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The effective drug design, especially for combating the multi-drug-resistant bacterial pathogens, requires more and more sophisticated procedures to obtain novel lead-like compounds. New classes of enzymes should be explored, especially those that help bacteria overcome existing treatments. The homology modeling is useful in obtaining the models of new enzymes; however, the active sites of them are sometimes present in closed conformations in the crystal structures, not suitable for drug design purposes. In such difficult cases, the combination of homology modeling, molecular dynamics simulations, and fragment screening can give satisfactory results.
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Diseño de Fármacos , Simulación de Dinámica Molecular , Homología Estructural de Proteína , Modelos Químicos , Dominio Catalítico , Conformación ProteicaRESUMEN
A series of novel diosgenin (DSG) derivatives has been synthesized and tested in vitro for their antioxidant activity. Initially, four analogues have been evaluated for their cytotoxicity using normal human skin fibroblast (NHDF) as model cells. As a result, 84% of NHDF cells were still alive at 5 µM, so these compounds can be considered as innoxious to fibroblasts at this concentration. Then, hemolytic activity against human erythrocytes was studied in order to evaluate the potential impact of tested compounds against normal host cells. The result < 5% of hemolysis rates suggest no lytic activity for most compounds. After that, the main test - evaluation the antioxidant effect of DSG and its new derivatives against lipid peroxidation in the o/w emulsion model - was performed. The most promising compound (8) exhibited the significant antioxidant activity and the biocompatibility towards normal human dermal fibroblasts and red bloods cells. This p-aminobenzoic derivative revealed 61.6% blocking of induced lipid oxidation. Furthermore, eleven predicted ADME properties were predicted for all tested compounds and revealed that they are in compliance with drug-likeness criteria.
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Diosgenina , Humanos , Diosgenina/farmacología , Antioxidantes/farmacología , Hemólisis , Muerte CelularRESUMEN
BACKGROUND: Anastrozole (ATZ) is a selective non-steroidal inhibitor widely used for the treatment of breast cancer in post-menopausal women. ATZ exerts its biological activity by inhibiting the enzyme aromatase, which is responsible for converting androgens to estrogens. Piperine (PIP), a natural alkaloid and the main component of black pepper, is used as a bioenhancer and for combating a variety of health issues ranging from upset stomach to dental problems. INTRODUCTION: ATZ has been reported to have poor water solubility and less bioavailability. The novel combination of ATZ and PIP was proposed to enhance the bioavailability of both the compounds. However, there are no reported studies on the simultaneous estimation of ATZ and PIP as well as stability studies to explore their potential interactions and degradation profiling. METHOD: A simple, accurate, precise, robust, sensitive, reliable, and economic analytical method for the simultaneous estimation of ATZ and PIP was developed using acetonitrile and water (60:40) as the mobile phase. Forced degradation studies and characterization of degradants were performed, and degradants were identified for molecular weight using LC-QTOF-ESI-MS; the structures of degradants were confirmed with mass accuracy measurements. The mechanism of each degradant has also been described in more detail in the manuscript. RESULTS AND CONCLUSION: A total of fourteen degradants were characterized and reported for their good human oral absorption. A precise, robust, accurate, cheap, and sensitive RP-HPLC-DAD simultaneous method for the estimation of ATZ and PIP has been developed. From the future point of view, there is huge scope to conduct pharmacological, pharmacodynamic, and drug-herb interaction studies based on this fruitful outcome. All the degradants may be screened against MDR-resistant breast cancer in the future to check their potential as a drug target.
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Alcaloides , Neoplasias de la Mama , Alcaloides/farmacología , Anastrozol , Benzodioxoles , Neoplasias de la Mama/tratamiento farmacológico , Estabilidad de Medicamentos , Femenino , Humanos , Piperidinas , Alcamidas Poliinsaturadas , AguaRESUMEN
Farnesol (FAR) is a sesquiterpene molecule with high lipophilicity that has antibacterial and other pharmacological properties along with broad nutritional values with high commercial values. Although having potential, FAR stability behavior and degradation kinetics are not available in the literature. Hence, it is very essential to develop a simple, rapid, accurate, precise, robust, cheap UHPLC-DAD method for FAR. It was also proposed to study mechanistic insights into FAR under different degradation conditions. Therefore, we hypothesized to do systematic stability studies along with degradation kinetic and accelerated stability studies. The developed method was validated. FAR was studied for stress studies, degradation kinetics and ADMET prediction of degradants. Degradation products were characterized using LC-QTOF-ESI-MS. Developed method consists of an isocratic mobile phase with a wavelength of 215 nm. The percent recoveries for FAR were observed within the acceptance limit of 98-102%. The eight major degradation products were formed during stress studies. FAR follows first-order degradation kinetics. FAR and all degradants were found to have more than 75% good human oral absorption, and are non-toxic. FAR UHPLC-DAD method was developed, validated and performed stability studies to know the possible degradation pattern along with degradation kinetic studies.
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Farnesol , Espectrometría de Masas en Tándem , Humanos , Cromatografía Líquida de Alta Presión/métodos , Espectrometría de Masas en Tándem/métodos , Cinética , Cromatografía Liquida/métodos , Estabilidad de Medicamentos , HidrólisisRESUMEN
New acetyl derivatives of uracil, 6-methyluracil, and thymine were obtained in the course of an unconventional synthesis in methylene chloride. It was shown that products with the acetyloxymethyl fragment are formed according to a mechanism different from that for products with the acetyloxyethyl group. In particular, for uracil it was proven that the reaction with Ac2O, TEA, and CH2Cl2 leads to 1-acetyloxymethyluracil, where the N1 substituent is composed of the -CH2- fragment that originated from CH2Cl2 and the 1-acetyloxy moiety from Ac2O. The reaction of uracil with Ac2O, TEA, CH2Cl2, and DMAP leads to an acetyloxyethyl derivative in which the -CH2-CH2- fragment originates from TEA and the 1-acetyloxy moiety from Ac2O. A possible mechanism for the formation of new compounds was suggested and supported by the density functional theory/B3LYP quantum mechanical calculations. New compounds (39 in total, including seven deuterated) were fully characterized by nuclear magnetic resonance and high-resolution mass spectrometry techniques.
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Cloruro de Metileno , Uracilo , Anhídridos Acéticos , TiminaRESUMEN
GSK-3ß directly phosphorylate tubulin binding site of tau protein, indicating its importance in tau aggregation and, therefore, in Alzheimer's disease pathology. New GSK-3ß inhibitors were identified using a structure-based screening, ADMET analysis. These studies revealed that ZINC09036109, ZINC72371723, ZINC72371725, and ZINC01373165 approached optimal ADMET properties along with good MM-GBSA dG binding. Protein kinase assays of these compounds against eight disease-relevant kinases were performed. During disease-relevant kinase profiling, ZINC09036109 ((E)-2-((3,4-dimethylphenyl)imino)-5-(3-methoxy-4-(naphthalen-2-ylmethoxy)benzyl)thiazolidin-4-one) emerged as a selective GSK-3ß inhibitor with more than 10-fold selectivity over other disease-relevant kinases. Molecular dynamics study of ZINC09036109 molecule revealed interactions with Ile62, Phe67, Val135, Leu188, Asp200 amino acid residues of the binding site of GSK-3ß, which were highly comparable to the co-crystallized molecule and hence validating comparative better activity of this compound compared to overall screened molecules.
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Descubrimiento de Drogas , Glucógeno Sintasa Quinasa 3 beta/antagonistas & inhibidores , Fármacos Neuroprotectores/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Tiazolidinas/farmacología , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Humanos , Estructura Molecular , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/química , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Relación Estructura-Actividad , Tiazolidinas/síntesis química , Tiazolidinas/químicaRESUMEN
The recent developments of fast reliable docking, virtual screening and other algorithms gave rise to discovery of many novel ligands of histamine receptors that could be used for treatment of allergic inflammatory disorders, central nervous system pathologies, pain, cancer and obesity. Furthermore, the pharmacological profiles of ligands clearly indicate that these receptors may be considered as targets not only for selective but also for multi-target drugs that could be used for treatment of complex disorders such as Alzheimer's disease. Therefore, analysis of protein-ligand recognition in the binding site of histamine receptors and also other molecular targets has become a valuable tool in drug design toolkit. This review covers the period 2014-2020 in the field of theoretical investigations of histamine receptors mostly based on molecular modeling as well as the experimental characterization of novel ligands of these receptors.
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Algoritmos , Descubrimiento de Drogas , Agonistas de los Receptores Histamínicos/química , Antagonistas de los Receptores Histamínicos/química , Simulación del Acoplamiento Molecular , Receptores Histamínicos/química , HumanosRESUMEN
The histamine H4 receptor, belonging to the family of G-protein coupled receptors, is an increasingly attractive drug target. It plays an indispensable role in many cellular pathways, and numerous H4R ligands are being studied for the treatment of several inflammatory, allergic, and autoimmune disorders, including pulmonary fibrosis. Activation of H4R is involved in cytokine production and mediates mast cell activation and eosinophil chemotaxis. The importance of this receptor has also been shown in inflammatory models: peritonitis, respiratory tract inflammation, colitis, osteoarthritis, and rheumatoid arthritis. Recent studies suggest that H4R acts as a modulator in cancer, neuropathic pain, vestibular disorders, and type-2 diabetes, however, its role is still not fully understood.
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The seizure controlling activity of human adenosine kinase (AK) has been identified as a promising target for the development of small-molecule inhibitors to be used as potential anti-epileptic agents. Overexpression of AK has been considered as a pathologic hallmark of epilepsy. However, the exploration of AK for the treatment of epilepsy still remains a challenge in drug discovery. In a pursuit to recognize novel inhibitors of AK, a structure-based virtual screening study based on the molecular docking analysis of the compounds of Asinex database was performed. Crystal structure of human AK in complex with inhibitor revealed the crucial ligand-protein interactions (Asn14, Asn18, Ser65 and Phe170) within the active site and offers opportunities for further development of the potential anti-epileptic agents. Overall, 20 novel diverse potential hits appear to be important scaffolds for the design of novel AK inhibitors with better docking scores, dG bind scores with in silico desired pharmacokinetic parameters and synthetic accessibility scores than the co-crystallized ligand. Computational hits obtained through validated virtual screening protocol (superposition and enrichment) followed by simulation studies, quantum mechanics with better pharmacokinetic performance and hit optimization study provides in silico evidence for the applicability of these valuable tools in drug discovery and towards the development of a better therapeutic regime of epilepsy.Communicated by Ramaswamy H. Sarma.
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Adenosina Quinasa , Adenosina , Anticonvulsivantes , Adenosina Quinasa/antagonistas & inhibidores , Anticonvulsivantes/química , Humanos , Ligandos , Simulación del Acoplamiento MolecularRESUMEN
Chemical entities targeting kinase signalling pathways serve as a potential strategy to combat malignancies. Protein Kinase B or Akt is a validated target for various malignancies and Akt3 remains the least explored isoform among all its isoforms. Initially, homology modelling technique was used for generating protein structure and further validation was performed using molecular dynamics simulation and Ramachandran plot. The validated protein structure was then subjected for active site analysis which led to identification of active site residues based on metrics provided by site score. The important residues in binding site were identified as Thr81, Asp271 and Asp289 for binding energetics and inhibition. Subsequently, virtual screening methodologies were used for identification of novel hits for inhibition of Protein Kinase B or Akt3. This led to the identification of two hits, i.e. thiophene derivative and thieno-pyridine derivative which were selected on the basis of their binding affinity and drug likeliness. These identified hits were subjected for molecular dynamics simulations, quantum mechanical and synthetic accessibility studies. The role of crucial residues in binding site stood validated as suggested by molecular dynamics simulations studies. Communicated by Ramaswamy H. Sarma.
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Simulación de Dinámica Molecular , Preparaciones Farmacéuticas , Simulación del Acoplamiento Molecular , Proteínas Proto-Oncogénicas c-akt , SerinaRESUMEN
Conjugated structure based and ligand based drug design techinques have been used previously to unearth putative binding ligands for kinase inhibition. PI3K-δ is a lipid kinase and it has been found abberant in diseases such as cancer,inflammation etc. Preliminarily, protein crystal structure analysis suggest avaibility of two crystal structures with varying degree of root mean square de throughtion in protein back bone and root mean square fluctuation in side chain geometry. Therefore, PI3K-δ crystal structure was selected based on charactristic reciever operating characterstic curve and % enrichment of actives analysis. Active site analysis through molecular dynamics simulations provided insights about four residues Ile910, Asp911, Met752, Lys755, which act as flap. These residues fecilitate ligand binding in a unique manner.Thereafter, a validated designed protocol has been used to screen asinex ligand database using molecular docking and binding energy calculations. Based on binding affinity & energy scores and interaction pattern analysis total top 50 ligands were selected for PI3K-δ inhibition studies. Moreover, two molecules ethyl 2-(2-((4-chloro-1-methyl-1H-pyrazole-3-carbonyl) oxy)acetamido) benzo[1]thiazole-6-carboxylate and 1,6,7-trimethyl-8-((tetrahydrofuran-2-yl) methyl)-1H-imidazo [1',2':1,5] pyrrolo[3,2-d]pyrimidine-2,4(3H,8H)-dione have been identified, which could be potential hits for PI3K-δ using insights provided by molecular modelling studies. The identified compunds were subjected to pan assay interference compound filter and were found to be compliant. Quantum mechanical calculations were perfromed for identified hits. The above strategy could be implemented as a strategy for rational drug design. Communicated by Ramaswamy H. Sarma.
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Fosfatidilinositol 3-Quinasa Clase I/química , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Purinas/química , Quinazolinonas/química , Sitios de Unión , Dominio Catalítico , Fosfatidilinositol 3-Quinasa Clase I/antagonistas & inhibidores , Fosfatidilinositol 3-Quinasa Clase I/metabolismo , Diseño de Fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacología , Humanos , Estructura Molecular , Hidrolasas Diéster Fosfóricas , Conformación Proteica , Purinas/metabolismo , Purinas/farmacología , Quinazolinonas/metabolismo , Quinazolinonas/farmacología , Relación Estructura-ActividadRESUMEN
Development of resistance against existing anti-epileptic drugs has alarmed the scientific innovators to find novel potential chemical starting points for the treatment of epilepsy and GABAA inhibition is a promising drug target strategy against epilepsy. The crystal structure of a subtype-selective ß3-homopentameric ligand-gated ion channel of GABAA receptor has been used for the first time for screening the Asinex library for discovery of GABAA agonists as potential anti-epileptic agents. Co-crystallized ligand established the involvement of part of the ß7-ß8 loop (Glu155 and Tyr157) and ß9-ß10 loop (Phe200 and Tyr205) residues as the crucial amino acids in effective binding, an essential feature, being hydrogen bond or ionic interaction with Glu155 residue. Top ranked hits were further subjected to binding energy estimation, ADMET analysis and ligand efficiency matric calculations as consecutive filters. About 19 compounds qualifying all parameters possessed interaction of one positively charged group with Glu155 with good CNS drug-like properties. Simulation studies were performed on the apo protein, its complex with co-crystallized ligand and the best hit qualifying all screening parameters. The best hit was also analyzed using Quantum mechanical studies, off-target analysis and hit modification. The off-target analysis emphasized that these agents did not have any other predicted side-effects.
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Epilepsia/tratamiento farmacológico , Agonistas de Receptores de GABA-A/química , Agonistas de Receptores de GABA-A/farmacología , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Teoría Cuántica , Receptores de GABA-A/metabolismo , Benzamidinas/química , Benzamidinas/metabolismo , Benzamidinas/farmacología , Benzamidinas/uso terapéutico , Evaluación Preclínica de Medicamentos , Agonistas de Receptores de GABA-A/metabolismo , Agonistas de Receptores de GABA-A/uso terapéutico , Humanos , Ligandos , Conformación Proteica , Receptores de GABA-A/química , Relación Estructura-Actividad , Interfaz Usuario-ComputadorRESUMEN
The present paper describes the synthesis, biological evaluation and molecular simulation studies of a series of N-(4-hydroxyphenyl)-3,4,5-trimethoxybenzamide derivatives with N,N-dialkylaminoethoxy/propoxy moiety as potential memory enhancers with acetylcholinesterase-inhibiting activity having IC50 in low micromolar range (4.0-16.5 µM). All the compounds showed a good degree of agreement between in vivo and in vitro results as most of these derivatives showed dose-dependent increase in percent retention. Compound 10a showed significant % retention of 84.73 ± 4.51 as compared to piracetam (46.88 ± 5.42) at 3 mg kg-1 and also exhibited a maximal percent inhibition of 97% at 50 µM. Molecular docking, MM-GBSA and molecular simulation studies were performed establishing a correlation between the experimental biology and in silico results. In silico results indicate that all the compounds have better docking scores and predicted binding free energies as compared to cocrystallized ligand with the best potent ligand retaining conserved hydrophobic interactions with residues of catalytic triad (HIS447), catalytic anionic site (CAS) (TRP86, TYR337, PHE338) and peripheral anionic site (PAS) (TYR72, TYR124, TRP286 and TYR341). Root mean square deviation (RMSD = 2.4 Å) and root mean square fluctuations of 10a-AChE complex during simulation proved its stable nature in binding toward acetylcholinesterase. The docked conformation of 10a and other analogs at the binding site have also been simulated with polar and nonpolar interactions interlining the gorge residues from PAS to catalytic triad.
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Benzamidas/química , Benzamidas/farmacología , Memoria/efectos de los fármacos , Acetilcolinesterasa/química , Acetilcolinesterasa/metabolismo , Animales , Sitios de Unión , Dominio Catalítico , Inhibidores de la Colinesterasa/química , Inhibidores de la Colinesterasa/farmacología , Femenino , Interacciones Hidrofóbicas e Hidrofílicas , Ligandos , Masculino , Ratones , Simulación del Acoplamiento Molecular/métodos , Simulación de Dinámica Molecular , Unión ProteicaRESUMEN
Multidrug resistance along with side-effects of available anti-epileptic drugs and unavailability of potent and effective agents in submicromolar quantities presents the biggest therapeutic challenges in anti-epileptic drug discovery. The molecular modeling techniques allow us to identify agents with novel structures to match the continuous urge for its discovery. KCNQ2 channel represents one of the validated targets for its therapy. The present study involves identification of newer anti-epileptic agents by means of a computer-aided drug design adaptive protocol involving both structure-based virtual screening of Asinex library using homology model of KCNQ2 and 3D-QSAR based virtual screening with docking analysis, followed by dG bind and ligand efficiency calculations with ADMET studies, of which 20 hits qualified all the criterions. The best ligands of both screenings with least potential for toxicity predicted computationally were then taken for molecular dynamic simulations. All the crucial amino acid interactions were observed in hits of both screenings such as Glu130, Arg207, Arg210 and Phe137. Robustness of docking protocol was analyzed through Receiver operating characteristic (ROC) curve values 0.88 (Area under curve AUC = 0.87) in Standard Precision and 0.84 (AUC = 0.82) in Extra Precision modes. Novelty analysis indicates that these compounds have not been reported previously as anti-epileptic agents.
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Anticonvulsivantes/química , Epilepsia/tratamiento farmacológico , Canal de Potasio KCNQ2/química , Modelos Moleculares , Anticonvulsivantes/uso terapéutico , Epilepsia/patología , Humanos , Canal de Potasio KCNQ2/antagonistas & inhibidores , Ligandos , Simulación del Acoplamiento Molecular , Relación Estructura-Actividad Cuantitativa , Interfaz Usuario-ComputadorRESUMEN
Structure-based screening approach targeting mGlu2 receptor was carried out to identify good chemical starting points for anti-epileptic therapy. Interactive modes of final 12 compounds identified on the basis of screening of Asinex library, binding energy analysis, ADME profiling with special emphasis for CNS ranges, and toxicity analysis were studied and showed good binding modes in the mGluR2-active site. Enrichment studies for validating screening protocol were carried out which gave ROC values 0.98 (AUC = 0.96) for SP, 0.97 (AUC = 0.95) for XP with BEDROC analysis. Our results indicate that all the 12 hits showed good CNS drug-like properties, have better binding free energy and ADME profile as compared to co-crystallized ligand with the best ligand hit retaining conserved hydrogen bond interactions with Ala-166, Thr-168, Ser-145, and Arg-61 residues in bilobatevenus fly-trap domain of mGluR2 receptor. Molecular dynamics simulations proved that the two potential hits, qualifying all screening parameters, are stable in the receptor active site pocket, confirming the potential of the identified hits as a specific target for mGluR2. Because the newly discovered mGluR2 agonists are structurally different with Tc values ranging from 0.57 to 0.92, all of them can be considered for further de novo design methods.
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Anticonvulsivantes/química , Receptores de Glutamato Metabotrópico/química , Bibliotecas de Moléculas Pequeñas/química , Secuencias de Aminoácidos , Anticonvulsivantes/metabolismo , Dominio Catalítico , Diseño de Fármacos , Epilepsia/tratamiento farmacológico , Epilepsia/metabolismo , Humanos , Enlace de Hidrógeno , Interacciones Hidrofóbicas e Hidrofílicas , Ligandos , Simulación del Acoplamiento Molecular , Unión Proteica , Dominios y Motivos de Interacción de Proteínas , Multimerización de Proteína , Estructura Secundaria de Proteína , Receptores de Glutamato Metabotrópico/agonistas , Receptores de Glutamato Metabotrópico/metabolismo , Bibliotecas de Moléculas Pequeñas/metabolismo , Relación Estructura-Actividad , Interfaz Usuario-ComputadorRESUMEN
Biological mechanism attributing mutations in KCNQ2/Q3 results in benign familial neonatal epilepsy (BFNE), a rare form of epilepsy and thus neglected. It offers a potential target for antiepileptic drug discovery. In the present work, a pharmacophore-based 3D-QSAR model was generated for a series of N-pyridyl and pyrimidine benzamides possessing KCNQ2/Q3 opening activity. The pharmacophore model generated contains one hydrogen bond donor (D), one hydrophobic (H), and two aromatic rings (R). They are the crucial molecular write-up detailing predicted binding efficacy of high affinity and low affinity ligands for KCNQ2/Q3 opening activity. Furthermore, it has been validated by using a biological correlation between pharmacophore hypothesis-based 3D-QSAR variables and functional fingerprints of openers responsible for the receptor binding and also by docking of these benzamides into the validated homology model. Excellent statistical computational tools of QSAR model such as good correlation coefficient (R2 > 0.80), higher F value (F > 39), and excellent predictive power (Q2 > 0.7) with low standard deviation (SD <0.3) strongly suggest that the developed model could be used for prediction of antiepileptic activity of newer analogs. A preliminary pharmacokinetic profile of these derivatives was also performed on the basis of QikProp predictions.
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Benzamidas/química , Descubrimiento de Drogas , Epilepsia Benigna Neonatal/tratamiento farmacológico , Canal de Potasio KCNQ2/química , Canal de Potasio KCNQ3/química , Anticonvulsivantes/química , Anticonvulsivantes/uso terapéutico , Benzamidas/uso terapéutico , Sitios de Unión , Simulación por Computador , Epilepsia Benigna Neonatal/genética , Epilepsia Benigna Neonatal/patología , Humanos , Enlace de Hidrógeno , Interacciones Hidrofóbicas e Hidrofílicas , Canal de Potasio KCNQ2/antagonistas & inhibidores , Canal de Potasio KCNQ2/genética , Canal de Potasio KCNQ3/antagonistas & inhibidores , Canal de Potasio KCNQ3/genética , Modelos Moleculares , Simulación del Acoplamiento Molecular , Mutación , Pirimidinas/química , Relación Estructura-Actividad CuantitativaRESUMEN
Alzheimer's disease (AD), a progressive neurodegenerative disorder is the most common cause of dementia among elderly people. To date, the successful therapeutic strategy to treat AD is maintaining the levels of acetylcholine via inhibiting acetylcholinesterase (AChE). The present study involves identification of newer AChE inhibitors by dual approach of e-pharmacophore and structure-based virtual screening of Asinex library. Robustness of docking protocol was validated by enrichment calculation with ROC value .71 and BEDROC value .028. Among 11 selected hits, ZINC72338524 with best MM-GBSA dG binding shows optimal range of CNS properties and ligand-AChE complex stability. Further, molecular dynamics study revealed its molecular interactions with Trp86, Phe338, and Tyr341 amino acid residues of catalytic anionic site and Tyr124, Ser125, and Trp286 amino acid residues of peripheral anionic site. Physicochemical properties and ADMET risk prediction indicates their potential in druggability and safety.