Screening of Multitarget-Directed Natural Compounds as Drug Candidates for Alzheimer’s Disease Using In Silico Techniques: Their Extraction and In Vitro Validation DOI Creative Commons

Sukriti Srivastava,

Shilpa Sharma, Shashank Deep

et al.

ACS Omega, Journal Year: 2023, Volume and Issue: 8(41), P. 38118 - 38129

Published: Oct. 3, 2023

Alzheimer's disease (AD) is a neurodegenerative disorder that impairs neurocognitive function. Acetylcholinesterase (AChE) and β-site APP cleaving enzyme 1 (BACE1) are the two main proteins implicated in AD. Indeed, major available commercial drugs (donepezil, rivastigmine, galantamine) against AChE inhibitors. However, none of these known to reverse or reduce pathophysiological condition since there multiple contributing factors Therefore, need develop multitarget-directed ligand approach for its treatment. In present study, plant bioactive compounds were screened their BACE1 inhibition potential by conducting molecular docking studies. Considering score pharmacokinetic properties, limonin, peimisine, serratanine B, withanolide A selected as lead compounds. Molecular dynamics simulations protein-ligand complexes confirmed conformational energetically stabilized enzyme-inhibitor complexes. The was validated vitro assay. Withanolide inhibited (IC50 value 107 μM) showed mixed-type inhibition. At this concentration, it activity 57.10% stated most effective. Both compounds, well crude extracts, found have no cytotoxic effect on SH-SY5Y cell line.

Language: Английский

Synthesis of New Organoselenium-Based Succinanilic and Maleanilic Derivatives and In Silico Studies as Possible SARS-CoV-2 Main Protease Inhibitors DOI Creative Commons
Saad Shaaban, Yasair S. Al‐Faiyz, Ghayah M. Alsulaim

et al.

Inorganics, Journal Year: 2023, Volume and Issue: 11(8), P. 321 - 321

Published: July 29, 2023

Herein we report the synthesis of organic selenide-based maleanilic and succinanilic acids in good yields (up to 95%). Their structural identities were elucidated by spectroscopic techniques (e.g., IR, 1H- & 13C-NMR, MS). The ADMET analysis, molecule electrostatic potential map, DFT, frontier molecular orbital used study organoselenium compounds’ pharmacokinetics, drug-likeness characteristics, geometries, chemical electronic properties. Moreover, a docking tool was employed investigate selenides’ ability inhibit SARS-CoV-2 Mpro target (PDB: 7BFB). Within this context, selenides exhibited promising binding affinities receptor following order (12 > 11 10 9 7 8). Furthermore, dynamics simulations also carried out for 200 ns evaluate exact behavior most active compound (12) within pocket compared with its co-crystallized inhibitor (Co).

Language: Английский

Citations

53
Synthesis, structural characterization, DFT calculations, molecular docking, and molecular dynamics simulations of a novel ferrocene derivative to unravel its potential antitumor activity DOI

Mohamed M. Hammoud,

Muhammad Khattab,

Marwa Abdel‐Motaal

et al.

Journal of Biomolecular Structure and Dynamics, Journal Year: 2022, Volume and Issue: unknown, P. 1 - 18

Published: June 8, 2022

In this article, we describe a set of subsequent five-steps chemical reactions to synthesize ferrocene derivative named 1-(5-(diphenylphosphaneyl)cyclopenta-1,3-dien-1-yl)ethyl)imino)-1,3-dihydroisobenzofuran-5-yl)methanol (compound 10). Structural characterization 10 and its intermediate products was also performed reported attest their formation. A molecular docking study propose the novel synthesized (10) as potential antitumor candidate targeting mitogen-activated protein (MAP) kinases interacting kinase (Mnk) 1. The computed score at -9.50 kcal/mol compared native anticancer staurosporine -8.72 postulated promising activity. Also, dynamics (MD) simulations were carried out for 500 ns followed by MM-GBSA-binding free energy calculations both docked complexes give more deep insights into dynamic behavior in physiological conditions. Furthermore, DFT unravel some physiochemical characteristics (10). quantum mechanics shed light on structural electrochemical configurations which would open horizon further investigation. HighlightsThe synthesis 10) described.Structural characterizations performed.DFT calculations, docking, dynamics, MM-GBSA out.Computational studies revealed through inhibiting 1.Communicated Ramaswamy H. Sarma.

Language: Английский

Citations

52
Ligand-Based Design on the Dog-Bone-Shaped BIBR1532 Pharmacophoric Features and Synthesis of Novel Analogues as Promising Telomerase Inhibitors with In Vitro and In Vivo Evaluations DOI
Ahmed A. Al‐Karmalawy, Mohamed S. Nafie, Moataz A. Shaldam

et al.

Journal of Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 66(1), P. 777 - 792

Published: Dec. 16, 2022

Telomerase is an outstanding biological target for cancer treatment. BIBR1532 a non-nucleoside selective telomerase inhibitor; however, it experiences ineligible pharmacokinetics. Herein, we aimed to design new BIBR1532-based analogues as promising inhibitors. Therefore, two novel series of pyridazine-linked cyclopenta[b]thiophene (8a-f) and tetrahydro-1-benzothiophene (9a-f) were synthesized. A quantitative real-time polymerase chain reaction was utilized investigate the inhibitory activity candidates. Notably, 8e 9e exhibited best inhibition profiles. Moreover, showed strong antitumor effects against both MCF-7 A549 cell lines. The on cycle apoptosis measured. Besides, evaluated its in vivo using solid Ehrlich carcinoma. reduction tumor weight volume greater than doxorubicin. Also, molecular docking ADME studies performed. Finally, SAR study conducted gain further insights into different potentials upon variable structural modifications.

Language: Английский

Citations

43
Anticoagulants as Potential SARS-CoV-2 Mpro Inhibitors for COVID-19 Patients: In Vitro, Molecular Docking, Molecular Dynamics, DFT, and SAR Studies DOI Open Access
Ayman Abo Elmaaty, Wagdy M. Eldehna, Muhammad Khattab

et al.

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(20), P. 12235 - 12235

Published: Oct. 13, 2022

In this article, 34 anticoagulant drugs were screened in silico against the main protease (Mpro) of SARS-CoV-2 using molecular docking tools. Idraparinux, fondaparinux, eptifibatide, heparin, and ticagrelor demonstrated highest binding affinities towards Mpro. A dynamics study at 200 ns was also carried out for most promising anticoagulants to provide insights into dynamic thermodynamic properties compounds. Moreover, a quantum mechanical conducted which helped us attest some findings. biological evaluation (in vitro) compounds performed by carrying MTT cytotoxicity assay crystal violet order assess inhibitory concentration 50 (IC50). It is worth noting that displayed intrinsic potential inhibition with an IC50 value 5.60 µM safety index 25.33. addition, fondaparinux sodium dabigatran showed activities values 8.60 9.40 µM, respectively, indexes 17.60 15.10, respectively. Mpro enzyme investigated utilizing tipranavir as reference standard. Interestingly, attained 2.36 surpassing (IC50 = 7.38 µM) more than three-fold. Furthermore, highly eligible 10.59 µM. Finally, SAR discussed, counting on findings both vitro approaches.

Language: Английский

Citations

42
Design and synthesis of novel benzoazoninone derivatives as potential CBSIs and apoptotic inducers: In Vitro, in Vivo, molecular docking, molecular dynamics, and SAR studies DOI
Mohamed M. Hammouda, Ayman Abo Elmaaty, Mohamed S. Nafie

et al.

Bioorganic Chemistry, Journal Year: 2022, Volume and Issue: 127, P. 105995 - 105995

Published: June 30, 2022

Language: Английский

Citations

41
Metformin ameliorates doxorubicin-induced cardiotoxicity targeting HMGB1/TLR4/NLRP3 signaling pathway in mice DOI
Amany A. Alzokaky, Ahmed A. Al‐Karmalawy, Mohamed A. Saleh

et al.

Life Sciences, Journal Year: 2023, Volume and Issue: 316, P. 121390 - 121390

Published: Jan. 14, 2023

Language: Английский

Citations

25
Rationale design of novel substituted 1,3,5-triazine candidates as dual IDH1(R132H)/ IDH2(R140Q) inhibitors with high selectivity against acute myeloid leukemia: In vitro and in vivo preclinical investigations DOI
Haytham O. Tawfik, Mai H. A. Mousa, Mohamed Y. Zaky

et al.

Bioorganic Chemistry, Journal Year: 2024, Volume and Issue: 149, P. 107483 - 107483

Published: May 21, 2024

Language: Английский

Citations

9
A novel role of Nano selenium and sildenafil on streptozotocin-induced diabetic nephropathy in rats by modulation of inflammatory, oxidative, and apoptotic pathways DOI
Mona F. El-Azab, Ahmed A. Al‐Karmalawy, Samar A. Antar

et al.

Life Sciences, Journal Year: 2022, Volume and Issue: 303, P. 120691 - 120691

Published: June 4, 2022

Language: Английский

Citations

37
Ligand-based design, synthesis, computational insights, andin vitrostudies of novelN-(5-Nitrothiazol-2-yl)-carboxamido derivatives as potent inhibitors of SARS-CoV-2 main protease DOI Creative Commons
Mohamed Elagawany, Ayman Abo Elmaaty,

Ahmed Mostafa

et al.

Journal of Enzyme Inhibition and Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 37(1), P. 2112 - 2132

Published: July 31, 2022

The global outbreak of the COVID-19 pandemic provokes scientists to make a prompt development new effective therapeutic interventions for battle against SARS-CoV-2. A series

Language: Английский

Citations

36
Design, synthesis, biological evaluation, and SAR studies of novel cyclopentaquinoline derivatives as DNA intercalators, topoisomerase II inhibitors, and apoptotic inducers DOI

Mohamed M. Hammoud,

Alaa S. Nageeb,

M.A. Morsi

et al.

New Journal of Chemistry, Journal Year: 2022, Volume and Issue: 46(23), P. 11422 - 11436

Published: Jan. 1, 2022

Novel cyclopentaquinoline derivatives as promising DNA intercalators, topoisomerase II inhibitors, and apoptotic inducers.

Language: Английский

Citations

35