Aug 2026· Current Medicinal Chemistry· Vol 33· 0 citations
Medicine
TL;DR
Overall, compound B2 emerged as a promising PARP1 inhibitor with strong binding affinity, structural stability, and significant in vitro anticancer activity, warranting further optimization and preclinical investigation.
Abstract
INTRODUCTION
The objective was to design, synthesize, and evaluate novel naphthoxy and phenoxy amide derivatives as potential poly(ADP-ribose) polymerase-1 (PARP1) inhibitors, aiming to identify compounds with improved binding affinity, favorable pharmacokinetic properties, and enhanced anticancer activity compared with existing PARP1 inhibitors.
Methods
A series of naphthoxy and phenoxy amide derivatives (A1-A9 and B1-B9) were evaluated using combined computational and experimental approaches. Molecular docking against PARP1 (PDB ID: 4ZZZ) was performed using Glide to assess binding affinity. ADMET and drug-likeness properties were predicted via SWISS-ADME, and binding free energies were refined using Prime MM-GB/SA. The lead compound B2 underwent a 50-ns molecular dynamics simulation using Desmond. In vitro cytotoxicity was assessed against MCF-7 human breast cancer cell lines.
Results
Compounds B2 and B3 exhibited strong docking scores comparable to the reference PARP1 inhibitor and demonstrated favourable ADMET profiles. MM-GB/SA analysis supported their high binding affinity toward PARP1. Molecular dynamics simulations revealed that compound B2 formed a stable complex within the PARP1 active site. In vitro assays showed enhanced cytotoxic activity of B2 against MCF-7 cells.
Discussion
The findings highlight the effectiveness of combining computational and biological approaches to identify promising PARP1 inhibitors, with B2 showing strong binding, stability, and cytotoxicity, despite lacking in vivo validation.
Conclusion
Overall, compound B2 emerged as a promising PARP1 inhibitor with strong binding affinity, structural stability, and significant in vitro anticancer activity, warranting further optimization and preclinical investigation.
The present work describes the synthesis, molecular docking, and preliminary anticancer evaluation of a hybrid compound, product-
C
composed of a fluorinated sulfur heterocyclic core and an adamantane moiety. The synthesis method was designed to tune the electronic, lipophilic and structural properties of the compound through the introduction of CF₃, F and Cl functional groups, which are well known for the improving metabolic stability, physicochemical properties and drug-likeness. The structure of the synthesized compound was confirmed by
1
H and
13
C nuclear magnetic resonance (NMR) spectra. Molecular docking against phosphoinositide 3-kinase (PI3K), a protein target implicated in multiple cancers, showed that product-
C
exhibited a binding affinity of -10.6 kcal/mol, suggesting favorable interaction with the target. In parallel, the SRB (Sulforhodamine B) assay was used to evaluate the cytotoxicity of product-
C
toward PANC-1 cells. Preliminary results showed cell viabilities of 98.86% and 95.55% after exposure to 10 μM and 100 μM of product-
C
, respectively. These findings indicate that product-
C
displays low cytotoxicity toward PANC-1 cells under the tested conditions; however, they do not by themselves demonstrate marked antiproliferative activity.
M. Alamri, Yassine Riadi, A. Altharawi et al.· Arabian Journal of Chemistry· 0 citations
Oxidative stress is a key driver of the pathogenesis of numerous chronic inflammatory and metabolic diseases emphasizing the requirement for the development of potent and selective antioxidant therapeutics. In present study, a series of novel piperazine-linked 1,3,5-triazine derivatives (6a-h) was rationally designed, synthesised and evaluated for antioxidant activity using integrated computational and experimental approaches. Molecular docking studies were carried out against myeloperoxidase (MPO; PDB ID: 1DNU), a heme-containing enzyme involved in reactive oxygen species (ROS) generation, to examine ligand–protein interactions and binding affinities. The synthesized compounds exhibited binding energies ranging from -3.816 to -4.987 kcal/mol. Among them, compound 6f, bearing a para-fluorophenyl substituent, shows the highest binding affinity (-4.987 kcal/mol). The enhanced binding was attributed to the formation of two hydrogen bonds with ARG27 and LEU97 and exceeded the binding energy of the reference antioxidant, ascorbic acid (-4.690 kcal/mol). The antioxidant potential was assessed by the DPPH free radical scavenging assay. Compound 6f displayed the strongest activity with an IC50 value of 14.15 ± 0.14 µM, which was comparable to that of ascorbic acid (IC50 = 14.06 ± 0.18 µM). Structure-activity relationship analysis indicated that the electron-withdrawing substituents at the para-position of aryl ring, together with nitrogen-containing heteroaromatic moieties, improve both binding affinity and free radical scavenging activity. The results identify piperazine-linked 1,3,5-triazine derivatives as promising antioxidant scaffolds and provide a strong basis for future myeloperoxidase inhibition studies and in vivo pharmacological evaluation.
Nitesh Diyora, N. Parekh· Asian Journal of Chemistry· 0 citations
Genistein and hematoxylin demonstrate promising molecular interactions and pharmacological profiles as potential natural RR inhibitors and supports further preclinical development as anticancer agents.
Oun Deli Khudhair, Muhammad Azrul Zabidi, A. M. Gazzali et al.· Current Computer - Aided Dru...· 0 citations
Structural–activity relationship analysis revealed the importance of the TZD core, electron-rich aromatic moieties, and balanced lipophilicity for enhanced anticancer activity, identifying TZD hybrids as promising EGFR-targeted anticancer leads.
Rajyalaxmi Injamuri, D. Makula· International journal of res...· 0 citations
In this study, due to the side effect profiles and low efficacy of currently used inhibitors, novel benzimidazole-oxadiazole derivatives (6a–6e, 7a–7e) were synthesized as dual inhibitors of α-GLY and AR. Their structures were elucidated using 13C-NMR and 1H-NMR techniques. Their binding properties were investigated by molecular docking studies, and their ADME properties were screened in silico. AR and α-GLY inhibitory effects of the synthesized compounds were examined. The compounds were observed to exhibit partially similar inhibitory effects to the reference drug epalrestate (IC50: 0.78 nM; KI: 0.74 ± 0.0 nM) on AR inhibition. Among them, compounds 6a, 6b, and 6c showed the highest activity with KI values of 8.6 ± 0.4, 3.5 ± 0.3 and 6.3 ± 0.5 nM, respectively. Compounds 6a and 7e were found to have higher inhibitory activity against the α-GLY enzyme than the reference drug Acarbose (IC50: 128.4 µM; KI: 96.2 ± 5.7 µM) with KI values of 5.8 ± 0.4 and 7.9 ± 0.8 µM, respectively. Overall, the newly synthesized compounds demonstrated pronounced AR inhibitory activity and notable α-GLY inhibition. Nevertheless, further pharmacological and toxicity evaluations are required to confirm their therapeutic potential. Among the tested molecules, compounds 6a and 7e may therefore be considered potential candidates for further investigation as anti-diabetic agents.
Mesut Işık, Abdüllatif Karakaya, U. A. Çevik et al.· Molecules· 0 citations
Development of safer and more effective anti-inflammatory agents remains a significant challenge. Peptide-based conjugates have attracted increasing attention as alternative therapeutic strategies, owing to their enhanced selectivity and potentially improved safety profiles. In the present study, a combined computational and experimental approach was employed to investigate a series of novel dipeptide–coumarin conjugates as candidate anti-inflammatory agents. A series of rationally designed dipeptides conjugated with coumarin-3-carboxylic acid was first evaluated through molecular docking to estimate their binding affinity toward cyclooxygenase-2 (COX-2). Their pharmacokinetic and toxicity properties were further predicted using ADMETLab 3.0. Compounds showing favorable profiles were synthesized via solid-phase peptide synthesis (SPPS) and characterized by 1H NMR, 13C NMR, and ESI-MS analyses. Anti-inflammatory activity was initially assessed using the albumin denaturation assay. Based on these findings, the most promising compound (C011) was selected for further investigation. Its cytotoxicity was evaluated using an MTT assay on normal human cell lines prior to in vivo studies. Subsequently, C011 was tested in a formaldehyde-induced paw edema model in rats, followed by hematological, histopathological, and behavioral evaluations. Docking analysis revealed consistently favorable binding affinities among the designed compounds, with C011 (VA–coumarin) exhibiting the strongest interaction (ΔG = −9.73 kcal mol−1), exceeding that of the reference drug ketoprofen. In vitro screening confirmed its notable anti-inflammatory activity, supporting its selection for further studies. The MTT assay demonstrated acceptable cytocompatibility at the tested concentrations, supporting the continued evaluation of C011 in subsequent in vivo studies. In vivo evaluation further validated these findings, as C011 produced a significant and dose-dependent reduction in paw edema and inflammatory responses. Notably, treatment with the higher dose resulted in a marked decrease in white blood cell count and key inflammatory indices, including the neutrophil-to-lymphocyte ratio (NLR) and systemic immune-inflammation index (SII). These findings were further supported by histopathological observations and behavioral assessments, which demonstrated anti-inflammatory and analgesic effects while indicating no severe treatment-related tissue injury under the experimental conditions employed. Collectively, these findings identify C011 as a promising peptide-based scaffold for anti-inflammatory drug development. The study highlights the effectiveness of a stepwise evaluation strategy that integrates computational design with in vitro screening, preliminary safety assessment, and in vivo validation. Further studies are required to clarify the molecular mechanisms underlying the anti-inflammatory activity and to establish the long-term safety profile of C011.
S. J. Hamid, T. Salih, T. Aziz· RSC Advances· 0 citations
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