دورية أكاديمية
أعرض في EDS

Identification of novel αβ-tubulin modulators with antiproliferative activity directed to cancer therapy using ligand and structure-based virtual screening.

التفاصيل البيبلوغرافية
العنوان: Identification of novel αβ-tubulin modulators with antiproliferative activity directed to cancer therapy using ligand and structure-based virtual screening.
المؤلفون: Federico LB; Computational Laboratory of Pharmaceutical Chemistry, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Av. do Café, s/n, Ribeirão Preto, SP 14040-903, Brazil. Electronic address: lbfederico@usp.br., Silva GM; Departamento de Química, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, 14040-901 Ribeirão Preto, SP, Brazil., de Fraga Dias A; Graduate Program in Biological Sciences: Biochemistry, Institute of Health Sciences, Federal University of Rio Grande do Sul, Av. Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS 90035-003, Brazil., Figueiró F; Graduate Program in Biological Sciences: Biochemistry, Institute of Health Sciences, Federal University of Rio Grande do Sul, Av. Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS 90035-003, Brazil; Department of Biochemistry, Institute of Health Sciences, Federal University of Rio Grande do Sul, Av. Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS 90035-003, Brazil., Battastini AMO; Graduate Program in Biological Sciences: Biochemistry, Institute of Health Sciences, Federal University of Rio Grande do Sul, Av. Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS 90035-003, Brazil., Dos Santos CBR; Laboratory of Modeling and Computational Chemistry, Department of Biological and Health Sciences, Federal University of Amapá, Macapá, AP 68902-280, Brazil., Costa LT; MolMod-CS, Institute of Chemistry, Federal Fluminense University, Outeiro de São João Batista, Niterói, Rio de Janeiro, Brazil., Rosa JMC; Department of Pharmaceutical and Organic Chemistry, Faculty of Pharmacy, Institute of Biosanitary Research ibs. GRANADA, University of Granada, 18071, Spain., de Paula da Silva CHT; Computational Laboratory of Pharmaceutical Chemistry, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Av. do Café, s/n, Ribeirão Preto, SP 14040-903, Brazil; Departamento de Química, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, 14040-901 Ribeirão Preto, SP, Brazil.
المصدر: International journal of biological macromolecules [Int J Biol Macromol] 2020 Dec 15; Vol. 165 (Pt B), pp. 3040-3050. Date of Electronic Publication: 2020 Oct 22.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Elsevier Country of Publication: Netherlands NLM ID: 7909578 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1879-0003 (Electronic) Linking ISSN: 01418130 NLM ISO Abbreviation: Int J Biol Macromol Subsets: MEDLINE
أسماء مطبوعة: Publication: Amsterdam : Elsevier
Original Publication: Guildford, Eng., IPC Science and Technology Press.
مواضيع طبية MeSH: Antineoplastic Agents/*pharmacology , Neoplasms/*metabolism , Tubulin/*metabolism , Tubulin Modulators/*pharmacology, Antineoplastic Agents/chemistry ; Binding Sites ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Colchicine/metabolism ; Computer Simulation ; Drug Screening Assays, Antitumor ; Hep G2 Cells ; Humans ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Neoplasms/drug therapy ; Structure-Activity Relationship ; Tubulin/chemistry ; Tubulin Modulators/chemistry
مستخلص: Among several strategies related to cancer therapy targeting the modulation of αβ-tubulin has shown encouraging findings, more specifically when this is achieved by inhibitors located at the colchicine binding site. In this work, we aim to fish new αβ-tubulin modulators through a diverse and rational VS study, and thus, exhibiting the development of two VS pipelines. This allowed us to identify two compounds 5 and 9 that showed IC 50 values of 19.69 and 21.97 μM, respectively, towards possible modulation of αβ-tubulin, such as assessed by in vitro assays in C6 glioma and HEPG2 cell lines. We also evaluated possible mechanisms of action of obtained hits towards the colchicine binding site of αβ-tubulin by using docking approaches. In addition, assessment of the stability of the active (5 and 9) and inactive compounds (3 and 13) within the colchicine binding site was carried out by molecular dynamics (MD) simulations, highlighting the solvent effect and revealing the compound 5 as the most stable in the complex. At last, deep analysis of these results provided some valuable insights on the importance of using mixed ligand- and structure-based strategies in VS campaigns, in order to achieve higher chemical diversity and biological effect as well.
Competing Interests: Declaration of competing interest All authors declare no conflict of interest.
(Copyright © 2020 Elsevier B.V. All rights reserved.)
فهرسة مساهمة: Keywords: ADME/Tox; Antiproliferative activity; Cancer; Docking; Ligand-based drug design; Tubulin modulators; Virtual screening
المشرفين على المادة: 0 (Antineoplastic Agents)
0 (Tubulin)
0 (Tubulin Modulators)
SML2Y3J35T (Colchicine)
تواريخ الأحداث: Date Created: 20210319 Date Completed: 20210727 Latest Revision: 20210727
رمز التحديث: 20221213
DOI: 10.1016/j.ijbiomac.2020.10.136
PMID: 33736292
قاعدة البيانات: MEDLINE
الوصف
تدمد:1879-0003
DOI:10.1016/j.ijbiomac.2020.10.136