Lead Molecules Research Articles

Design, synthesis, and biological evaluation of 3-benzenesulfonamide-linked 3-hydrazinoisatin derivatives as carbonic anhydrase inhibitors.

A new series of isatin-linked benzenesulfonamide derivatives (9a-w) were synthesized using the tail approach and assayed for their inhibitory potency against four different human carbonic anhydrase (hCA) isoforms, hCA I, II, IX, and XII. Most of these synthesized compounds exhibited interesting inhibition potency against isoforms hCA I, IX, and XII in the nanomolar range and by taking the standard drug acetazolamide. The most potent compounds in the case of hCA I were 9c (435.8 nM) and 9s (956.4 nM), for hCA IX, 9a (60.5 nM), 9d (95.6 nM), 9g (92.1 nM), and 9k (75.4 nM), and for hCA XII, 9p (84.5 nM). However, these compounds showed more selectivity toward hCA IX over hCA I, II, and XII. Thus, these compounds can be further developed as potential lead molecules for the development of isoform-selective hCA IX inhibitors with further structural modifications.

Rational Design of TDP-43 Derived α-Helical Peptide Inhibitors: An In Silico Strategy to Prevent TDP-43 Aggregation in Neurodegenerative Disorders.

TDP-43, an essential RNA/DNA-binding protein, is central to the pathology of neurodegenerative diseases, such as amyotrophic lateral sclerosis and frontotemporal dementia. Pathological mislocalization and aggregation of TDP-43 disrupt RNA splicing, mRNA stability, and mRNA transport, thereby impairing neuronal function and survival. The formation of amyloid-like TDP-43 filaments is largely facilitated by the destabilization of an α-helical segment within the disordered C-terminal region. In this study, we hypothesized that preventing the destabilization of the α-helical domain could potentially halt the growth of these pathological filaments. To explore this, we utilized a range of in silico techniques to design and evaluate peptide-based therapeutics that bind to pathological TDP-43 amyloid-like filament crystal structures and resist β sheet conversion. Our computational approaches, including biophysical and secondary structure property prediction, molecular docking, 3D structure prediction, and molecular dynamics simulations, were used to assess the structure, stability, and binding affinity of these peptides in relation to pathological TDP-43 filaments. The results of our in silico analyses identified a selection of promising peptides which displayed a stable α-helical structure, exhibited an increased number of intramolecular hydrogen bonds within the helical domain, and demonstrated high binding affinities for pathological TDP-43 amyloid-like filaments. Molecular dynamics simulations provided further support for the structural and thermodynamic stability of these peptides, as they exhibited lower root-mean-square deviation and more favorable free energy landscapes over 300 ns. These findings establish α-helical propensity peptides as potential lead molecules for the development of novel therapeutics against TDP-43 aggregation. This structure-based computational approach for the rational design of peptide inhibitors opens a new direction in the search for effective interventions for ALS, FTD, and other related neurodegenerative diseases. The peptides identified as the most promising candidates in this study are currently subject to further testing and validation through both in vitro and in vivo experiments.

In silico exploration of CB2 receptor agonist in the management of neuroinflammatory conditions by pharmacophore modeling

Endocannabinoid system plays a pivotal role in controlling neuroinflammation, and modulating this system may not only aid in managing symptoms of neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Multiple sclerosis, Epilepsy, Central and Peripheral neuropathic pain, but also, have the potential to target these diseases at an early-stage. In the present study, six different pharmacophore hypotheses were generated from Cannabidiol (CBD)-Cannabinoid Receptor subtype-2 (CB2) and then Zinc database was screened for identification of hit molecules. Identified 215 hit molecules were subjected to preliminary screening with ADMET and drug likeness properties, and about 48 molecules were found with no violations and toxicity properties. In molecular docking studies, six compounds showed better binding energy than CBD and β-caryophyllene (known inhibitor of CB2). These six molecules were designated as leads and subjected to re-docking with glide tool and Lead1 (ZINC000078815430) showed docking score of −9.877 kcal/mol, whereas CBD and β-caryophyllene showed score of −9.664 and −8.499 kcal/mol, respectively. Lead1 and CBD were evaluated for stability studies with Desmond tool by molecular dynamic simulation studies. Lead1 showed better stability than CBD in all studied parameters such as RMSD, RMSF, SSE, Rg, SASA, etc. In MM-GBSA free energy calculations, ΔGbinding energy of CB2-CBD complex and CB2-Lead1 were found to be −103.13±11.19 and −107.94±5.42 kcal/mol, respectively. Six lead molecules stated in the study hold promise with respect to CBD agonistic activity for treating and/or managing chronic conditions and can be explored as an alternative for early-stage cure, which has not yet been experimentally explored.

Environmental Evaluation on Toxicity, Toxic Mechanism, and Hydrolysis Behavior of Potential Acethydrazide Fungicide Candidates.

The evaluation of toxicity and environmental behavior of bioactive lead molecules is helpful in providing theoretical support for the development of agrochemicals, in line with the sustainable development of the ecological environment. In previous work, some acethydrazide structures have been demonstrated to exhibit excellent and broad-spectrum fungicidal activity; however, its environmental compatibility needs to be further elucidated if it is to be identified as a potential fungicide. In this project, the toxicity of fungicidal acethydrazide lead compounds F51, F58, F72, and F75 to zebrafish was determined at 10 μg mL-1 and 1 μg mL-1. Subsequently, the toxic mechanism of compound F58 was preliminarily explored by histologic section and TEM observations, which revealed that the gallbladder volume of common carp treated with compound F58 increased, accompanied by a deepened bile color, damaged plasma membrane, and atrophied mitochondria in gallbladder cells. Approximately, F58-treated hepatocytes exhibited cytoplasmic heterogeneity, with partial cellular vacuolation and mitochondrial membrane rupture. Metabolomics analysis further indicated that differential metabolites were enriched in the bile formation-associated steroid biosynthesis, primary bile acid biosynthesis, and taurine and hypotaurine metabolism pathways, as well as in the membrane function-related glycerophospholipid metabolism, linolenic acid metabolism, α-linolenic acid metabolism, and arachidonic acid metabolism pathways, suggesting that the acethydrazide F58 may have acute liver toxicity to common carp. Finally, the hydrolysis dynamics of F58 was investigated, with the obtained half-life of 5.82 days. The above results provide important guiding significance for the development of new green fungicides.

Structural insights into the modulation Of SOD1 aggregation By a fungal metabolite Phialomustin-B: Therapeutic potential in ALS.

Amyotrophic lateral sclerosis (ALS) is a fatal human motor neuron disease leading to muscle atrophy and paralysis. Mutations in superoxide dismutase 1 (SOD1) are associated with familial ALS (fALS). The SOD1 mutants in ALS have a toxic-gain of function by destabilizing the functional SOD1 homodimer, consequently inducing fibril-like aggregation with a cytotoxic non-native trimer intermediate. Therefore, reducing SOD1 oligomerization via chemical modulators is an optimal therapy in ALS. Here, we report the discovery of Phialomustin-B, an unsaturated secondary metabolite from the endophytic fungus Phialophora mustea, as a modulator of SOD1 aggregation. The crystal structure of the SOD1-Phialomustin complex refined to 1.90 Å resolution demonstrated for the first time that the ligand binds to the dimer interface and the lateral region near the electrostatic loop. The aggregation analyses of SOD1WT and the disease mutant SOD1A4V revealed that Phialomustin-B reduces cytotoxic trimerization. We propose that Phialomustin-B is a potent lead molecule with therapeutic potential in fALS.

Molecular design and virtual screening of novel heterocyclic derivatives as Glucokinase activators

Background: Deficiency of insulin signaling in type 2 diabetes results from insulin resistance or defective insulin secretion and induce hyperglycemia. Diabetes is a global threat that continues to increase day by day at a very high rate in both developing and developed countries. Glucokinase activators (GKA) can be a novel target used for better management of type 2 diabetes. Recently novel GKA Dorzagliatin received market approval by Japan FDA for treatment of type 2 diabetes. Objective: The purpose of designing glucokinase activators was to develop novel therapeutic molecules with minimum side effects. Methods: A docking study was conducted using AutoDock Vina 1.5.6, and the structures were created using ChemBiodraw Ultra. The Swiss ADME algorithm was used for online log p prediction. Results: Among all the molecules designed, AM35 had the highest binding affinity to GK receptors. For good absorption and elimination, Log P values range from 2-3.08, indicating good lipophilic properties. Conclusion: The new lead molecules were designed as glucokinase activators, which had a better pharmacokinetic profile and higher binding affinity.

Discovery of TRPA1 Antagonist GDC-6599: Derisking Preclinical Toxicity and Aldehyde Oxidase Metabolism with a Potential First-in-Class Therapy for Respiratory Disease.

Transient receptor potential ankyrin 1 (TRPA1) is a nonselective calcium ion channel highly expressed in the primary sensory neurons, functioning as a polymodal sensor for exogenous and endogenous stimuli, and has been implicated in neuropathic pain and respiratory disease. Herein, we describe the optimization of potent, selective, and orally bioavailable TRPA1 small molecule antagonists with strong in vivo target engagement in rodent models. Several lead molecules in preclinical single- and short-term repeat-dose toxicity studies exhibited profound prolongation of coagulation parameters. Based on a thorough investigative toxicology and clinical pathology analysis, anticoagulation effects in vivo are hypothesized to be manifested by a metabolite─generated by aldehyde oxidase (AO)─possessing a similar pharmacophore to known anticoagulants (i.e., coumarins, indandiones). Further optimization to block AO-mediated metabolism yielded compounds that ameliorated coagulation effects in vivo, resulting in the discovery and advancement of clinical candidate GDC-6599, currently in Phase II clinical trials for respiratory indications.

Targeting epidermal growth factor receptor and its downstream signaling pathways by natural products: A mechanistic insight.

The epidermal growth factor receptor (EGFR) is a transmembrane receptor tyrosine kinase (RTK) that maintains normal tissues and cell signaling pathways. EGFR is overactivated and overexpressed in many malignancies, including breast, lung, pancreatic, and kidney. Further, the EGFR gene mutations and protein overexpression activate downstream signaling pathways in cancerous cells, stimulating the growth, survival, resistance to apoptosis, and progression of tumors. Anti-EGFR therapy is the potential approach for treating malignancies and has demonstrated clinical success in treating specific cancers. The recent report suggests most of the clinically used EGFR tyrosine kinase inhibitors developed resistance to the cancer cells. This perspective provides a brief overview of EGFR and its implications in cancer. We have summarized natural products-derived anticancer compounds with the mechanistic basis of tumor inhibition via the EGFR pathway. We propose that developing natural lead molecules into new anticancer agents has a bright future after clinical investigation.

Acute Oral Toxicity, Antioxidant Activity and Molecular Docking Study of 2-(4-Bromo-phenoxy)-N-[6-chloro-4-(4-chlorophenyl)-3-cyano-4H-chromen- 2-yl]-acetamide.

Several studies have been conducted on 4-H chromene compounds because of their intriguing pharmacological and biological properties. Various new natural compounds having a chromene foundation have been reported over the past 20 years. In the present study, we reported the acute oral toxicity, antioxidant activity, and molecular docking study of the most active 4H-chromene derivative2-(4-Bromo-phenoxy)-N-[6-chloro-4-(4- chlorophenyl)-3-cyano-4H-chromen-2-yl]-acetamide (A9). The acute oral toxicity was carried out as per OECD 423 guidelines. For investigating the antioxidant activity, various biochemical parameters in colon tissue like SOD, CAT, MDA, PC and GSH and also enzyme levels, such as ALT, AST, ALP, and LDH, were measured in this experiment. Acute oral toxicity study indicated that the A9 ligand was found to be safer in animals. Additionally, the A9 ligand had significant antioxidant properties at various doses and was not found to be harmful to the liver. Due to its stronger binding energy and the appropriate interactions that induce inhibition, the A9 ligand's antioxidant function was also validated by additional molecular docking research. This compound can be exploited as a lead molecule in further research.

Chalcones As Potent Agents Against Staphylococcus aureus: A Computational Approach

Background: Studies on natural or synthetic products from chalcones have shown to be very promising due to their peculiar structure that allows different possibilities of reallocation that will define their diverse bioactivities in the creation of new substances. This creation is facilitated by the synthesis of substances in conjunction with the molecular study, which allows a considerable advancement in research, reducing the number of in vitro tests. Objective: This work focuses on the antibacterial activity of chalcones against Staphylococcus aureus, which causes several diseases and is one of the main microorganisms with increasing resistance to conventional drugs. Methods: Articles that studied antibacterial activity, efflux pump, or molecular docking were considered complimentary analyses of chalcones. From these data, molecular docking and ADMET of the first five chalcones were performed with the best activity found. Results: The result of the antimicrobial activity against Staphylococcus aureus was confirmed through in silico study and pharmacokinetic data. Conclusion: The results of the antimicrobial activity of the most active chalcones against Staphylococcus aureus were supported by in silico and pharmacokinetic studies, which not only confirmed their potential to act against resistant strains but also established the future utility of chalcones as lead molecules or prototypes for the synthesis of potent new antimicrobial agents against Staphylococcus aureus.

Discovery of 2,9-diaryl-6-carbamoylpurines as a novel class of antitubercular agents

A series of novel 9-alkyl/aryl-2-aryl-6-carbamoylpurines were synthesized, and their activity against Mycobacterium tuberculosis strain H37Rv was assessed. The SAR analysis on the first set of derivatives, with an alkyl or aryl unit at N-9 and a phenolic unit at C-2, showed that the activity depends on the purine ring substituents at N-9 and C-2. A phenyl group at N-9 combined with a 3-hydroxyphenyl or 4-hydroxyphenyl at C-2 improve the activity. The most active compound of this set has a phenyl group at N-9 and a 4-hydroxyphenyl group at C-2, displaying an IC90 = 1.2 μg/mL and a selectivity index higher than 25.5. This compound served as a Hit to design the second set of derivatives. A phenyl group at N-9 was maintained, and the group at C-2 was diversified. The SAR analysis showed that the aryl unit at C-2 must have an oxygen or nitrogen atom bonded in the para position. A proton, a small alkyl or a substituted aryl group may also be bonded to the oxygen. The compound with the 4-methoxyphenyl group at C-2, 1Bd, exhibits the highest activity with an IC90 < 0.19 μg/mL. This compound is highly potent against M. tuberculosis strain H37Rv and non-toxic for VERO mammalian cells with an SI > 153.8. Compound 1Bd was also non-cytotoxic against primary macrophage cultures at IC90, 2xIC90, and 10xIC90 and significantly reduced the bacterial load in M. tuberculosis-infected macrophages at the same concentrations. Compound 1Bd showed a favorable pharmacokinetic profile when administered orally, with major lung and liver accumulation. In vivo antimycobacterial efficacy of 1Bd was tested at 25 mg/kg. At the tested regimen, a decrease in bacterial burden was observed in the liver. Optimization of the treatment regimen should be performed to fully potentiate the in vivo efficacy of our lead molecule, particularly in the lung, the main target organ of M. tuberculosis.

Identification of Novel PPAR-β/δ Agonists from Kaempferol, Quercetin, and Resveratrol Derivatives by Targeting Cancer: An Integrative Molecular Docking and Dynamics Simulation Approach

Background: Drug resistance in cancer is a serious threat to human well-being. There is a dire need to develop novel and efficient lead molecules to treat the disease. In lieu of anti-cancer activities, Peroxisome proliferator–activated receptors (PPARs)-β/δ proven to be potential therapeutic targets against cancer. However, there are yet no PPAR-β/δ agonists reported for clinical use. Objective: The present study features in silico screening and identification of 8708 derivatives based on backbone of natural compounds like Kaempferol, Quercetin and Resveratrol against PPAR-β/δ using molecular docking, and molecular dynamics (MD) simulations. Methods: Initial screening of 8708 derivatives was done by recruiting Lipinski’s rule of five. Docking calculations were assessed through FlexX software tool. GROMACS was used to analyze dynamic perturbations and binding free energy (MM/GBSA) analysis of the top compounds. SwissADME was used to analyze pharmacokinetic properties. Results: The results of molecular docking indicated that 2-[2-(2,4-Dihydroxyphenyl)-2- oxoethoxy]benzoate (DOB), (E)-1-(3,4,5-Trihydroxyphenyl)-3-(3,4-dihydroxyphenyl) propene (TDP) and 2-Hydroxy-3-(2,6,7-trihydroxy-3-oxo-3H-xanthen-9-YL) benzoic acid (HTOB); respective derivatives of Kaempferol, Resveratrol and Quercetin strongly binds to the active site residues of PPAR-β/δ. Furthermore, ADME (absorption, distribution, metabolism &amp; excretion) profile conferred their high druglikeness properties. On monitoring their dynamic perturbations, HTOB acquired the most favorable interaction and stability within the vicinity of PPAR-β/δ protein. Conclusion: These outcomes constitute preliminary studies and the obtained lead derivatives could be great options to treat various types of cancer and formulate as oral drug candidates.

Role of Pineapple and its Bioactive Compound Bromelain in COVID 19

Background:: Ananas comosus (L.) Merr., which is commonly known as pineapple, is a well-studied plant for its medicinal properties. In terms of commercial importance, it ranks third among tropical fruits. It has been used for its antidiabetic, antimalarial, anticancer, abortifacient, antioxidant, and antidiarrhoeal activities. The review aimed to study the effects of pineapples and their bioactive compounds on the SARS-CoV-2 virus. Methods:: Research methods comprise significant studies on the treatment of COVID-19 utilizing pineapple and its bioactive compounds. To carry out the e-literature review, articles were downloaded from online search engines, including Elsevier, PubMed, and Google Scholar, using pineapple, bioactive compounds, bromelain, clinical trial, and COVID-19. Results:: The literature showed that pineapple and its bioactive compounds showed antiviral effects in COVID-19 patients by inhibiting the proinflammatory cytokines and affecting various signaling molecules, including NF-κB, proinflammatory cytokines, and cyclooxygenase-2. They modulate apoptotic protein levels and also cause a reduction of ACE-2 and TMPRSS2 expression. Conclusion:: For the development of phytomedicine that adheres to all safety regulations, pineapple, and its bioactive compounds can serve as lead molecules for clinical studies in SARS-CoV-2 infection treatment and therapy.

Exploring the Therapeutic Potential of &lt;i&gt;Caesalpinia bonducella&lt;/i&gt; for Male and Female Reproductive Health: A Comprehensive Review

This review explores the potential of Caesalpinia bonducella Linn., particularly its seeds, known as ‘bounducella’ or ‘little ball’, and its impact on diverse pharmacological activities. Its use in treating various illnesses, including male and female reproductive health, has been investigated. The data, gathered from reliable sources worldwide, transcend language barriers and align with Indian Ayurvedic and Siddha Pharmacopoeias. This article has compiled the pharmacognostic and phytochemical profiles of the seeds, emphasizing their influence on reproductive health, potentially aiding in PCOS management and addressing hyperandrogenism. Additionally, the seed extract of this plant has abortifacient and anti-fertility effects, suggesting that it is a potential alternative to Mifepristone. Nevertheless, further in vivo and in vitro research on seed constituents is essential for developing lead molecules for use in allopathic treatment.

In silico Exploration of the Potential Inhibitory Activity of Novel Compounds Against Candida albicans N-myristoyltransferase

Background: Candida albicans is a fungal species associated with opportunistic fungal infectious agents in human populations, especially in immunocompromised patients, such as transplant patients, HIV-positive patients, chemotherapy patients, and low-birth-weight newborns. The death rate for systemic Candida illnesses ranges from 29 to 76 percent. Only a few medications are available to treat them, such as amphotericin B, fluconazole, terbinafine, and caspofungin, which have adverse reactions and are harmful. Objective: The goal of this research is to apply specialized bioinformatics approaches, such as molecular docking, scaffold hopping, virtual screening, pharmacophore modeling, and molecular dynamics (MD) simulation, to discover possibly novel and potent therapeutic drug candidates against Candida albicans in a shorter period and at a low cost. Methods: MDPI, MayBridge, Hitfinder, Mcule library, SQLite Database, DrugBank, ZINC, and NCI database were used to perform pharmacophore modeling, scaffold hopping, virtual screening, docking, and ADMET characteristics study against NMT. The molecular dynamics simulations for the best ten docked protein-ligand complexes were examined to determine the stability of protein-ligand interactions during a 200 ns simulation period, demonstrating their potential for lead molecule production via more improvement and experimental verification. Results: We have identified that compounds DB01940 ((3R,4R)-3-(4-hydroxybenzamido)azepan-4-yl 4- (2-hydroxybenzoyl)benzoate), DB01772 (3-(3-{[(2S)-2,3-dihydroxypropyl]amino}phenyl)-4-(5-fluoro-1- methyl-1H-indol-3-yl)-2,5-dihydro-1H-pyrrole-2,5-dione), and NCI5485 (1,3-bis((7-chloro-4- quinolinyl)amino)-2-propanol) could be more promising Candida albicans NMT inhibitors. Conclusion: In conclusion, these compounds have the potential to be effective anti-NMT medicines. The results demonstrated that our computational technique found some potential and effective NMT inhibitors that may be tested in clinical trials.

Novel benzene sulfonamides with acetylcholinesterase and carbonic anhydrase inhibitory actions.

A series of benzene sulfonamides 15-26 were synthesized and determined for their in vitro and in silico inhibitory profiles towardacetylcholinesterase (AChE) and carbonic anhydrases (CAs). Commercially available 3,4-dimethoxytoluene was reacted with chlorosulfonic acid to furnish benzene sulfonyl chloride derivatives. The reaction of substituted benzene sulfonyl chloride with some amines also including (±)-α-amino acid methyl esters afforded a series of novel benzene sulfonamides. In this study, the enzyme inhibition abilities of these compounds were evaluated against AChE and CAs. They exhibited a highly potent inhibition ability on AChE and -CAs (Ki values are in the range of 28.11 ± 4.55 nM and 145.52 ± 28.68 nM for AChE, 39.20 ± 2.10 nM to 131.54 ± 12.82 nM for CA I, and 50.96 ± 9.83 nM and 147.94 ± 18.75 nM for CA II). The present newly synthesized novel benzene sulfonamides displayed efficient inhibitory profiles against AChE and CAs, and it is anticipated that they may emerge as lead molecules for some diseases including glaucoma, epilepsy, and Alzheimer's disease.

Antibody druggability screening process and evaluation strategy

Since the approval of OKT3 as the first therapeutic monoclonal antibody in 1986, there has been rapid development in antibody technology and antibody drugs. Monoclonal antibodies, antibody fragments, bi (multi) specific antibodies, fusion proteins, nanobodies, and antibody-drug conjugates (ADCs) have been introduced and play a significant role in the treatment of oncology, hematology, immunology, respiratory, metabolic and other related diseases. The process of antibody drug discovery involves multiple rounds of biological function and druggability assessments to identify the best candidate sequences that are safe, effective, stable, and scalable. This lays the foundation for the efficiency and success of drug development and clinical studies. In the phase of antibody drug discovery, "druggability screening and evaluation" has received increasing attention. It involves drug discovery and design, screening and optimization of lead molecules as well as the validation of candidate molecules, with the aim of detecting potential physicochemical risk factors and evaluating controllability to ensure the quality stability of the subsequent drug development process. This paper classifies and defines the process of druggability screening and evaluation in the antibody discovery phase, covering monoclonal antibodies, bispecific antibodies, nanobodies, ADCs and other related technologies and drug forms. It also summarizes the quality attributes and high-throughput detection technology that should be emphasized in the druggability screening and evaluation. The systematic elaboration of the druggability development process and strategy provides a reference for the druggability screening and evaluation of emerging innovative drugs, significantly improving the efficiency and success rate of antibody drug development.

Fabrication of cost-effective green assisted synthesis of MoO 3 NPs: its photocatalytic activity and electrochemical sensing actions on lead, mercury, and paracetamol molecules

Fabrication of cost-effective green assisted synthesis of MoO ₃ NPs: its photocatalytic activity and electrochemical sensing actions on lead, mercury, and paracetamol molecules

Approaches, Strategies and Procedures for Identifying Anti-Inflammatory Drug Lead Molecules from Natural Products.

Natural products (NPs) have played a vital role in human survival for millennia, particularly for their medicinal properties. Many traditional medicine practices continue to utilise crude plants and animal products for treating various diseases, including inflammation. In contrast, contemporary medicine focuses more on isolating drug-lead compounds from NPs to develop new and better treatment drugs for treating inflammatory disorders such as inflammatory bowel diseases. There is an ongoing search for new drug leads as there is still no cure for many inflammatory conditions. Various approaches and technologies are used in drug discoveries from NPs. This review comprehensively focuses on anti-inflammatory small molecules and describes the key strategies in identifying, extracting, fractionating and isolating small-molecule drug leads. This review also discusses the (i) most used approaches and recently available techniques, including artificial intelligence (AI), (ii) machine learning, and computational approaches in drug discovery; (iii) provides various animal models and cell lines used in in-vitro and in-vivo assessment of the anti-inflammatory potential of NPs.

Mechanistic QSAR modeling derived virtual screening, drug repurposing, ADMET and in-vitro evaluation to identify anticancer lead as lysine-specific demethylase 5a inhibitor

A lysine-specific demethylase is an enzyme that selectively eliminates methyl groups from lysine residues. KDM5A, also known as JARID1A or RBP2, belongs to the KDM5 Jumonji histone demethylase subfamily. To identify novel molecules that interact with the LSD5A receptor, we created a quantitative structure-activity relationship (QSAR) model. A group of 435 compounds was used in a study of the quantitative relationship between structure and activity to guess the IC50 values for blocking LASD5A. We used a genetic algorithm-multilinear regression-based quantitative structure-activity connection model to forecast the bioactivity (PIC50) of 1615 food and drug administration pharmaceuticals from the zinc database with the goal of repurposing clinically used medications. We used molecular docking, molecular dynamic simulation modelling, and molecular mechanics generalised surface area analysis to investigate the molecule’s binding mechanism. A genetic algorithm and multi-linear regression method were used to make six variable-based quantitative structure-activity relationship models that worked well (R 2 = 0.8521, Q 2 LOO = 0.8438, and Q 2 LMO = 0.8414). ZINC000000538621 was found to be a new hit against LSD5A after a quantitative structure-activity relationship-based virtual screening of 1615 zinc food and drug administration compounds. The docking analysis revealed that the hit molecule 11 in the KDM5A binding pocket adopted a conformation similar to the pdb-6bh1 ligand (docking score: −8.61 kcal/mol). The results from molecular docking and the quantitative structure-activity relationship were complementary and consistent. The most active lead molecule 11, which has shown encouraging results, has good absorption, distribution, metabolism, and excretion (ADME) properties, and its toxicity has been shown to be minimal. In addition, the MTT assay of ZINC000000538621 with MCF-7 cell lines backs up the in silico studies. We used molecular mechanics generalise borne surface area analysis and a 200-ns molecular dynamics simulation to find structural motifs for KDM5A enzyme interactions. Thus, our strategy will likely expand food and drug administration molecule repurposing research to find better anticancer drugs and therapies. Communicated by Ramaswamy H. Sarma