the structural determinants of 5- nitrofuranyl-based antituberculosis agents. Compounds with favorable descriptor profiles and strong GlfT2 binding affinity represent promising leads for further development. This approach demonstrates the effectiveness of combining ligand- and structure-based strategies for rational antitubercular drug design.

Microglia are the immune cells resident in the central nervous system (CNS) and are involved in CNS homeostasis and in responses to injury and disease. Microglia, upon activation, become pro‐inflammatory (M1) or anti‐inflammatory (M2), with M1 being neurotoxic and M2 participating in tissue repair. The activation of microglia in neuroinflammation and pain hypersensitivity is important in the neurodegenerative disorders such as Parkinson's (PD) and Alzheimer's disease ( AD ). Recent investigations have identified GLP‐1 receptor agonists (GLP‐1 RAs) as potent pharmacological agents that can regulate the activity of the microglia. GLP‐1RA attaches to the GLP‐1 receptor found on the microglia to cause a phenotypic shift to the anti‐inflammatory M2 form, which, in turn, reduces neuroinflammation and increases neuronal protection. Experimental evidence shows that GLP‐1 RAs are effective at reducing hypersensitivity to pain, improving cognitive performance, and attenuating inflammatory effects in preclinical models of AD , PD, and multiple sclerosis (MS). All these facts suggest that GLP‐1 RAs are a significant treatment option in chronic pain and neurodegenerative disease management, as they can change microglial polarization and suppress neuroinflammation.

Introduction: Mitochondria play an important role in maintaining redox balance, energy, calcium, and the viability of neurons. The mitochondrial dysfunction is one of the primary sources of glial activation and dopaminergic neuron loss in Parkinson's disease (PD). The key biochemical elements of the pathogenesis of PD include impaired oxidative phosphorylation, elevated generation of reactive oxygen species (ROS), and impaired mitophagy. Methods: This review is a synthesis and stringent evaluation of recent experimental, clinical and genetic studies relating mitochondrial dysfunction and Parkinson's disease (PD). We examined information on bioenergetics, mitochondrial dynamics, calcium homeostasis, and interactions between neurons and glia. The molecular and therapeutic importance of therapies, such as mitophagy modulators, bioenergetic enhancers, and mitochondrial antioxidants, was investigated. The absence of Complex I, excess ROS, mitochondrial DNA damage, and nonfunctioning fusionfission cycles leads to neurodegeneration. The glial metabolic abnormalities worsen the oxidative stress and neuroinflammation, weakening the support of the neurons. The effects of impaired mitophagy are the accumulation of dysfunctional mitochondria, and the effects of calcium overload disrupt energy metabolism. Neuroprotective effects of such substances as spermidine, urolithin A, resveratrol, αlipoic acid, MitoQ, SkQ1, or CoQ10 have been shown using preclinical research. Sacrifices such as exercising and proper dieting enable the mitochondria to perform better and become stronger. Discussion: Mitochondrial dysfunction enhances the progression of PD through oxidative stress, bioenergetic breakdown, and inflammatory signalling. Attention to these related systems is an entire way to alter the direction of a disease. Conclusion: PD can be treated using an increase in mitochondrial quality control, redox regulation, and metabolic efficiency. Continued studies in the framework of precision medicine are required to validate the safety and effectiveness of mitochondrial-targeted medications.

Background: Ritonavir (RTV) is an antiviral drug that prevents human immunodeficiency virus (HIV). However, it has low bioavailability, which can be improved with the assistance of Solid Lipid Nanoparticles (SLNs). Objective: The present work aimed to formulate and optimize RTV-loaded SLNs using Box–Behnken design and evaluate the permeability coefficient using ex vivo permeation studies. Methods: RTV-SLNs were prepared using the ultrasonication technique. The SLN formulation was optimized based on particle size, % entrapment efficiency, and % cumulative drug release using response surface methodology resulting from Box-Behnken design. The Fourier-Transform Infrared spectroscopy (FT-IR), Differential Scanning Calorimetry (DSC), and transmission Electron Microscopy (TEM) studies were carried out for the characterization of optimized SLN formulation. Ex vivo permeation studies were also performed using chicken ileum. Results: The optimized RTV-SLNs had a particle size of 270.34 nm, polydispersity index of 0.157, and zeta potential of -25.2 mV. The % entrapment efficiency and % cumulative drug release were found to be 94.33% and 67.13%, respectively. The FT-IR study revealed that SLNs showed no significant interactions between the drug and lipid in the formulation. The % crystalline index of the RTV-loaded SLN formulation was found to be 44.31% compared to the reference value of 100% for lipids. TEM analysis showed spherical nanoparticles that were uniform in shape. The release kinetics data demonstrated the drug release behavior, followed by the Korsmeyer-Peppas model, and suggested that the release from SLNs followed the non-fiction diffusion. The permeability coefficient of optimized SLN formulation was found to be significantly (p < 0.05) more compared to free RTV suspension. The enhancement ratio results suggested that RTV-SLNs permeated significantly (p < 0.05) faster (approximately 3.5 times) as compared to free RTV suspension. Conclusion: The optimized RTV-SLNs could be a promising carrier for improving the oral bioavailability of RTV.

Targeted protein degradation is a rapidly expanding area that offers hope for novel approaches to combat drug resistance. The creation of heterobifunctional proteolysis-targeting chimeras [PROTACs], a new group of pharmaceutical compounds, has made TPD a useful method for completely getting rid of harmful proteins using regular small-molecule inhibitors. A big plus is that PROTACs can target multi-domain proteins that cannot be broken down. This is the case, particularly for proteins lacking a conserved interaction surface for small-molecule ligands SMIs and featuring smooth surfaces. Poor oral bioavailability and pharmacokinetic PK and ADMET absorption, distribution, metabolism, excretion, and toxicity characteristics are among the long-term issues with traditional PROTACs. Their larger size and more complex structure set them apart from other smallmolecule inhibitors, which is why they are so effective. Clinical studies have been conducted on a plethora of PROTAC compounds in the past 20 years, all with the goal of inducing the degradation of targets relevant to cancer. In this article, we closely examine the major developments and recent advancements in PROTAC technology. We seek to summarize and fully assess PROTAC-based targeted protein degradation studies on "undruggable" targets. Discussing their molecular structure, action mechanism, design concepts, development benefits, and obstacles will help to illustrate the significance of developing highly successful PROTAC-based techniques in treating many illnesses, including cancer treatment resistance.

AIDS (acquired immunodeficiency syndrome) is a potentially life-threatening infectious disease caused by human immunodeficiency virus (HIV). To date, thousands of people have lost their lives annually due to HIV infection, and it continues to be a big public health issue globally. Since the discovery of the first drug, Zidovudine (AZT), a nucleoside reverse transcriptase inhibitor (NRTI), to date, 30 drugs have been approved by the FDA, primarily targeting reverse transcriptase, integrase, and/or protease enzymes. The majority of these drugs target the catalytic and allosteric sites of the HIV enzyme reverse transcriptase. Compared to the NRTI family of drugs, the diverse chemical class of non-nucleoside reverse transcriptase inhibitors (NNRTIs) has special anti-HIV activity with high specificity and low toxicity. However, current clinical usage of NRTI and NNRTI drugs has limited therapeutic value due to their adverse drug reactions and the emergence of multidrug-resistant (MDR) strains. To overcome drug resistance and efficacy issues, combination therapy is widely prescribed for HIV patients. Combination antiretroviral therapy (cART) includes more than one antiretroviral agent targeting two or more enzymes in the life cycle of the virus. Medicinal chemistry researchers apply different optimization strategies including structure- and fragment-based drug design, prodrug approach, scaffold hopping, molecular/fragment hybridization, bioisosterism, high-throughput screening, covalent-binding, targeting highly hydrophobic channel, targeting dual site, and multi-target-directed ligand to identify and develop novel NNRTIs with high antiviral activity against wild-type (WT) and mutant strains. The formulation experts design various delivery systems with single or combination therapies and long-acting regimens of NNRTIs to improve pharmacokinetic profiles and provide sustained therapeutic effects.