ADMET Analysis Research Articles

Identification of novel benzothiazole-thiadiazole-based thiazolidinone derivative: in vitro and in silico approaches to develop promising anti-Alzheimer's agents.

Aim: The present study describes benzothiazole derived thiazolidinone based thiadiazole derivatives (1-16) as anti-Alzheimer agents.Materials & methods: Synthesis of benzothiazole derived thiazolidinone based thiadiazole derivatives was achieved using thebenzothiazole bearing 2-amine moiety. These synthesized compounds were confirmed via spectroscopic techniques (1H NMR, 13C NMR and HREI-MS). These compounds were biologically evaluated for their anti-Alzheimer potential. Binding interactions with proteins and drug likeness of the analogs were explored through molecular docking and ADMET analysis, respectively. In the novel series, compound-3 emerged as the most potent inhibitor when compared with other derivatives of the series.Conclusion: The present study provides potent anti-Alzheimer's agents that can be further optimized to discover novel anti-Alzheimer's drugs.

A new Thiadiazole-triazine derivative: Structural investigation, DFT studies, ADME-T analysis and SARS-CoV-2 activity by docking simulation

The present work involves the synthesis of thiadiazole-triazine derivative 7-[2-(4-bromophenyl)ethenyl]-3‑tert‑butyl‑4H-[1,3,4]thiadiazolo[2,3-c][1,2,4]triazin-4-one (TCA3) and spectroscopic characterization is done using NMR and X-ray diffraction techniques. The single crystal X-ray diffraction study unravels the 3D structure of the compound TCA3. The compound crystallizes in the monoclinic crystal system with the space group P21/c. The crystal structure analysis revealed that various CH…O, CH…N, and CH…Br interactions are responsible for crystal packing. Furthermore, Hirshfeld surface analysis has been performed to visualize and analyze the intermolecular interactions observed in the crystal structure. Energy framework analysis was used to explore the molecular architecture in the crystal, and to calculate the molecular interaction energies of the compound TCA3. DFT calculations have also been carried out to explore the various physicochemical properties of the compound like HOMO-LUMO energy gap of the molecule, reactive sites present in the molecule using MEP analysis. The energy gap of the molecule is found to be 4.592 eV. Also, to know the strength and nature of intramolecular interaction energy using RDG analysis. Finally, the potential inhibitory activity of the titled compounds and their drug-likeness are demonstrated by ADME-T calculations. Further, The structure-activity relationships established through molecular docking studies showed that the compound TCA3 strongly binds to the receptors Mpro (-8.2 Kcal/mol) which confirm its inhibition activity against COVID-19.

Effects of Syzygium aromaticum (clove) Extract on the Acquisition and Expression of Morphine-Induced Conditioned Place Preference in Swiss Albino Mice: an In vivo, In Silico Approach

Empirical findings have demonstrated that the application of an N-Methyl-D-aspartate (NMDA) receptor antagonist effectively prevents the formation of morphine-induced location preference. Eugenol, the primary constituent found in the extract of S. aromaticum (SA), exhibits notable efficacy in traversing the blood-brain barrier and possesses inhibitory properties against the metabotropic NMDA receptor. This study aimed to evaluate the actions of the hydro-alcoholic extract of S. aromaticum on the acquisition and expression of morphine-induced conditioned place preference (CPP) in mice, followed by in silico studies. The conditioned place preference (CPP) test was used for investigating addictive-seeking behavior. Morphine (5 mg/kg) was used to produce CPP, and saline was used as a control. Morphine significantly increased the preference scores on the drug-paired side (p<0.001), whereas both doses of S. aromaticum extract (200 and 400 mg/kg) did not reveal any liking compared to the control group. Higher doses of S. aromaticum extract (400 mg/kg) reduced the acquisition of MOR-induced CPP (p<0.001) but had no significant effect on the expression of morphine CPP. Molecular docking analysis showed that the binding affinities of eugenol to NMDA receptor are -5.1 kcal/mol, comparable to the reference NMDA antagonist memantine which has -5.6 kcal/mol binding affinity to NMDA receptor. Eugenol formed hydrophobic bonds with NMDA receptors at VAL644, PHE554, TRP563 and TYR647 residues, comparable to the binding affinity of NMDA antagonist memantine. ADMET analysis showed that eugenol has high intestinal absorption and good bioavailability (>90%) and can cross the BBB easily (logBB> 0.3). On the basis of our in vivo trials and in silico report, we settled that the acquisition effect of S. aromaticum might be due to the antioxidant and antagonistic properties of eugenol to NMDA receptor. It would be reasonable to conduct mechanistic research in the forthcoming days to elucidate the underlying mechanisms utilizing various methodologies. Dhaka Univ. J. Pharm. Sci. 23(1): 77-92, 2024 (June)

In silico screening for potential inhibitors from the phytocompounds of Carica papaya against Zika virus NS5 protein.

The Zika virus (ZIKV) infection has emerged as a global health threat. The causal reasoning is that Zika infection is linked to the development of microcephaly in newborns and Guillain-Barré syndrome in adults. With no clinically approved antiviral treatment for ZIKV, the need for the development of potential inhibitors against the virus is essential. In this study, we aimed to screen phytochemicals from papaya ( Carica papaya L.) against NS5 protein domains of ZIKV. Approximately 193 phytochemicals from an online database (IMPACT) were subjected to molecular docking using AutoDock Vina against the NS5-MTase protein domain (5WXB) and -RdRp domain (5U04). Our results showed that β-sitosterol, carpaine, violaxanthin, pseudocarpaine, Δ7-avenasterols, Rutin, and cis-β-carotene had the highest binding affinity to both protein domains, with β-sitosterol having the most favorable binding energy. Furthermore, ADMET analysis revealed that selected compounds had good pharmacokinetic properties and were nontoxic. Our findings suggest that papaya-derived phytochemicals could be potential candidates for developing antiviral drugs against ZIKV. However, further experimental studies using cell lines and in vivo models are needed to validate their efficacy and safety.

In Silico and In Vitro Alpha-amylase Activities of Previously Synthesized Pyridazine Derivatives

Diabetes mellitus is one of the fastest-growing metabolic disorders. Worldwide, one out of 10 people suffer from diabetes mellitus. In this manuscript, we establish the antidiabetic potential of previously synthesized pyridazine derivatives using in silico and in vitro experiments. Molecular docking studies of pyridazine derivatives with pullulanase Amy12, isomaltase, and alpha-amylase receptors revealed that Molecules 45, 46, and 29 showed good docking interaction scores. ADMET analysis of the top three docked pyridazine derivatives (45, 46, and 29) showed lesser solubility and poor distribution behavior. Molecules 45, 46, and 29 maintained drug-like properties with good oral bioavailability. Molecules 45 and 29 showed reproductive toxicity without any sign of mutagenicity, tumorigenicity, or other irritancy. Molecule 46 emerged as a nontoxic molecule in all aspects. In vitro alpha-amylase inhibition data of molecules 45, 46, 29, and acarbose showed IC50 values of 8.67, 8.46, 8.83, and 66.65 μg/mL, respectively. The antidiabetic activity of pyridazine derivatives is increased with the presence of phenothiazine coupled with a biphenyl group, indole with a biphenyl group, and phenothiazine with an ethylphenyl group. Establishing these pyridazine derivatives using in vivo experiments could be beneficial in managing diabetes.

Discovery of new Schiff bases of the disalicylic acid scaffold as DNA gyrase and topoisomerase IV inhibitors endowed with antibacterial properties.

DNA gyrase and topoisomerase IV show great potential as targets for antibacterial medicines. In recent decades, various categories of small molecule inhibitors have been identified; however, none have been effective in the market. For the first time, we developed a series of disalicylic acid methylene/Schiff bases hybrids (5a-k) to act as antibacterial agents targeting DNA gyrase and topoisomerase IV. The findings indicated that the new targets 5f-k exhibited significant antibacterial activity against Gram-positive and Gram-negative bacteria, with efficacy ranging from 75% to 115% of the standard ciprofloxacin levels. Compound 5h demonstrated the greatest efficacy compared to the other compounds tested, with minimum inhibitory concentration (MIC) values of 0.030, 0.065, and 0.060μg/mL against S. aureus, E. coli, and P. aeruginosa. 5h had a MIC value of 0.050μg/mL against B. subtilis, which is five times less potent than ciprofloxacin. The inhibitory efficacy of the most potent antibacterial derivatives 5f, 5h, 5i, and 5k against E. coli DNA gyrase was assessed. The tested compounds demonstrated inhibitory effects on E. coli DNA gyrase, with IC50 values ranging from 92 to 112nM. These results indicate that 5f, 5h, 5i, and 5k are more effective than the reference novobiocin, which had an IC50 value of 170nM. Compounds 5f, 5h, 5i, and 5k were subjected to additional assessment against E. coli topoisomerase IV. Compounds 5h and 5i, which have the highest efficacy in inhibiting E. coli gyrase, also demonstrated promising effects on topoisomerase IV. Compounds 5h and 5i exhibit IC50 values of 3.50µM and 5.80 µM, respectively. These results are much lower and more potent than novobiocin's IC50 value of 11µM. Docking studies demonstrate the potential of compound 5h as an effective dual inhibitor against E. coli DNA gyrase and topoisomerase IV, with ADMET analysis indicating promising pharmacokinetic profiles for antibacterial drug development.

Identification and Absorption–Distribution–Metabolism–Excretion–Toxicity Prediction of Potential MTHFD2 Enzyme Inhibitors from Urtica dioica Ethanolic Leaf Extract

This study aimed to explore the potential of Urtica dioica (U. dioica) ethanolic leaf extract for cancer treatment by identifying its components, evaluating its effects on cancer cell lines, and analyzing its molecular docking. The objective of this study was to investigate the anticancer properties of U. dioica ethanolic leaf extract and assess its potential as a therapeutic strategy for cancer treatment. This study utilized high-performance liquid chromatography (HPLC) to analyze the chemical composition of U. dioica ethanolic leaf extract. The anticancer effects of the extract were evaluated by assessing cell viability, determining IC50 values, and conducting ADMET analysis after oral administration. U. dioica ethanolic leaf extract was found to contain methyl hexadecanoate as its primary component, along with flavonoids and polyphenols. It effectively reduced cell viability in various tested cancer cell lines, with IC50 values varying for each cell line. The duration of treatment significantly influenced cell viability, with the most significant reduction observed after 48 h. Molecular docking studies suggested that catechin, kaempferol, and quercetin-3-O-rutinoside may have potential as inhibitors of the MTHFD2 enzyme. This study revealed the potential of U. dioica and its compounds in cancer treatment. Ethanolic leaf extract has been shown to have anticancer effects on various cancer cell lines, with catechin and kaempferol showing promise as inhibitors of the MTHFD2 enzyme. Further research is warranted to explore the therapeutic implications of U. dioica in cancer treatment.

Evaluation of the efficacy of marine natural products against PARP-1/2 proteins in high-grade serous ovarian cancer: insights into MD and SMD simulations

High-grade serous ovarian cancer (HGSOC) is the most malignant and ubiquitous phenotype of epithelial ovarian cancer. Originating in the fallopian tubes and rapidly spreading to the ovaries, this highly heterogeneous disease is a result of serous tubal intraepithelial carcinoma. The proteins known as poly(ADP-ribose) polymerase (PARP) aid in the development of HGSOC by repairing the cancer cells that proliferate and spread metastatically. By using molecular docking to screen 1100 marine natural products (MNPs) from different marine environments against PARP-1/2 proteins, prominent PARP inhibitors (PARPi) were identified. Four compounds, alisiaquinone A, alisiaquinone C, ascomindone D and (+)-zampanolide referred to as MNP-1, MNP-2, MNP-3 and MNP-4, respectively, were chosen based on their binding affinity towards PARP-1/2 proteins, and their bioavailability and drug-like qualities were accessed using ADMET analysis. To investigate the structural stability and dynamics of these complexes, molecular dynamics simulations were performed for 200 ns. These results were compared with the complexes of olaparib (OLA), a PARPi that has been approved by the FDA for the treatment of advanced ovarian cancer. We determined that MNP-4 exhibited stronger binding energies with PARP-1/2 proteins than OLA by using MM/PBSA calculations. Hotspot residues from PARP-1 (E883, M890, Y896, D899 and Y907) and PARP-2 (Y449, F450, A451, S457 and Y460) showed strong interactions with the compounds. To comprehend the unbinding mechanism of MNP-4 complexed with PARP-1/2, steered molecular dynamics (SMD) simulations were performed. We concluded from the free energy landscape (FEL) map that PARP-1/2 are well-stabilised when the compound MNP-4 is bound rather than being pulled away from its binding pockets. This finding provides significant evidence regarding PARPi, which could potentially be employed in the therapeutic treatment of HGSOC. Communicated by Ramaswamy H. Sarma

Identification of inhibitors for neurodegenerative diseases targeting dual leucine zipper kinase through virtual screening and molecular dynamics simulations

ABSTRACT Neurodegenerative diseases lead to a gradual decline in cognitive and motor functions due to the progressive loss of neurons in the central nervous system. The role of dual leucine zipper kinase (DLK) in regulating stress responses and neuronal death pathways highlights its significance as a target against neurodegenerative diseases. The non-availability of FDA-approved drugs emphasizes a need to identify novel DLK-inhibitors. We screened NPAtlas (Natural products) and MedChemExpress (FDA-approved) libraries to identify potent ATP-competitive DLK inhibitors. ADMET analyses identified four compounds (two natural products and two FDA-approved) with favourable features. Subsequently, we performed molecular dynamics simulations to examine the binding-stability and ligand-induced conformational dynamics. Molecular mechanics Poisson Boltzmann surface area (MM-PBSA) calculations demonstrated CID139591660, dithranol, and danthron having greater affinity, while CID156581477 showed lower affinity than control sunitinib. PCA and network analysis results indicated structural and network alteration post-ligand binding. Furthermore, we identified an analogue of CID156581477 using the deep learning-based web server DeLA Drug which demonstrated a higher affinity than its parent compound and the control and identified several crucial interacting residues. Overall, our study provides significant theoretical guidance for designing potent novel DLK inhibitors and compounds that could emerge as promising drug candidates against DLK following laboratory validation.

Explore new quinoxaline pharmacophore tethered sulfonamide fragments as in vitro α-glucosidase, α-amylase, and acetylcholinesterase inhibitors with ADMET and molecular modeling simulation.

A new series of quinoxaline-sulfonamide derivatives 3-12 were synthesized using fragment-based drug design by reaction of quinoxaline sulfonyl chloride (QSC) with different amines and hydrazines. The quinoxaline-sulfonamide derivatives were evaluated for antidiabetic and anti-Alzheimer's potential against α-glucosidase, α-amylase, and acetylcholinesterase enzymes. These derivatives showed good to moderate potency against α-amylase and α-glucosidase with inhibitory percentages between 24.34 ± 0.01%-63.09 ± 0.02% and 28.95 ± 0.04%-75.36 ± 0.01%, respectively. Surprisingly, bis-sulfonamide quinoxaline derivative 4 revealed the most potent activity with inhibitory percentages of 75.36 ± 0.01% and 63.09 ± 0.02% against α-glucosidase and α-amylase compared to acarbose (IP = 57.79 ± 0.01% and 67.33 ± 0.01%), respectively. Moreover, the quinoxaline derivative 3 exhibited potency as α-glucosidase and α-amylase inhibitory with a minute decline from compound 4 and acarbose with inhibitory percentages of 44.93 ± 0.01% and 38.95 ± 0.01%. Additionally, in vitro acetylcholinesterase inhibitory activity for designed derivatives exhibited weak to moderate activity. Still, sulfonamide-quinoxaline derivative 3 emerged as the most active member with inhibitory percentage of 41.92 ± 0.02% compared with donepezil (IP = 67.27 ± 0.60%). The DFT calculations, docking simulation, target prediction, and ADMET analysis were performed and discussed in detail.

Imidazole Carbamates as a Promising Alternative for Treating Trichomoniasis: In Vitro Effects on the Growth and Gene Expression of Trichomonas vaginalis.

Metronidazole (MTZ) is the most common drug used against Trichomonas vaginalis (T. vaginalis) infections; however, treatment failures and high rates of recurrence of trichomoniasis have been reported, suggesting the presence of resistance in T. vaginalis to MTZ. Therefore, research into new therapeutic options against T. vaginalis infections has become increasingly urgent. This study investigated the trichomonacidal activity of a series of five imidazole carbamate compounds (AGR-1, AGR-2, AGR-3, AGR-4, and AGR-5) through in vitro susceptibility assays to determine the IC50 value of each compound. All five compounds demonstrated potent trichomonacidal activity, with IC50 values in the nanomolar range and AGR-2 being the most potent (IC50 400 nM). To gain insight into molecular events related to AGR-induced cell death in T. vaginalis, we analyzed the expression profiles of some metabolic genes in the trophozoites exposed to AGR compounds and MTZ. It was found that both AGR and MTZ compounds reduced the expression of the glycolytic genes (CK, PFK, TPI, and ENOL) and genes involved in metabolism (G6PD, TKT, TALDO, NADHOX, ACT, and TUB), suggesting that disturbing these key metabolic genes alters the survival of the T. vaginalis parasite and that they probably share a similar mechanism of action. Additionally, the compounds showed low cytotoxicity in the Caco-2 and HT29 cell lines, and the results of the ADMET analysis indicated that these compounds have pharmacokinetic properties similar to those of MTZ. The findings offer significant insights that can serve as a basis for future in vivo studies of the compounds as a potential new treatment against T. vaginalis.

New halo-enaminones as potential CNS drugs: Synthesis, characterization, DFT, NLO, molecular docking, and ADMET analysis

Some new halo-enaminones (2b-2g) of (Z)-1-(((2-acetylphenyl)amino)methylene)naphthalen-2(1H)-one (2a) were successfully synthesized in a very good yield. They were characterized by spectroscopic techniques. The single crystal XRD analysis confirmed the structure, stereochemistry, and hydrogen bond interactions of the synthesized enaminones. Density Functional Theory (DFT) and Time-Dependent Density Functional Theory (TDDFT) were employed to study theoretical attributes such as Structural analysis, Natural Bond Order analysis (NBO), Frontier molecular Orbital Analysis (FMO), Global and local reactivity descriptors, Molecular Electrostatic Potential (MEP) analysis, Absorption, Emission and Non-Linear Optical (NLO) properties. Molecular docking analysis revealed that all these compounds had an excellent binding energy of ∼ -12 kcal/mol, with the human Sirtuin 2 (SIRT2) protein (PDB ID: 5Y5N), which is predominantly expressed in the brain. In addition, ADMET analysis revealed that all of them have drug-like properties, Blood Brain Barrier (BBB) permeable, and are not P–Glycoprotein substrates, implying that they are potential Central Nervous System (CNS) drugs.

Bioinformatics approach for structure modeling, vaccine design, and molecular docking of Brucella candidate proteins BvrR, OMP25, and OMP31

Brucellosis is a zoonotic disease with significant economic and healthcare costs. Despite the eradication efforts, the disease persists. Vaccines prevent disease in animals while antibiotics cure humans with limitations. This study aims to design vaccines and drugs for brucellosis in animals and humans, using protein modeling, epitope prediction, and molecular docking of the target proteins (BvrR, OMP25, and OMP31). Tertiary structure models of three target proteins were constructed and assessed using RMSD, TM-score, C-score, Z-score, and ERRAT. The best models selected from AlphaFold and I-TASSER due to their superior performance according to CASP 12 – CASP 15 were chosen for further analysis. The motif analysis of best models using MotifFinder revealed two, five, and five protein binding motifs, however, the Motif Scan identified seven, six, and eight Post-Translational Modification sites (PTMs) in the BvrR, OMP25, and OMP31 proteins, respectively. Dominant B cell epitopes were predicted at (44–63, 85–93, 126–137, 193–205, and 208–237), (26–46, 52–71, 98–114, 142–155, and 183–200), and (29–45, 58–82, 119–142, 177–198, and 222–251) for the three target proteins. Additionally, cytotoxic T lymphocyte epitopes were detected at (173–181, 189–197, and 202–210), (61–69, 91–99, 159–167, and 181–189), and (3–11, 24–32, 167–175, and 216–224), while T helper lymphocyte epitopes were displayed at (39–53, 57–65, 150–158, 163–171), (79–87, 95–108, 115–123, 128–142, and 189–197), and (39–47, 109–123, 216–224, and 245–253), for the respective target protein. Furthermore, structure-based virtual screening of the ZINC and DrugBank databases using the docking MOE program was followed by ADMET analysis. The best five compounds of the ZINC database revealed docking scores ranged from (− 16.8744 to − 15.1922), (− 16.0424 to − 14.1645), and (− 14.7566 to − 13.3222) for the BvrR, OMP25, and OMP31, respectively. These compounds had good ADMET parameters and no cytotoxicity, while DrugBank compounds didn't meet Lipinski's rule criteria. Therefore, the five selected compounds from the ZINC20 databases may fulfill the pharmacokinetics and could be considered lead molecules for potentially inhibiting Brucella’s proteins.

Skin anti-aging potential of Launaea procumbens extract: Antioxidant and enzyme inhibition activities supported by ADMET and molecular docking studies

Aging is a natural process that occurs in all living organisms. Particularly, the skin embodies aging since it serves as a barrier between the body and its surroundings. Previously, we reported the wound healing effect of Launaea procumbens and identified compounds therein. The study aims to explore the skin anti-aging properties of the plant extract. To that effect, the antioxidant potential of L. procumbens methanolic extract (LPM) was assessed using two complementary DPPH and FRAP assays. The enzyme inhibitory effect of the extract on collagenase, elastase, hyaluronidase, and tyrosinase was evaluated to assess the direct skin anti-aging effects. Similarly, the anti-inflammatory activity was evaluated to explore the indirect anti-aging effects via the assessment of extract inhibitory effects on cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX). In addition, ADMET and molecular docking studies were performed to explore the interaction mechanisms of identified compounds in LPM with target enzymes. LPM demonstrated significant antioxidant activity in DPPH (IC50 = 29.08 µg/mL) and FRAP (1214.67 µM FeSO4/g extract) assays. Plant extract showed significant inhibition of collagenase, elastase, hyaluronidase, and tyrosinase (IC50 = 52.68, 43.76, 31.031, and 37.13 µg/mL, respectively). The extract demonstrated significant COX-2 and 5-LOX inhibition capacity with IC50 values of 8.635 and 10.851 µg/mL, respectively. The molecular docking study revealed the high potential of the identified compounds to bind to the active sites of enzymes crucially involved in the skin aging process. ADMET analysis of the compounds revealed their good absorption, distribution, and metabolism profiles, and they were found to be safe as well. Study findings suggest L. procumbens as a promising source for the development of natural skin anti-aging and antioxidant compounds. This, in turn, may facilitate its incorporation into cosmetic formulations after further investigation.

Investigating natural plant products as potential inhibitors to disrupt NS1 β-roll domain polymerisation in DENV2: a detailed computational chemistry approach

ABSTRACT The aim of this investigation is to design a novel drug, screened through various computational methods, that harnesses the historical evidence of plant products inhibiting viral infections. The beta-roll domain of Flavivirus NS1, crucial for its stability, membrane interaction and viral RNA replication, underscores its significance in disease pathogenesis, being the sole non-structural protein detected in the sera of DENV-infected patients. Our goal is to develop optimised compounds that disrupt NS1 β-roll domain polymerisation, mitigating hydrophobic core formation, to effectively inhibit DENV2 cytopathic infection by leveraging natural interference with viral replication. We created 10 plant-based ligand libraries and applied scaffold hopping and bioisosteric replacement to improve them. Computational methodologies, including virtual screening, molecular dynamics simulation, contact matrix and dynamic cross correlation matrix, were employed for analysing the dynamics of the protein with the association of ligand. ADMET analysis of ligand 126 revealed a favourable ADME profile with no observed toxicity properties. Calculations of pKd, pKi and pIC50 values indicated a heightened affinity of the ligand for the receptor protein, suggesting enhanced inhibitory action and a reduced dissociation rate. These encouraging findings suggest a greater potency of the drug, warranting further in vitro testing for validation.

DFT calculation and molecular docking studies of designing quinoline-derived anti-Alzheimer agents with NLO response

In the recent decade, the invention and design of novel molecules with nonlinear optical responses have become an enticing prospect for advancing optoelectronic and photonic devices. In the present work, the two novel compounds are designed from quinoline derivative, and their DFT calculation has been completed with the B3LYP/CAM-B3LYP approach and 6–311++G(d,p) basis set to inspect their electronic and geometrical nature. The TD-DFT simulation demonstrates that compounds (1–3) possess high βtot and βHRS values, which makes them suitable NLO-active materials. AutoDock Vina was used for molecular docking, and docking results demonstrate that compounds 1–3 exhibit good inhibition against the targeted enzymes (AChE and BChE). The ADMET analysis was performed to investigate the pharmacological parameters of compounds 1–3. Furthermore, all the results of the studied compounds reveal that these compounds possess merged NLO response and anti-Alzheimer characteristics.

Identification of Selisistat Derivatives as SIRT1-3 Inhibitors by in Silico Virtual Screening

Sirtuins family are a Nicotinamide Adenine Dinucleotide (NAD+) dependent histone deacetylase enzyme. Sirtuins have been implicated in the pathogenesis of various diseases including cancer, neurological disorders and metabolic syndromes, hence sirtuins appointed as a promising therapeutic target for diseases, by regulating of its activity by small molecules modulators. The indole containing selisistat (EX-527) and its derivatives set as the most potent and selective SIRT1 inhibitors. Selisistat showed an effective sirtuin inhibition on various cancer cell line, and has reached the clinical trials for endometriosis and Huntington’s disease. In this study a set of selisistat derivatives were designed and virtually studied by means of molecular docking, ADMET, and molecular dynamics (MD) simulations. Two molecules were showed promising virtual binding affinity on the SIRT1-3 proteins. Compound 1 exhibits stronger in silico SIRT1 and SIRT2 affinities than EX-527, whereas compound 8 prefers SIRT3 binding. The ADMET analysis of the virtually active molecules demonstrated an acceptable drug-like profile and desirable pharmacokinetics properties. The MD simulation analysis revealed that compound 1 had significantly better alignment with SIRT1 and SIRT2 proteins than EX-527 according to Root Mean Square Deviation (RMSD) and Root Mean Square Fluctuation (RMSF) data, while compound 8 had a perfect alignment and fitting with SIRT3 protein than EX-527.

Synthesis, biological evaluation, and DFT analysis of s-triazine analogues with medicinal potential integrated with bioactive heterocyclic scaffolds

This paper introduces a series of novel s-triazine analogues (designated as compounds (14–26) incorporating diverse bioactive heterocyclic scaffolds such as 1-adamantylamine, sulfamerazine, sulfadiazine, morpholine, 2-amino-5-methylthiazole, n-phenylpiperazine, and n-ethyl piperazine. These analogues were meticulously incorporated due to their potential medicinal relevance. Their antimicrobial properties were evaluated against Pseudomonas chlororaphis and Malassezia furfur. Notably, compounds 20 and 26, derived from distinct synthetic schemes, demonstrated the highest activity, with IC50 values of 57.66±0.47 and 17.33±0.47 µg/mL, respectively, against Pseudomonas chlororaphis, and IC50 values of 43.66±0.57 and 37.66±0.57 µg/mL, respectively, against Malassezia furfur. A comprehensive analysis utilizing Density Functional Theory (DFT) was employed to validate the experimental findings. This manuscript encapsulates the synthesis, biological assessment, and computational scrutiny of the novel s-triazine analogues, shedding light on their potential as antimicrobial agents and providing insights into their molecular characteristics. The ADMET analysis showed that the synthesized compounds had pharmacokinetic properties that are potentially suitable for clinical use.

Designing JAK2 Inhibitors Beyond Myeloproliferative Neoplasms ‐ Theoretical and Experimental Analysis for Solid Cancers

AbstractSomatic mutations in JAK2 have been reported to cause myeloproliferative neoplasms, autoimmune disorders, rheumatoid arthritis, and inflammation. JAK2 protein with PDB id 3FUP was selected for docking analysis via cross‐docking. Molecular docking of JAK2 with ATP and crystal ligand revealed their binding affinities and interactions. 3D QSAR models with R2=0.997 and Q2=0.984 having high stability and predictivity were generated. The biological activity of the hit compound obtained from virtual screening, LAS 26879206, was predicted to be 4.21 using the 3D QSAR model. Modification of LAS 26879206 utilizing 3D QSAR contours for modulating its JAK2 inhibitory potential yielded two novel inhibitors with a 2‐aminopyrimidine core – ACP1 and ACPM1. Molecular docking, molecular dynamics simulations, and ADMET analysis indicated improvements in the efficiency of these compounds compared to the hit compound. Synthesis of these compounds was carried out using a two‐step reaction‐ first Buchwald – Hartwig coupling reaction to yield an intermediate ACB1 which was then coupled with appropriate boronic acids via Suzuki reaction to get ACP1 and ACPM1. The effects of these designed compounds as anticancer agents were analyzed in hCT‐116 (human colorectal carcinoma), HeLa (cervical carcinoma), A549 (human lung adenocarcinoma), and A375 (human melanoma) cell lines. ACPM1 was found to be active in all the cell lines with a pIC50 of 5 which was in concordance with the in silico studies. Western blot analysis validated the JAK2 inhibitory property of ACPM1 which can be further ensured by in vivo studies.

Exploring Mechanism of Actions for Eugenol and Beta-Caryophyllene to Combat Colorectal Cancer Chemotherapy Using Network Pharmacology

This study explores the potential of essential oils, Eugenol (EUG), and Beta-Caryophyllene (BCP) in enhancing the efficacy of the chemotherapeutic drug 5-fluorouracil (5-FU) in treating metastatic colorectal cancer (CRC). Pharmacokinetic assessment through ADMET analysis indicates that EUG and BCP adhere to the rule of five with good bioavailability, ensuring their drug-likeness properties. The study employs a multitarget strategy to reduce drug dosage and enhance effectiveness, testing the compounds on the HCT116 human colorectal cancer cell line. MTT assay revealed in-vitro cytotoxic effects of EUG, BCP, and 5-FU, with a noteworthy reduction in IC50 values observed when combining the compounds, indicating synergistic effects (CI < 1) as depicted in the Fa-CI plot. Network pharmacology-based analysis of the compound-disease-target (C-D-T) network identifies 58, 24, and 49 target proteins for EUG, BCP, and 5-FU, respectively, in metastatic CRC. Venn diagram intersection reveals 11 common target proteins, and the merged C-D-T network highlights 84 target proteins, with 16 selected based on edge count, including HSP90AA1, IGF-1R, ESR1, and CASP3. Molecular docking studies indicate that EUG, BCP, and 5-FU effectively inhibit the core target protein HSP90AA1 within the C-D-T network, suggesting their potential as modulators for CRC metastasis. These findings propose a promising approach for developing drugs targeting specific proteins to mitigate metastasis in colorectal cancer.