RESUMEN
Tankyrase (TNKS) enzymes remained central biotargets to treat Wnt-driven colorectal cancers. The success of Olaparib posited the druggability of PARP family enzymes depending on their role in tumor proliferation. In this work, an MD-simulation-based comparative assessment of the protein-ligand interactions using the best-docked poses of three selected compounds (two of the designed and previously synthesized molecules obtained through molecular docking and one reported TNKS inhibitor) was performed for a 500 ns period. The PDB:ID-7KKP and 3U9H were selected for TNKS1 and TNKS2, respectively. The Molecular Mechanics Generalized Born Surface Area (MM-GBSA) based binding energy data exhibited stronger binding of compound-15 (average values of -102.92 and -104.32 kcal/mol for TNKS1 and TNKS2, respectively) as compared to compound-22 (average values of -82.99 and -85.68 kcal/mol for TNKS1 and TNKS2, respectively) and the reported compound-32 (average values of -81.89 and -74.43 kcal/mol for TNKS1 and TNKS2, respectively). Compound-15 and compound-22 exhibited comparable or superior binding to both receptors forming stable complexes when compared to that of compound-32 upon examining their MD trajectories. The key contributors were hydrophobic stacking and optimum hydrogen bonding allowing these molecules to occupy the adenosine pocket by interfacing D-loop residues. The results of bond distance analysis, radius of gyration, root mean square deviation, root mean square fluctuation, snapshots at different time intervals, LUMO-HUMO energy differences, electrostatic potential calculations, and binding free energy suggested better binding efficiency for compound-15 to TNKS enzymes. The computed physicochemical and ADMET properties of compound-15 were encouraging and could be explored further for drug development.Communicated by Ramaswamy H. Sarma.
Asunto(s)
Simulación de Dinámica Molecular , Tanquirasas , Simulación del Acoplamiento Molecular , Tanquirasas/química , Triazoles/farmacologíaRESUMEN
INTRODUCTION: Tankyrase inhibitors gained significant attention as therapeutic targets in oncology because of their potency. Their primary role in inhibiting the Wnt signaling pathway makes them an important class of compounds with the potential to be used as a combination therapy in future treatments of colorectal cancer. AREAS COVERED: This review describes pertinent work in the development of tankyrase inhibitors with a great emphasis on the recently patented TNKS inhibitors published from 2013 to 2020. This article also highlights a couple of promising candidates having tankyrase inhibitory effects and are currently undergoing clinical trials. EXPERT OPINION: Following the successful clinical applications of PARP inhibitors, tankyrase inhibition has gained significant attention in the research community as a target with high therapeutic potential. The ubiquitous role of tankyrase in cellular homeostasis and Wnt-dependent tumor proliferation brought difficulties for researchers to strike the right balance between potency and on-target toxicity. The need for novel tankyrase inhibitors with a better ADMET profile can introduce an additional regimen in treating various malignancies in monotherapy or adjuvant therapy. The development of combination therapies, including tankyrase inhibitors with or without PARP inhibitory properties, can potentially benefit the larger population of patients with unmet medical needs.
Asunto(s)
Antineoplásicos/farmacología , Neoplasias Colorrectales/tratamiento farmacológico , Tanquirasas/antagonistas & inhibidores , Animales , Antineoplásicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Desarrollo de Medicamentos , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/farmacología , Humanos , Patentes como Asunto , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Tanquirasas/metabolismo , Vía de Señalización Wnt/efectos de los fármacosRESUMEN
The synthesis of 1,2,5-trisubstituted benzimidazole derivatives was carried out using liquid phase combinatorial approach using soluble polymer assisted support (PEG5000). Synthesised compounds were characterised by FTIR, ESI-MS, 1H NMR and 13C NMR. The purity of compounds was confirmed with HPLC analysis. Compounds were also docked into the binding site of human dihydroorotate dehydrogenase (hDHODH). The synthesised compounds were screened for hDHODH enzyme inhibition assay using brequinar as standard compound. The synthesised compounds demonstrated comparative biological activity. Synthesised compounds 8d and 8e demonstrated IC50 value of 81±2nM and 97±2nM, respectively.