Abd El-Karim, S. S., Y. M. Syam, A. M. El Kerdawy, and T. M. Abdelghany, New thiazol-hydrazono-coumarin hybrids targeting human cervical cancer cells: Synthesis, CDK2 inhibition, QSAR and molecular docking studies, , vol. 86, pp. 80 - 96, 2019. AbstractWebsite

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.

El Kerdawy, A. M., A. A. Osman, and M. A. Zaater, Receptor-based pharmacophore modeling, virtual screening, and molecular docking studies for the discovery of novel GSK-3β inhibitors, , vol. 25, issue 6, pp. 171, 2019. AbstractWebsite

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.

Fouad, M. A., E. H. Tolba, M. A. El-Shal, and A. M. El Kerdawy, "QSRR modeling for the chromatographic retention behavior of some β-lactam antibiotics using forward and firefly variable selection algorithms coupled with multiple linear regression", Journal of Chromatography A, vol. 1549, pp. 51-62, 2018. AbstractWebsite

AbstractThe justified continuous emerging of new β-lactam antibiotics provokes the need for developing suitable analytical methods that accelerate and facilitate their analysis. A face central composite experimental design was adopted using different levels of phosphate buffer pH, acetonitrile percentage at zero time and after 15 min in a gradient program to obtain the optimum chromatographic conditions for the elution of 31 β-lactam antibiotics. Retention factors were used as the target property to build two QSRR models utilizing the conventional forward selection and the advanced nature-inspired firefly algorithm for descriptor selection, coupled with multiple linear regression. The obtained models showed high performance in both internal and external validation indicating their robustness and predictive ability. Williams-Hotelling test and student’s t-test showed that there is no statistical significant difference between the models’ results. Y-randomization validation showed that the obtained models are due to significant correlation between the selected molecular descriptors and the analytes’ chromatographic retention. These results indicate that the generated FS-MLR and FFA-MLR models are showing comparable quality on both the training and validation levels. They also gave comparable information about the molecular features that influence the retention behavior of β-lactams under the current chromatographic conditions. We can conclude that in some cases simple conventional feature selection algorithm can be used to generate robust and predictive models comparable to that are generated using advanced ones.

Roaiah, H. M., I. A. Y. Ghannam, I. H. Ali, A. M. El Kerdawy, M. M. Ali, S. E. - S. Abbas, and S. S. El-Nakkady, "Design, synthesis, and molecular docking of novel indole scaffold-based VEGFR-2 inhibitors as targeted anticancer agents", Archiv der Pharmazie, pp. e1700299–n/a, 2018. AbstractWebsite

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Halawa, A. H., M. A. H. M. O. U. D. M. ELAASSER, A. M. El Kerdawy, A. M. A. I. Abd El-Hady, H. A. Emam, and A. M. El-Agrody, "Anticancer activities, molecular docking and structure–activity relationship of novel synthesized 4H-chromene, and 5H-chromeno[2,3-d]pyrimidine candidates", Medicinal Chemistry Research, vol. 26, no. 10, pp. 2624–2638, Oct, 2017. AbstractWebsite

In the present study, a series of 4H-chromene and 5H-chromeno[2,3-d]pyrimidine derivatives was synthesized and evaluated as potential cytotoxic agents. The cytotoxic activities of the target compounds were evaluated against four cancer cell lines MCF-7, HCT-116, HepG-2, and A549 in comparison with vinblastine and colchicine as reference drugs. We explored the structure–activity relationship of 4H-chromenes with modification at the 2-,4- or 7-position, and fused pyrimidine ring at 2,3-position. Most of the screened compounds showed marginal antitumor activity against the different cell lines in comparison to the standard drugs. The structure–activity relationship study revealed that the antitumor activity of the synthesized compounds was significantly affected by the lipophilicity of the substituent at the 2-,4- or 7-position for the 4H-chromenes, and 5,8-position or fused pyrimidine ring at 2,3-positions for 5H-chromeno[2,3-d]pyrimidines. Structure–activity relationship was elaborated with the help of molecular docking studies. The structures of the synthesized compounds were established on the basis of the spectral data, infrared, proton nuclear magnetic resonance, 13-Carbon nuclear magnetic resonance and mass spectroscopic data.

Abdullaziz, M. A., H. T. Abdel-Mohsen, A. M. El Kerdawy, F. A. F. Ragab, M. M. Ali, S. M. Abu-bakr, A. S. Girgis, and H. I. El Diwani, "Design, synthesis, molecular docking and cytotoxic evaluation of novel 2-furybenzimidazoles as VEGFR-2 inhibitors", Eur. J. Med. Chem., vol. 136, pp. 315 - 329, 2017/8/18/. AbstractWebsite

AbstractInhibition of angiogenesis through inhibition of vascular endothelial growth factor receptor 2 (VEGFR-2) has been applied in cancer therapy because of its important role in promoting cancer growth and metastasis. In the presented study, a series of benzimidazol-furan hybrids was designed and synthesized through facile synthetic pathways. Evaluation of the synthesized compounds for their in vitro cytotoxic activity against breast (MCF-7) and hepatocellular (HepG2) carcinoma cell lines was performed. Two of the synthesized conjugates, 10b and 15, showed potent antiproliferative properties against MCF-7 cell line (IC50 = 21.25, 21.35 μM, respectively) in comparison to tamoxifen (IC50 = 21.57 μM). Additionally, compounds 10a, 10b, 15 and 17 showed promising potency (IC50 = 25.95, 22.58, 26.94 and 31.06 μM, respectively) against liver carcinoma cell line HepG2 in contrast to cisplatin (IC50 = 31.16 μM). Moreover, in vitro evaluation of the synthesized compounds for their effect on the level of VEGFR-2 in MCF-7 cell line showed their potent inhibitory activity relative to control untreated cells. Four compounds 10a, 10b, 14 and 15 showed 92–96% reduction in VEGFR-2 level, compared with tamoxifen and sorafenib which showed inhibition percentage of 98% and 95.75%, respectively. Compound 10a was found to have promising VEGFR-2 inhibitory activity (IC50 = 0.64 μM) in comparison to sorafenib (IC50 = 0.1 μM). Molecular docking was performed to study the binding pattern of the newly synthesized compounds with VEGFR-2 active site. Molecular docking attributed their good VEGFR-2 inhibitory activity to their hydrogen bonding interaction with the key amino acids in VEGFR-2 active site, Glu885 and Asp1046, and their hydrophobic interaction by their 2-furylbenzimidazole moiety with the allosteric hydrophobic back pocket in a type III inhibitors-like binding mode. The binding interaction is augmented by a ring substituent with long chain extension at position 1 of the benzimidazole due to its hydrophobic interaction with the hydrophobic side chains of the amino acids at the interface between the ATP binding site and the allosteric back pocket. Structure-activity relationship (SAR) was inferred for future optimization based on the performed biological and docking studies.

Sommer, T., H. Hübner, A. El Kerdawy, P. Gmeiner, M. Pischetsrieder, and T. Clark, "Identification of the Beer Component Hordenine as Food- Derived Dopamine D2 Receptor Agonist by Virtual Screening a 3D Compound Database", Scientific Reports, vol. 7:44201, 2017.
Ragab, F. A., N. A. El-Sayed, A. A. Eissa, and A. M. El Kerdawy, "Synthesis and anticonvulsant activity of certain substituted furochromones, benzofuran and flavone derivatives.", Chem. Pharm. Bull., vol. 58, issue 9, pp. 1148-1156, 2010. 2010_master_paper.pdf
Hassanein, H. H., H. H. Georgey, M. A. Fouad, A. M. El Kerdawy, and M. F. Said, "Synthesis and molecular docking of new imidazoquinazolinones as analgesic agents and selective COX-2 inhibitors", Future Med. Chem., 2017.