Arquitetura e construção de um peptídeo inibidor de angiogênese em células tumorais.

Abstract

Angiogenesis is an essential event for normal development and homeostasis in the tissues. However, if it is of the pathogenic type it can cause neovascularization, which occurs in diseases such as cancer. This process of neovascularization aids in tumor nutrition and accelerates metastasis. Cancer is a multifactorial disease characterized by exacerbated cell multiplication and it is considered a global public health problem. Rational drug planning, based on the molecular structure of tyrosine kinase receptors, has been the most efficient strategy for the development of drugs in the treatment of various diseases, including cancer. Specifically, inhibition of binding of these receptors to growth factors prevents cell signaling for essential events of tumor progression, such as multiplication, maintenance and survival of cells. The aim of the present work was to construct a peptide capable of specifically binding to the KDR (VEGFR-2) and Midkina (MK) receptor, in silico, with potential to inhibit the action of these proteins, which are essential in the process of tumor angiogenesis. For the development of the peptide were analyzed the models methyl N- (6-propylsulfanyl-1H-benzimidazol-2-yl) carbamate (Albendazole) and methyl N- (6-benzoyl-1H benzimidazol-2-yl) carbamate (Mebendazole), compounds with proven antitumor action and having in their structure a benzimidazole ring. The peptide developed in this work, called KDRIP (Kinase domain receptor receptor inhibitor peptide), was cut from structures deposited in the PDB to meet the topological characteristics of the receptors. In silico experiments for both VEGFR-2 and MK revealed that KDRIP is energetically more favorable than the base templates, leading to an interaction with a greater number of residues of interest than the other inhibitors analyzed. Therefore, the developed peptide represents a potential inhibitor of VEGFR-2 and MK proteins, a drug candidate for the development of more efficient drugs for the treatment of the cancers that these molecules are involved in, which is free of royalties and passive to be patented.