Multi-stage structure-based virtual screening approach combining 3D pharmacophore, docking and molecular dynamic simulation towards the identification of potential selective PARP-1 inhibitors

BMC Chemistry, Год журнала: 2025, Номер 19(1)

Опубликована: Фев. 1, 2025

Abstract Presently, humanity is confronted with a range of diseases that have high death rates, especially those linked to cancerous growths. Several enzymes and proteins been discovered as highly attractive targets for cancer treatment. The PARP family consists 17 members plays crucial role in repairing DNA damage, which enables the survival cells. PARP-1 and, lesser extent, PARP-2 display above 90% activity response thereby distinguishing them apart from other family. Elevated levels were observed many types tumor cells, such breast, lung, ovarian, prostate, melanomas. In an attempt provide future guide developing selective inhibitors over minimize resulting side effects inhibitors, we constructed structure-based virtual screening approach (SBVS). Firstly. A 3D pharmacophore was based on interaction inhibitor compound IV . After that, database nearly 450,000 phthalimide-containing screened through validated pharmacophore, 165 compounds retrieved. retrieved docked into active site where only 5 MWGS-1-5 achieved favorable docking score than reference (-16.8 Kcal/mol). Redocking five should excellent selectivity PARP-2, MWGS-1 Further endorsement via molecular dynamics has proven higher affinity towards PARP-1- RMSD values 1.42 2.8 Å, respectively.

Язык: Английский

---

Development of novel amino-benzenesulfonamide derivatives and their analogues as carbonic anhydrase inhibitors: Design, synthesis, anticancer activity assessment, and pharmacokinetic studies using UPLC-MS/MS

Bioorganic Chemistry, Год журнала: 2025, Номер 159, С. 108335 - 108335

Опубликована: Март 6, 2025

Язык: Английский

---

Investigation on Human Carbonic Anhydrase IX and XII Inhibitory Activity and A549 Antiproliferative Activity of a New Class of Coumarinamides

Pharmaceuticals, Год журнала: 2025, Номер 18(3), С. 372 - 372

Опубликована: Март 5, 2025

Background—Aggressive solid tumors are commonly characterized by both basic intracellular pH and acidic extracellular pH, which increase cell survival proliferation. As carbonic anhydrases IX/XII involved in this regulation, their inhibition is an appealing approach cancer therapy, avoiding Substituted coumarins selective non-classical CA IX XII inhibitors. Methods—In study, new 7-hydroxycoumarinamides were synthesized assayed for antiproliferative activity. Results—All of the coumarinamides showed human over off-target I II isoforms. Coumarin acts as a suicide inhibitor because its heterocyclic ring can be hydrolyzed esterase activity to give corresponding 2-hydroxycinnamic acid derivative blocks entrance active site. The derivatives deriving from most potent docked into better understand selectivity against two also produced decrease A549 proliferation able arrest cells at G1/S checkpoint. Conclusions—These results may open perspectives developing coumarin-based

Язык: Английский

---

Design, synthesis and biological evaluation of pyrazolo[3,4- b ]pyridine derivatives as dual CDK2/PIM1 inhibitors with potent anti-cancer activity and selectivity

Journal of Biomolecular Structure and Dynamics, Год журнала: 2025, Номер unknown, С. 1 - 25

Опубликована: Март 13, 2025

The discovery of novel, selective inhibitors targeting CDK2 and PIM1 kinases, which regulate cell survival, proliferation, treatment resistance, is crucial for advancing cancer therapy. This study reports the design, synthesis, biological evaluation three novel pyrazolo[3,4-b]pyridine derivatives (6a-c), confirmed via spectral analyses. These compounds were assessed anti-cancer activity against breast, colon, liver, cervical cancers using MTT assay. Among tested compounds, 6b exhibited superior efficacy, with higher selectivity indices HCT-116 (15.05) HepG2 (9.88) compared to reference drug staurosporine. Mechanistic studies revealed that induced apoptosis (63.04-fold increase) arrested cycle at G0-G1 phase, highlighting its anti-proliferative effects. In an in-vivo solid Ehrlich carcinoma (SEC) mouse model, compound significantly reduced tumor weight volume, exceeding efficacy doxorubicin. Additionally, potently inhibited kinases (IC50: 0.27 0.67 µM, respectively) tumor-promoting TNF-alpha expression, as by histopathological immunohistochemical studies. Computational analyses, including molecular docking, dynamics simulations, DFT calculations, provided insights into binding stability interaction mechanisms PIM1, while in-silico pharmacokinetic toxicity evaluations favorable drug-like profile safety. highlights a promising dual CDK2/PIM1 inhibitor potent selectivity, paving way further optimization development lead molecule in

Язык: Английский

---

Discovery of 1-phenyl-1,2,3-triazole ureas as dual VEGFR-2/JNK-1 type II kinase inhibitors targeting pancreatic cancer

International Journal of Biological Macromolecules, Год журнала: 2025, Номер unknown, С. 142372 - 142372

Опубликована: Март 1, 2025

Язык: Английский

---

Novel Benzenesulfonamide Derivatives Linked to Diaryl Pyrazole Tail as Potential Carbonic Anhydrase II/VII Inhibitors with Anti-epileptic Activity

European Journal of Medicinal Chemistry, Год журнала: 2025, Номер unknown, С. 117619 - 117619

Опубликована: Апрель 1, 2025

Язык: Английский

---

Shooting an Arrow against Convulsion: Novel Triazole-Grafted Benzenesulfonamide Derivatives as Carbonic Anhydrase II and VII Inhibitors

Journal of Medicinal Chemistry, Год журнала: 2025, Номер unknown

Опубликована: Апрель 16, 2025

This study investigates new anticonvulsant substances that target the epilepsy-associated carbonic anhydrase isoforms II and VII. The 1,2,3-triazole with a benzenesulfonamide motif is present in produced molecules. Of these, 5b 5c exhibited remarkable selectivity inhibitory efficacy toward hCA VII over I. KI values of were 6.3 10.1 nM, respectively, 21.6 18.9 respectively. In pilocarpine-induced paradigm, vivo assessments showed decreased seizure severity susceptibility delayed onset diminished intensity. quick absorption stability demonstrated by pharmacokinetic investigations. Evaluations toxicity no neurotoxic effects high safety margin (LD50 > 2000 mg/kg). Mechanistic research has shown effectiveness maintaining neuronal integrity, reducing mTOR activation, raising hippocampus KCC2 levels. Compound 5b's binding interactions clarified docking dynamics experiments.

Язык: Английский

---

Novel benzofuran-conjugated indolin-2-ones as anticancer agents; design, synthesis, biological assessments, and molecular modeling insights

Bioorganic Chemistry, Год журнала: 2025, Номер unknown, С. 108494 - 108494

Опубликована: Апрель 1, 2025

Язык: Английский

---

Development of isatin-functionalized benzenesulfonamides as novel Carbonic Anhydrase II and VII Inhibitors with Antiepileptic Potential

European Journal of Medicinal Chemistry, Год журнала: 2025, Номер unknown, С. 117706 - 117706

Опубликована: Апрель 1, 2025

Язык: Английский

---