Searching new structural scaffolds for BRAF inhibitors. An
integrative study using theoretical and experimental techniques

J 2019

Searching new structural scaffolds for BRAF inhibitors. An integrative study using theoretical and experimental techniques

CAMPOS, LE; FM GARIBOTTO; E ANGELINA; J KOS; T TOMASIC et al.

Základní údaje

Originální název

Searching new structural scaffolds for BRAF inhibitors. An integrative study using theoretical and experimental techniques

Autoři

CAMPOS, LE; FM GARIBOTTO; E ANGELINA; J KOS; T TOMASIC; N ZIDER; D KIKELJ; Tomáš GONĚC; Pavlína MARVANOVÁ; Petr MOKRÝ; J JAMPILEK; SE ALVAREZ a RD ENRIZ

Vydání

Bioorganic Chemistry, SAN DIEGO, ACADEMIC PRESS INC ELSEVIER SCIENCE, 2019, 0045-2068

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Utajení

není předmětem státního či obchodního tajemství

Impakt faktor

Impact factor: 4.831

Označené pro přenos do RIV

Klíčová slova anglicky

BRAF inhibitors; Virtual screening; Synthesis; Bioassays; Molecular modeling

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 9. 3. 2021 23:43, PharmDr. Tomáš Goněc, Ph.D.

Anotace

V originále

The identification of the V600E activating mutation in the protein kinase BRAF in around 50% of melanoma patients has driven the development of highly potent small inhibitors (BRAFi) of the mutated protein. To date, Dabrafenib and Vemurafenib, two specific BRAFi, have been clinically approved for the treatment of metastatic melanoma. Unfortunately, after the initial response, tumors become resistant and patients develop a progressive and lethal disease, making imperative the development of new therapeutic options. The main objective of this work was to find new BRAF inhibitors with different structural scaffolds than those of the known inhibitors. Our study was carried out in different stages; in the first step we performed a virtual screening that allowed us to identify potential new inhibitors. In the second step, we synthesized and tested the inhibitory activity of the novel compounds founded. Finally, we conducted a molecular modelling study that allowed us to understand interactions at the molecular level that stabilize the formation of the different molecular complexes. Our theoretical and experimental study allowed the identification of four new structural scaffolds, which could be used as starting structures for the design and development of new inhibitors of BRAF. Our experimental data indicate that the most active compounds reduced significantly ERK1/2 phosphorylation, a measure of BRAF inhibition, and cell viability. Thus, from our theoretical and experimental results, we propose new substituted hydroxynaphthalenecarboxamides, N-(hetero)aryl-piperazinylhydroxyalkylphenylcarbamates, substituted piperazinylethanols and substituted piperazinylpropandiols as initial structures for the development of new inhibitors for BRAF. Moreover, by performing QTAIM analysis, we are able to describe in detail the molecular interactions that stabilize the different Ligand-Receptor complexes. Such analysis indicates which portion of the different molecules must be changed in order to obtain an increase in the binding affinity of these new ligands.

Citovat

CAMPOS, LE; FM GARIBOTTO; E ANGELINA; J KOS; T TOMASIC; N ZIDER; D KIKELJ; Tomáš GONĚC; Pavlína MARVANOVÁ; Petr MOKRÝ; J JAMPILEK; SE ALVAREZ a RD ENRIZ. Searching new structural scaffolds for BRAF inhibitors. An integrative study using theoretical and experimental techniques. Bioorganic Chemistry. SAN DIEGO: ACADEMIC PRESS INC ELSEVIER SCIENCE, 2019, roč. 91, 19 s. ISSN 0045-2068. Dostupné z: https://doi.org/10.1016/j.bioorg.2019.103125.

@article{1726949,
   author = {Campos, LE and Garibotto, FM and Angelina, E and Kos, J and Tomasic, T and Zider, N and Kikelj, D and Goněc, Tomáš and Marvanová, Pavlína and Mokrý, Petr and Jampilek, J and Alvarez, SE and Enriz, RD},
   article_location = {SAN DIEGO},
   doi = {https://doi.org/10.1016/j.bioorg.2019.103125},
   keywords = {BRAF inhibitors; Virtual screening; Synthesis; Bioassays; Molecular modeling},
   language = {eng},
   issn = {0045-2068},
   journal = {Bioorganic Chemistry},
   title = {Searching new structural scaffolds for BRAF inhibitors. An integrative study using theoretical and experimental techniques},
   volume = {91},
   year = {2019}
}

TY  - JOUR
ID  - 1726949
AU  - Campos, LE - Garibotto, FM - Angelina, E - Kos, J - Tomasic, T - Zider, N - Kikelj, D - Goněc, Tomáš - Marvanová, Pavlína - Mokrý, Petr - Jampilek, J - Alvarez, SE - Enriz, RD
PY  - 2019
TI  - Searching new structural scaffolds for BRAF inhibitors. An integrative study using theoretical and experimental techniques
JF  - Bioorganic Chemistry
VL  - 91
PB  - ACADEMIC PRESS INC ELSEVIER SCIENCE
SN  - 00452068
KW  - BRAF inhibitors
KW  - Virtual screening
KW  - Synthesis
KW  - Bioassays
KW  - Molecular modeling
N2  - The identification of the V600E activating mutation in the protein kinase BRAF in around 50% of melanoma patients has driven the development of highly potent small inhibitors (BRAFi) of the mutated protein. To date, Dabrafenib and Vemurafenib, two specific BRAFi, have been clinically approved for the treatment of metastatic melanoma. Unfortunately, after the initial response, tumors become resistant and patients develop a progressive and lethal disease, making imperative the development of new therapeutic options. The main objective of this work was to find new BRAF inhibitors with different structural scaffolds than those of the known inhibitors. Our study was carried out in different stages; in the first step we performed a virtual screening that allowed us to identify potential new inhibitors. In the second step, we synthesized and tested the inhibitory activity of the novel compounds founded. Finally, we conducted a molecular modelling study that allowed us to understand interactions at the molecular level that stabilize the formation of the different molecular complexes. Our theoretical and experimental study allowed the identification of four new structural scaffolds, which could be used as starting structures for the design and development of new inhibitors of BRAF. Our experimental data indicate that the most active compounds reduced significantly ERK1/2 phosphorylation, a measure of BRAF inhibition, and cell viability. Thus, from our theoretical and experimental results, we propose new substituted hydroxynaphthalenecarboxamides, N-(hetero)aryl-piperazinylhydroxyalkylphenylcarbamates, substituted piperazinylethanols and substituted piperazinylpropandiols as initial structures for the development of new inhibitors for BRAF. Moreover, by performing QTAIM analysis, we are able to describe in detail the molecular interactions that stabilize the different Ligand-Receptor complexes. Such analysis indicates which portion of the different molecules must be changed in order to obtain an increase in the binding affinity of these new ligands.
ER  -

CAMPOS, LE; FM GARIBOTTO; E ANGELINA; J KOS; T TOMASIC; N ZIDER; D KIKELJ; Tomáš GONĚC; Pavlína MARVANOVÁ; Petr MOKRÝ; J JAMPILEK; SE ALVAREZ a RD ENRIZ. Searching new structural scaffolds for BRAF inhibitors. An integrative study using theoretical and experimental techniques. \textit{Bioorganic Chemistry}. SAN DIEGO: ACADEMIC PRESS INC ELSEVIER SCIENCE, 2019, roč.~91, 19 s. ISSN~0045-2068. Dostupné z: https://doi.org/10.1016/j.bioorg.2019.103125.

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