Orientador: Prof. Dr. Maurício Domingues Coutinho Neto / Tese (doutorado) - Universidade Federal do ABC. Programa de Pós-Graduação em Ciência e Tecnologia/Química, 2015. / The theoretical study of the interaction between biomolecules that interact with DNA
has been growing in recent years. Understanding the mechanism of action of these
biomolecules in the process of intercalation with DNA is of fundamental importance in the
development of new drugs for the treatment of genetic and parasites diseases. Among these
diseases, malaria is one of the most important worldwide and is caused by a protozoan
parasite. The resistance of plasmodium P. falciparum, which causes the most severe form
of the disease to antimalarial drugs, has become a growing problem and the search for
more effective drugs is urgent. Many of these drugs interact with DNA by intercalation
process mediated mainly by dispersion interactions that contribute significantly to the
stability of the complex intercalator-DNA. With this idea, we propose to investigate
theoretically the interactions that occur between an antimalarial drug, the cryptolepine
and its derivatives, when intercalated between base pairs of DNA by means of first principles
methods based on Density Functional Theory and classical molecular dynamics methods.
The dispersion effects were included in the DCACP approach ( Dispersion Correct-Atom
Centered Potentials). In the classical approach, we used specific force fields such as
ff99bsc0 and GAFF for the treatment and quality of intercalation energy. The DCACP
results showed that the cryptolepine interacts strongly with DNA, whose the interaction
energy was -38.6 kcal/mol. Furthermore, the cryptolepine intercalation preference between
non-alternating CG sites was confirmed by more stable configuration energy in the crystal.
The free intercalation energy of drug calculated by molecular dynamics was about -30
kcal/mol showing that this process can be energetically favorable. The cryptolepine has a
potent in vitro activity against malaria parasites in addition to being the first of a class of
intercalating agents preferably having a intercalation sites of the DNA cytosine-guanine by
a non-alternating and parallel intercalation mode. This suggests that this new intercalating
process should lead to the development of new drugs against malaria and the theoretical
study proposed in this work can assist in the design of experimental work.
| Identifer | oai:union.ndltd.org:IBICT/oai:BDTD:77142 |
| Date | January 2015 |
| Creators | Fontineles, Tancredo Augusto de Carvalho |
| Contributors | Coutinho Neto, Maurício Domingues, Cordeiro, Rodrigo Maghdissian, Honório, Káthia Maria, Amorim, Rodrigo Garcia, Dias, Luis Gustavo |
| Source Sets | IBICT Brazilian ETDs |
| Language | Portuguese |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, info:eu-repo/semantics/doctoralThesis |
| Format | application/pdf, 125 f. : il. |
| Source | reponame:Repositório Institucional da UFABC, instname:Universidade Federal do ABC, instacron:UFABC |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | http://biblioteca.ufabc.edu.br/index.php?codigo_sophia=77142&midiaext=70496, http://biblioteca.ufabc.edu.br/index.php?codigo_sophia=77142&midiaext=70495, Cover: http://biblioteca.ufabc.edu.brphp/capa.php?obra=77142 |
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