Ahmed Elkerdawy

In the current investigation, two novel series of (tetrahydro)thioquinazoline-N-arylacetamides and (tetrahydro)thioquinazoline-N-arylacetohydrazides were designed, synthesized and investigated for their antiviral activity against SARS-CoV-2. The thioquinazoline-N-arylacetamide 17g as well as the tetrahydrothioquinazoline-N-arylacetohydrazides 18c and 18f showed potent antiviral activity with IC50 of 21.4, 38.45 and 26.4 µM, respectively. In addition, 18c and 18f demonstrated potential selectivity toward the SARS-CoV-2 over the host cells with SI of 10.67 and 16.04, respectively. Further evaluation of the mechanism of action of the three derivatives 17g, 18c, and 18f displayed that they can inhibit the virus at the adsorption as well as at the replication stages, in addition to their virucidal properties. In addition, 17g, 18c, and 18f demonstrated satisfactory physicochemical properties as well as drug-likeness properties to be further optimized for the discovery of novel antiviral agents. The docking simulation on Mpro binding site predicted the binding pattern of the target compounds rationalizing their differential activity based on their hydrophobic interaction and fitting in the hydrophobic S2 subsite of the binding site

Abstract Novel benzenesulfonamide derivatives linked to diverse functionalized thiouracils through a flexible N-ethyl acetamide linker were designed and synthesized as carbonic anhydrase (CA) inhibitors. The synthesized candidates demonstrated a potent inhibitory activity against four different CA isoforms in the nanomolar range. Compound 10d showed more than twofold higher potency than the reference AAZ against CA II with Ki of 5.65 and 12?nM, respectively. Moreover, compounds 10d and 20 revealed potent activity against CA IX with Ki of 18.1 and 14.2?nM, respectively. In addition, 10c, 10d, 11b, 11c, and 20 demonstrated high potency against the CA XII isozyme with a Ki range of 4.18?4.8?nM. Most of the synthesized derivatives displayed preferential selectivity toward the CA IX and CA XII isoforms over CA I and CA II. Compounds 11a and 20 exhibited favorable selectivity toward CA IX over CA II with a selectivity index (SI) of 14.36 and 16.62, respectively, and toward CA XII over CA II with SI of 71.01 and 51.19, respectively. Molecular docking simulations showed that the synthesized conjugates adopted comparable binding modes in the CA I, CA II, CA IX, and CA XII isoforms, involving the deep fitting of the sulfonamide moiety in the base of the CA active site via chelation of the Zn2+ ion and H-bond interaction with the key amino acids Thr199 and/or Thr200. Moreover, the N-ethyl acetamide flexible linker enables the substituted thiouracils and fused thiouracil tail to achieve multiple interactions with the surrounding hydrophobic and hydrophilic regions.

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A dual-tail approach was applied to the design of a novel series of 2-thiopyrimidine–benzenesulfonamides as carbonic anhydrase (CA) inhibitors. The design strategy is based on the hybridization between a benzenesulfonamide moiety as Zn2+ binding group and 2,4-disubstituted thiopyridimidine as a tail. Among the synthesized compounds, 14h displayed the highest potency (Ki = 1.72 nM) and selectivity for CA II over the isoforms CA IX and CA XII with selectivity indexes of 50 and 5.26, respectively. Meanwhile, compounds 14a and 14l displayed a potent inhibitory activity against CA IX (Ki = 7.4 and 7.0 nM, respectively) compared with the reference drug acetazolamide (AAZ) (Ki = 25 nM), and compound 14l showed higher potency (Ki = 4.67 nM) than AAZ (Ki = 5.7 nM) against the tumor-associated isoform CA XII. Evaluation of the antiproliferative activity in NCI single-dose testing of selected hybrids revealed a pronounced potency of the selective CA II inhibitor 14h against most of the tested NCI cancer cell lines. Moreover, compound 14h demonstrated an IC50 values ranging from 2.40 to 4.50 μM against MCF-7, T-47D, MDA-MB-231, HCT-116, HT29 and SW-620. These results demonstrate that CA II inhibition can be an alternative therapeutic target for cancer treatment. A cell cycle analysis of MCF-7 and MDA-MB-231 showed that treatment with 14h arrested both cell lines at the G2/M phase with significant accumulation of cells in the pre-G1 phase. Moreover, compound 14h showed a noticeable induction of late apoptosis and necrotic cell death of both cell lines compared with untreated cells as a control. A molecular docking study suggested that the sulfonamide moiety accommodates deeply in the CA active site and interacts with the Zn2+ ion while the dual-tail extension interacts with the surrounding amino acids via several hydrophilic and hydrophobic interactions, which affects the potency and selectivity of the hybrids.

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In the present study, 1-(un)substituted 2-(hetero)aryl imidazo[4,5-b]phenazines 4a-j and 6a-d were synthesized and evaluated for their cytotoxic activities against a panel of cell lines at 10 micromolar concentration. Compound 4f revealed a remarkable and broad spectrum of cytotoxic activity with growth inhibition percent (GI%) of 11-82%. It was found that cell lines derived from leukemia, and breast cancer were the most sensitive to the imidazophenazine derivative 4f. It showed GI% of 82% against MOLT-4 cell line from leukemia. Moreover, compound 4e showed GI% of 88% against SK-OV-3 cells from ovarian cancer. In addition, compound 4b showed GI% of 51% against M14 melanoma cell line, whereas compound 6a showed GI% of 44% against T-47D breast cancer cell line. The most promising compounds 4a and 4e-g were further tested for their Topo I and Topo IIα inhibitory activities. It was found that compound 4e is the most potent derivative against Topo I in comparison to camptothecin (IC50 = 29.25 and 25.71 µM, respectively), whereas the imidazophenazine derivatives 4f and 4g displayed comparable potency to etoposide against Topo IIα (IC50 = 26.74, 22.72, and 20.52 µM, respectively). Investigation of the effect of compound 4f on MCF-7 cell cycle at its IC50 concentration showed its effectiveness in arresting the cell cycle at the G2/M phase; furthermore, it induced apoptosis in MCF-7 cells. Molecular docking simulations in Topo I and Topo IIα revealed that the biological activity of the target compounds could be due to their mechanism of action that resembles the topoisomerase poisons which involves the accommodation of their polycyclic scaffold in the DNA cleavage site stacking between the base pairs interacting through several π-π stacking interactions with the surrounding DNA bases stabilizing the topoisomerase/DNA cleavage complex preventing the re-ligation reaction. SwissADME web tool proved that compounds 4f and 4g exhibit promising ADME profile, and drug likeness properties.

A new series of pyrazolo[3,4-b]pyridine compounds (3a,b–9a-c) was synthesized starting with 2-oxo-6-phenyl-1,2-dihydropyridine-3-carbonitriles 1a,b which converted to their 2- chloro analogues 2a,b. By further treatment of of 2a,b with hydrazine hydrate, the key intermediates 3-amino-pyrazolopyridine derivatives 3a,b were afforded. Whereas, the target 3-substituted-pyrazolopyridine derivatives (4a-d–9a-c) were obtained through treatment of 3a,b with different reagents. All the new compounds were evaluated as antimicrobial agents against six bacterial and six fungal strains. The most potent antimicrobial activity was showed by compounds (3a, 3b, 4a, 4d, 6a, 6c, 9a and 9c) with MIC values range (2-32) μg/mL. Moreover, the most active compounds were selected to be evaluated for their inhibition activity against the resistant bacteria methicillin-resistant Staphylococcus aureus (MRSA). In addition, the inhibitory activity of the potent compounds against dihydrofolate reductase (DHFR) was evaluated compared with Trimethoprim (TMP) as a reference DHFR inhibitor. The most potent inhibition of the target enzyme was also showed by compounds 4d, 6c and 9c of IC50 values 0.72, 0.95 and 1.09 µM, compared with the IC50 value 5.54 µM of TMP. Also, molecular docking study showed that compounds 4d, 6c and 9c having the most binding affinity in DHFR active site.

INTRODUCTION: Epidermal growth factor receptor (EGFR) regulates several cell functions which include cell growth, survival, multiplication, differentiation, and apoptosis. Currently, EGFR kinase inhibitors are of increasing interest as promising targeted antitumor therapeutic agents.

METHODS: Different thiazolyl-pyrazoline derivatives () were synthesized and were first tested for anti-proliferative effect towards the A549 lung cancer cell line and the T-47D breast cancer cell line in MTT assay. Thereafter, thiazolyl-pyrazolines (, and ) were subsequently evaluated for their PK inhibition for EGFR. Moreover, representative promising derivatives ( and ) in cytotoxic and PK inhibition assays were tested to investigate their impact on the apoptosis and cell cycle phases in T-47D cells in order to explore more insights into the antitumor actions of the target thiazolyl-pyrazolines. Furthermore, docking studies were accomplished to evaluate the patterns of binding of thiazolyl-pyrazolines , and in the EGFR active pocket (PDB ID: 1M17).

RESULTS: Testing the thiazolyl pyrazoline compounds on A549 and T-47D cell lines showed IC arrays between 3.92 and 89.03 µM, and between 0.75 and 77.10 µM, respectively. Also, the tested thiazolyl-pyrazolines (, and ) demonstrated significant sub-micromolar EGFR inhibitory actions with IC values 83, 262, 171 and 305 nM, respectively, in comparison to erlotinib (IC =57 nM).

DISCUSSION: Generally, it was observed that the tested thiazolyl pyrazolines showed more potent antiproliferative activity toward breast cancer cells T-47D than toward lung cancer cell lines A549. In particular, thiazolyl pyrazolines and showed the best activity against A549 cells (IC = 3.92 and 6.53 µM) and T-47D cells (IC = 0.88 and 0.75 µM). Compounds and provoked a sub-G1 phase arrest and cell apoptosis which are in agreement with the expected outcome of EGFR inhibition. Finally, the molecular docking of and in the active site of EGFR revealed a common binding pattern similar to that of erlotinib which involves the accommodation of the 1,3 thiazol-4-one ring and pyrazoline ring of target compounds in the binding region of erlotinib's quinazoline ring and anilino moiety.

In the current work, a series of novel 4-benzyloxy and 4-(2-phenylethoxy) chalcone fibrate hybrids (10a-o) and (11a-e) were synthesized and evaluated as new PPARα agonists in order to find new agents with higher activity and fewer side effects. The 2-propanoic acid derivative 10a and the 2-butanoic acid congener 10i showed the best overall PPARα agonistic activity showing Emax% values of 50.80 and 90.55%, respectively, and EC50 values of 8.9 and 25.0 μM, respectively, compared to fenofibric acid with Emax = 100% and EC50 = 23.22 μM, respectively. These two compounds also stimulated carnitine palmitoyltransferase 1A gene transcription in HepG2 cells and PPARα protein expression. Molecular docking simulations were performed for the newly synthesized compounds to study their predicted binding pattern and energies in PPARα active site to rationalize their promising activity. In vivo, compounds 10a and 10i elicited a significant hypolipidemic activity improving the lipid profile in triton WR-1339-induced hyperlipidemic rats, including serum triglycerides, total cholesterol, LDL, HDL and VLDL levels. Compound 10i possessed better anti-hyperlipidemic activity than 10a. At a dose of 200 mg/kg, it demonstrated significantly lower TC, TG, LDL and VLDL levels than that of fenofibrate at the same dose with similar HDL levels. Compounds 10i and 10a possessed atherogenic indices (CRR, AC, AI, CRI-II) like that of fenofibrate. Additionally, a promising antioxidant activity indicated by the increased tissue reduced glutathione and plasma total antioxidant capacity with decreased plasma malondialdehyde levels was demonstrated by compounds 10a and 10i. No histopathological alterations were recorded in the hepatic tissue of compound 10i (200 mg/kg).

Drug–drug interaction (DDI) is a major public health problem contributing to 30% of the unexpected clinical adverse drug events. Informatics-based studies for DDI signal detection have been evolving in the last decade. We aim at providing a boosted machine learning (ML) framework to predict novel DDI safety signals with high precision. We propose a similarity-based machine learning framework called “SMDIP” using DrugBank as one of the most reliable pharmaceutical knowledge bases. For this study, DrugBank provides the latest drug information in terms of DDIs, targets, enzymes, transporters, and carriers. We computed drug–drug similarities using a Russell–Rao measure for the available biological and structural information on DrugBank for representing the sparse feature space. Logistic regression is adopted to conduct DDI classification with a focus on searching for key similarity predictors. Six types of ML models are deployed on the selected DDI key features. Our study reveals that SMDIP has yielded favourable predictive performance compared to relevant studies with results as follows: AUC 76%, precision 82%, accuracy 79%, recall 62%, specificity 90%, and F-measure 78%. To further confirm the reliability and reproducibility of SMDIP, we investigate SMDIP on an unseen subset of direct-acting-antiviral (DAA) drugs for treating hepatitis C infections. Forty novel DAA DDIs are predicted that show consistency with the pharmacokinetic and pharmacodynamic profiles of these drugs. Furthermore, several reports from the pharmacovigilance literature corroborate our framework results. Those evaluations show that SMDIP is a promising framework for uncovering DDIs, which can be multifariously feasible in drug development, postmarketing surveillance, and public health fields.

Abstract A novel series of 2-arylbenzothiazoles 9, 10, and 12 were designed and synthesized as VEGFR-2/FGFR-1/PDGFR-? multiangiokinase inhibitors targeting breast cancer. Structural elongation of the known 2-phenylbenzothiazole scaffold (type I protein kinase inhibitor [PKI]), was carried out to afford series of type II PKIs 9, 10, and 12. Compounds 9d, 9f, 9i, and 9k exhibited potent multikinase inhibitory activity with IC50 values of 0.19, 0.18, 0.17, and 0.13??M, respectively, against VEGFR-2; IC50 values of 0.28, 0.37, 0.19, and 0.27??M, respectively, against FGFR-1; and IC50 values of 0.07, 0.04, 0.08, and 0.14??M, respectively, against PDGFR-?. Moreover, the synthesized benzothiazoles demonstrated promising cytotoxic activity against the MCF-7 cell line. The most potent benzothiazoles 9d and 9i exhibited IC50 values of 7.83 and 6.58??M, respectively, on the MCF-7 cell line in comparison to sorafenib (III), which showed IC50?=?4.33??M. Additionally, 9d and 9i showed VEGFR-2 inhibitory activity in MCF-7 cells of 81% and 83% when compared with sorafenib (III), which showed 88% inhibition. Molecular docking of the designed compounds in the VEGFR-2 and FGFR-1 active sites showed the accommodation of the 2-phenylbenzothiazole moiety, as reported, in the hinge region of the receptor tyrosine kinase (RTK)-binding site, while the amide moiety is involved in hydrogen bond interactions with the key amino acids in the gate area; this in turn directs the aryl group to the hydrophobic allosteric back pocket of the RTKs in a type II-like binding mode. The synthesized benzothiazoles showed satisfactory ADME properties for further optimization in drug discovery.

In the present work, a new series of thiopyrimidine-benzenesulfonamide conjugates was designed, synthesized and tested as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. Our design strategy was based on the molecular hybridization of the benzenesulfonamide moiety as a zinc binding group (ZBG), an alkylated thiopyrimidine moiety as a spacer and (un)substituted phenyl moieties with various electronic and hydrophobic environments as a tail. The designed and synthesized compounds were evaluated against four human (h) CA isoforms hCA I, hCA II, hCA IX and hCA XII. Series 6 showed promising activity and selectivity toward the cytosolic isoforms hCA I and hCA II versus the membrane bound isoforms hCA IX and hCA XII. Compounds 6e and 6f showed Ki of 0.04 µM against hCA II with a selectivity of 15.8- to 980-fold towards hCA II over hCA I, hCA IX, hCA XII isoforms. Molecular docking in the hCA II active site attributed the promising inhibitory activity of series 6 to the interaction of their sulfonamide moiety with the active site Zn2+ ion as well as its hydrogen bonding with the key amino acids Thr199 and Thr200. Through hydrophobic interaction, the benzenesulfonamide and the thiopyrimidine moieties interact with the hydrophobic side chains of the amino acids Val121/Leu198 and Ile91/Phe131, respectively. These results indicated that the designed and synthesized series is an interesting scaffold that can be further optimized for the development of selective antiglaucoma drugs.

Aurora kinases (AURKs) were identified as promising druggable targets for targeted cancer therapy. Aiming at the development of novel chemotype of dual AURKA/B inhibitors, herein we report the design and synthesis of three series of 4-anilinoquinoline derivatives bearing a sulfonamide moiety (5a-d, 9a-d and 11a-d). The % inhibition of AURKA/B was determined for all target quinolines, then compounds showed more than 50% inhibition on either of the enzymes, were evaluated further for their IC50 on the corresponding enzyme. In particular, compound 9d displayed potent AURKA/B inhibitory activities with IC50 of 0.93 and 0.09 µM, respectively. Also, 9d emerged as the most efficient anti-proliferative analogue in the US-NCI anticancer assay toward the NCI 60 cell lines panel, with broad spectrum activity against different cell lines from diverse cancer subpanels. Docking studies, confirmed that, the sulfonamide SO2 oxygen was involved in a hydrogen bond with Lys162 and Lys122 in AURKA and AURKB, respectively, whereas, the sulfonamide NH could catch hydrogen bond interaction with the surrounding amino acid residues Lys141, Glu260, and Asn261 in AURKA and Lys101, Glu177, and Asp234 in AURKB. Furthermore, N1 nitrogen of the quinoline scaffold formed an essential hydrogen bond with the hinge region key amino acids Ala213 and Ala173 in AURKA and AURKB, respectively.

On account of their overexpression in a wide range of human malignancies, cyclin-dependent kinases (CDKs) are among the most validated cancer targets, and their inhibition has been featured as a valuable strategy for anticancer drug discovery. In this study, a hybrid pharmacophore approach was adopted to develop two series of oxindole–indole conjugates (6a–i and 9a–f) and carbocycle–indole conjugates (11a,b) as efficient antitumor agents with potential inhibitory action toward CDK4. All oxindole–indole conjugates, except 6i, 9b, and 9c efficiently affected the growth of the human breast cancer MCF-7 (IC50: 0.39 ± 0.05–21.40 ± 1.58 μM) and/or MDA-MB-231 (IC50: 1.03 ± 0.04–22.54 ± 1.67 μM) cell lines, whereas bioisosteric replacement of the oxindole nucleus with indane or tetralin rings (compounds 11a,b) diminished the anti-proliferative activity. In addition, hybrids 6e and 6f displayed effective cell cycle disturbance and proapoptotic capabilities in MCF-7 cells. Furthermore, the efficient anti-proliferative agents towards MCF-7 and/or MDA-MB-231 cell lines (6a–h, 9a, and 9e) were investigated for their potential inhibitory action toward CDK4. Hybrids 6a and 6e displayed good CDK4 inhibitory activity with IC50s equal 1.82 and 1.26 µM, respectively. The molecular docking study revealed that oxindole moiety is implicated in two H-bonding interactions via both (NH) and (C=O) groups with the key amino acids Glu94 and Val96, respectively, whereas the indole framework is stably accommodated in a hydrophobic sub-pocket establishing hydrophobic interactions with the amino acid residues of Ile12, Val20, and Gln98 lining this sub-pocket. Collectively, these results highlighted hybrids 6a and 6e as good leads for further optimization as promising antitumor drugs toward breast malignancy and CDK inhibitors.

In this study, a novel series of 1,2-disubstituted benzo[d]imidazoles was rationally designed as VEGFR-2 inhibitors targeting hepatocellular carcinoma. Our design strategy is two-fold; it aimed first at studying the effect of replacing the 5-methylfuryl moiety of the well-known antiangiogenic 2-furylbenzimidazoles with an isopropyl moiety on the VEGFR-2 inhibitory activity and the cytotoxic activity. Our second objective was to further optimize the structures of the benzimidazole derivatives through elongation of the side chains at their one-position for the design of more potent type II-like VEGFR-2 inhibitors. The designed 1,2-disubstituted benzimidazoles demonstrated potent cytotoxic activity against the HepG2 cell line, reaching IC50 = 1.98 μM in comparison to sorafenib (IC50 = 10.99 μM). In addition, the synthesized compounds revealed promising VEGFR-2 inhibitory activity in the HepG2 cell line, e.g., compounds 17a and 6 showed 82% and 80% inhibition, respectively, in comparison to sorafenib (% inhibition = 92%). Studying the effect of 17a on the HepG2 cell cycle demonstrated that 17a arrested the cell cycle at the G2/M phase and induced a dose-dependent apoptotic effect. Molecular docking studies of the synthesized 1,2-disubstituted benzimidazoles in the VEGFR-2 active site displayed their ability to accomplish the essential hydrogen bonding and hydrophobic interactions for optimum inhibitory activity.

Motivated by the potential anticancer activity of both coumarin and 2-aminothiazole nuclei, a new set of thiazol-2-yl hydrazono-chromen-2-one analogs were efficiently synthesized aiming to obtain novel hybrids with potential cytotoxic activity. MTT assay investigated the significant potency of all the target compounds against the human cervical cancer cell lines (HeLa cells). Cell cycle analysis showed that the representative compound 8a led to cell cycle cessation at G0/G1 phase indicating that CDK2/E1complex could be the plausible biological target for these newly synthesized compounds. Thus, the most active compounds (7c and 8a-c) were tested for their CDK2 inhibitory activity. The biological results revealed their significant CDK2 inhibitory activity with IC50 range of 0.022–1.629 nM. Moreover, RT-PCR gene expression assay showed that compound 8a increased the levels of the nuclear CDK2 regulators P21 and P27 by 2.30 and 5.7 folds, respectively. ELISA tequnique showed also that compound 8a led to remarkable activation of caspases-9 and -3 inducing cell apoptosis. QSAR study showed that the charge distribution and molecular hydrophobicity are the structural features affecting cytotoxic activity in this series. Molecular docking study for the most potent cytotoxic compounds (7c and 8a-c) rationalized their superior CDK2 inhibitory activity through their hydrogen bonding and hydrophobic interactions with the key amino acids in the CDK2 binding site. Pharmacokinetic properties prediction of the most potent compounds showed that the newly synthesized compounds are not only with promising antitumor activity but also possess promising pharmacokinetic properties.

A series of new 2-arylbenzothiazole derivatives (4, 5, 6a-j, 7a-i and 8a,b) was synthesized and tested for their antimicrobial activity against different Gram-positive, Gram-negative bacteria and yeast using ciprofloxacin and fluconazole as positive controls for the antibacterial and antifungal activities, respectively. The target compounds showed stronger inhibitory activity against Gram-negative than Gram-positive bacteria. The minimum inhibitory concentration (MIC) values were determined for those compounds showed zone of inhibition ≥ 13 mm. Based on the MIC values for the tested compounds against E. coli, compounds (4, 5, 6c, 6d, 6g, 6i, 6j, 7b, 7c, 7g and 8a) were selected and tested for their E. coli gyrase inhibitory activity. The tested compounds showed moderate inhibitory activity against E. coli gyrase. Compounds 5, 6c, 6i, 6j and 7b displayed high inhibitory activity against E. coli gyrase with IC50 values below 10 µM, however, they were less active than ciprofloxacin (E. coli gyrase IC50 = 1.14 µM). The p-hydroxy-m-methoxy benzothiazole analogue 6c was the most active tested compound (E. coli gyrase IC50 = 4.85 µM). Quantitative structure–activity relationship (QSAR) study was also implemented for the newly synthesized compounds. The QSAR study indicated that the structural feature that governs the anti-microbial activity for the newly synthesized benzothiazole derivatives is their structural hydrophilic-lipophilic balance what agrees with the chemical intuition where this balance governs their cellular absorption and so their antimicrobial activity. Molecular docking showed that the newly synthesized compounds possess the required structural feature for E. coli gyrase B inhibition through interaction with the key amino acids Asp73 and Gly77.

Considering the emerging importance of glycogen synthase kinase 3 beta (GSK-3β) inhibitors in treatment of Alzheimer’s disease, multi-protein structure receptor-based pharmacophore modeling was adopted to generate a 3D pharmacophore model for (GSK-3β) inhibitors. The generated 3D pharmacophore was then validated using a test set of 1235 compounds. The ZINCPharmer web tool was used to virtually screen the public ZINC database using the generated 3D pharmacophore. A set of 12,251 hits was produced and then filtered according to their lead-like properties, predicted central nervous system (CNS) activity, and Pan-assay interference compounds (PAINS) fragments to 630 compounds. Scaffold Hunter was then used to cluster the filtered compounds according to their chemical structure framework. From the different clusters, 123 compounds were selected to cover the whole chemical space of the obtained hits. The SwissADME online tool was then used to filter out the compounds with undesirable pharmacokinetic properties giving a set of 91 compounds with promising predicted pharmacodynamic and pharmacokinetic properties. To confirm their binding capability to the GSK-3β binding site, molecular docking simulations were performed for the final 91 compounds in the GSK-3β binding site. Twenty-five compounds showed acceptable binding poses that bind to the key amino acids in the binding site Asp133 and Val135 with good binding scores. The quinolin-2-one derivative ZINC67773573 was found to be a promising lead for designing new GSK-3β inhibitors for Alzheimer’s disease treatment.