In Silico Screening of Semi-Synthesized Compounds as Potential Inhibitors for SARS-CoV-2 Papain-like Protease: Pharmacophoric Features, Molecular Docking, ADMET, Toxicity and DFT Studies DOI Creative Commons
Mohamed S. Alesawy, Eslam B. Elkaeed, Aisha A. Alsfouk

et al.

Molecules, Journal Year: 2021, Volume and Issue: 26(21), P. 6593 - 6593

Published: Oct. 30, 2021

Papain-like protease is an essential enzyme in the proteolytic processing required for replication of SARS-CoV-2. Accordingly, such important target development anti-SARS-CoV-2 agents which may reduce mortality associated with outbreaks A set 69 semi-synthesized molecules that exhibited structural features SARS-CoV-2 papain-like inhibitors (PLPI) were docked against coronavirus (PLpro) (PDB ID: (4OW0). Docking studies showed derivatives 34 and 58 better than co-crystallized ligand while 17, 28, 31, 40, 41, 43, 47, 54, 65 good binding modes free energies. The pharmacokinetic profiling study was conducted according to four principles Lipinski rules excluded derivative 31. Furthermore, ADMET toxicity 34, 47 have potential be drugs been demonstrated as safe when assessed via seven models. Finally, comparing molecular orbital energies electrostatic maps a DFT indicated 28 most promising candidate interact receptor (PLpro).

Language: Английский

Nitrogen Containing Heterocycles as Anticancer Agents: A Medicinal Chemistry Perspective DOI Creative Commons
Adarsh Kumar, Ankit Kumar Singh, Harshwardhan Singh

et al.

Pharmaceuticals, Journal Year: 2023, Volume and Issue: 16(2), P. 299 - 299

Published: Feb. 14, 2023

Cancer is one of the major healthcare challenges across globe. Several anticancer drugs are available on market but they either lack specificity or have poor safety, severe side effects, and suffer from resistance. So, there a dire need to develop safer target-specific drugs. More than 85% all physiologically active pharmaceuticals heterocycles contain at least heteroatom. Nitrogen constituting most common heterocyclic framework. In this study, we compiled FDA approved with nitrogen atoms their pharmacological properties. Moreover, reported containing heterocycles, including pyrimidine, quinolone, carbazole, pyridine, imidazole, benzimidazole, triazole, β-lactam, indole, pyrazole, quinazoline, quinoxaline, isatin, pyrrolo-benzodiazepines, pyrido[2,3-d]pyrimidines, which used in treatment different types cancer, concurrently covering biochemical mechanisms action cellular targets.

Language: Английский

Citations

144
New benzoxazole derivatives as potential VEGFR-2 inhibitors and apoptosis inducers: design, synthesis, anti-proliferative evaluation, flowcytometric analysis, and in silico studies DOI Creative Commons
Hazem Elkady, Alaa Elwan, Hesham A. El-Mahdy

et al.

Journal of Enzyme Inhibition and Medicinal Chemistry, Journal Year: 2021, Volume and Issue: 37(1), P. 403 - 416

Published: Dec. 27, 2021

A new series of benzoxazole derivatives were designed and synthesised to have the main essential pharmacophoric features VEGFR-2 inhibitors. Cytotoxic activities evaluated for all against two human cancer cell lines, MCF-7 HepG2. Also, effect most cytotoxic on protein concentration was assessed by ELISA. Compounds

Language: Английский

Citations

113
Design and synthesis of thiazolidine-2,4-diones hybrids with 1,2-dihydroquinolones and 2-oxindoles as potential VEGFR-2 inhibitors: in-vitro anticancer evaluation and in-silico studies DOI Creative Commons
Mohammed S. Taghour, Hazem Elkady, Wagdy M. Eldehna

et al.

Journal of Enzyme Inhibition and Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 37(1), P. 1903 - 1917

Published: July 8, 2022

A thiazolidine-2,4-dione nucleus was molecularly hybridised with the effective antitumor moieties; 2-oxo-1,2-dihydroquinoline and 2-oxoindoline to obtain new hybrids potential activity against VEGFR-2. The cytotoxic effects of synthesised derivatives Caco-2, HepG-2, MDA-MB-231 cell lines were investigated. Compound 12a found be most potent candidate investigated IC50 values 2, 10, 40 µM, respectively. Furthermore, tested in vitro for their VEGFR-2 inhibitory showing strong inhibition. Moreover, an viability study Vero non-cancerous line results reflected a high safety profile all compounds. further its apoptotic behaviour by assessing gene expression four genes (Bcl2, Bcl-xl, TGF, Survivin). Molecular dynamic simulations authenticated affinity, accurate binding, perfect dynamics compound

Language: Английский

Citations

81
Design, synthesis, docking, ADMET studies, and anticancer evaluation of new 3-methylquinoxaline derivatives as VEGFR-2 inhibitors and apoptosis inducers DOI Creative Commons
Mohammed M. Alanazi, Ibrahim H. Eissa, Nawaf A. Alsaif

et al.

Journal of Enzyme Inhibition and Medicinal Chemistry, Journal Year: 2021, Volume and Issue: 36(1), P. 1760 - 1782

Published: Jan. 1, 2021

Vascular endothelial growth factor receptor-2 (VEGFR-2) plays a critical role in cancer angiogenesis. Inhibition of VEGFR-2 activity proved effective suppression tumour propagation. Accordingly, two series new 3-methylquinoxaline derivatives have been designed and synthesised as inhibitors. The were evaluated vitro for their cytotoxic activities against MCF-7and HepG2 cell lines. In addition, the inhibitory target compounds estimated to indicate potential mechanism cytotoxicity. To great extent, results inhibition highly correlated with that Compound 27a was most potent inhibitor IC50 3.2 nM very close positive control sorafenib (IC50 = 3.12 nM). Such compound exhibited strong effect MCF-7 HepG2, respectively 7.7 4.5 µM comparison 3.51 2.17 µM). 28, 30f, 30i, 31b excellent range from 4.2 6.1 nM) promising activity. Cell cycle progression apoptosis induction investigated active member 27a. Also, on level caspase-3, caspase-9, BAX/Bcl-2 ratio determined. Molecular docking studies implemented interpret binding mode pocket. Furthermore, toxicity ADMET calculations performed study pharmacokinetic profiles.

Language: Английский

Citations

78
New quinoxaline-2(1H)-ones as potential VEGFR-2 inhibitors: design, synthesis, molecular docking, ADMET profile and anti-proliferative evaluations DOI
Reda G. Yousef,

Helmy Sakr,

Ibrahim H. Eissa

et al.

New Journal of Chemistry, Journal Year: 2021, Volume and Issue: 45(36), P. 16949 - 16964

Published: Jan. 1, 2021

Eleven new quinoxaline derivatives were designed and synthesized as modified VEGFR-2 inhibitors of our previous work.

Language: Английский

Citations

63
New quinoxaline-based VEGFR-2 inhibitors: design, synthesis, and antiproliferative evaluation with in silico docking, ADMET, toxicity, and DFT studies DOI Creative Commons
Mohammed M. Alanazi, Hazem Elkady, Nawaf A. Alsaif

et al.

RSC Advances, Journal Year: 2021, Volume and Issue: 11(48), P. 30315 - 30328

Published: Jan. 1, 2021

A new series of 3-methylquinoxaline-based derivatives having the same essential pharmacophoric features as VEGFR-2 inhibitors have been synthesized and evaluated for their antiproliferative activities against two human cancer cell lines, MCF-7 HepG-2. Compounds 15b 17b demonstrated a significant effect with IC50 ranging from 2.3 to 5.8 μM. An enzymatic assay was carried out all tested candidates VEGFR-2. Compound most potent inhibitor (IC50 = 2.7 nM). Mechanistic investigation including cycle arrest apoptosis performed compound HepG-2 cells, results revealed that induced arrested in G2/M phase. Moreover, analyses were conducted evaluate its apoptotic potential. The showed upregulation caspase-3 caspase-9 levels, improving Bax/Bcl-2 ratio by more than 10-fold. Docking studies determine possible interaction active site. Further docking cytochrome P450 present such compounds non-inhibitors. In silico ADMET, toxicity, physico-chemical properties members acceptable values drug-likeness. Finally, DFT calculate thermodynamic, molecular orbital electrostatic potential properties.

Language: Английский

Citations

58
New quinoline and isatin derivatives as apoptotic VEGFR-2 inhibitors: design, synthesis, anti-proliferative activity, docking, ADMET, toxicity, and MD simulation studies DOI Creative Commons
Eslam B. Elkaeed, Mohammed S. Taghour,

Hazem A. Mahdy

et al.

Journal of Enzyme Inhibition and Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 37(1), P. 2191 - 2205

Published: Aug. 16, 2022

New quinoline and isatin derivatives having the main characteristics of VEGFR-2 inhibitors was synthesised. The antiproliferative effects these compounds were estimated against A549, Caco-2, HepG2, MDA-MB-231. Compounds 13 14 showed comparable activities with doxorubicin Caco-2 cells. These strongly inhibited kinase activity. cytotoxic evaluated Vero Compound 7 highest value safety selectivity. Cell migration assay displayed ability compound to prevent healing abilities in cancer Furthermore, induced apoptosis through expressive down-regulation apoptotic genes, Bcl2, Bcl-xl, Survivin, upregulation TGF gene. Molecular docking emerged interactions synthesised a similar way sorafenib. Additionally, seven molecular dynamics simulations studies applied confirmed stability active pocket over 100 ns.

Language: Английский

Citations

56
Multi-Step In Silico Discovery of Natural Drugs against COVID-19 Targeting Main Protease DOI Open Access
Eslam B. Elkaeed, Fadia S. Youssef, Ibrahim H. Eissa

et al.

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(13), P. 6912 - 6912

Published: June 21, 2022

In continuation of our antecedent work against COVID-19, three natural compounds, namely, Luteoside C (130), Kahalalide E (184), and Streptovaricin B (278) were determined as the most promising SARS-CoV-2 main protease (Mpro) inhibitors among 310 naturally originated antiviral compounds. This was performed via a multi-step in silico method. At first, molecular structure similarity study done with PRD_002214, co-crystallized ligand Mpro (PDB ID: 6LU7), favored thirty Subsequently, fingerprint respect to PRD_002214 resulted election sixteen compounds (7, 128, 130, 156, 157, 158, 180, 184, 203, 204, 210, 237, 264, 276, 277, 278). Then, results docking versus PDB 6LU7 eight (128, 278) based on their binding affinities. toxicity studies for revealed that all them have good profiles. Finally, dynamic (MD) simulation experiments carried out 278, which exhibited best modes Mpro. MD tests luteoside (130) has greatest potential inhibit protease.

Language: Английский

Citations

54
Modified Benzoxazole-Based VEGFR-2 Inhibitors and Apoptosis Inducers: Design, Synthesis, and Anti-Proliferative Evaluation DOI Creative Commons
Alaa Elwan, Abdallah E. Abdallah,

Hazem A. Mahdy

et al.

Molecules, Journal Year: 2022, Volume and Issue: 27(15), P. 5047 - 5047

Published: Aug. 8, 2022

This work is one of our efforts to discover potent anticancer agents. We modified the most promising derivative previous concerned with development VEGFR-2 inhibitor candidates. Thirteen new compounds based on benzoxazole moiety were synthesized and evaluated against three human cancer cell lines, namely, breast (MCF-7), colorectal carcinoma (HCT116), hepatocellular (HepG2). The also kinase activity. biological testing fallouts showed that compound

Language: Английский

Citations

46
The Assessment of Anticancer and VEGFR-2 Inhibitory Activities of a New 1H-Indole Derivative: In Silico and In Vitro Approaches DOI Open Access
Eslam B. Elkaeed, Reda G. Yousef, Hazem Elkady

et al.

Processes, Journal Year: 2022, Volume and Issue: 10(7), P. 1391 - 1391

Published: July 17, 2022

Corresponding to the reported features of anti-VEGFR-2-approved compounds, a new 1H-indole derivative (compound 7) was designed. The inhibitory potential designed compound revealed via molecular docking study that showed appropriate binding. Then, MD simulation (six studies) over period 100 ns performed confirm precise binding and optimum energy. Additionally, MM-GBSA reaffirmed perfect binding, exhibiting total energy −40.38 Kcal/Mol. experiments named essential amino acids in protein–ligand interaction, employing decomposition revealing diversity interactions 7 inside VEGFR-2 enzyme. As is new, DFT were utilized for structure optimization. results validated coherent interaction with A good value drug-likeness acknowledged silico ADMET studies. Interestingly, experimental vitro prohibitory better than sorafenib, demonstrating an IC50 25 nM. Notably, strong effects 10 against two cancer cell lines (MCF-7 HCT 116) established values 12.93 11.52 μM, disclosing high selectivity indexes 6.7 7.5, respectively.

Language: Английский

Citations

45