Simulação e avaliação de ancoramento molecular do Metabólitoazadiractina à Proteína Hidrofolato Redutase.

Abstract

The Candida genus is the main group of yeasts that cause opportunistic infections in human beings, with around 200 different species. Facing this, the use of computational biology and the application of its tools are indispensable to the advance on the production of new drugs with higher efficiency and reduced demanded time and value. The inhibition of the folate metabolism is an important strategy on treatments of infectious diseases. On the metabolic pathway of folate, the enzyme dihydrofolate reductase (DHFR) catalyzes the reduction of dihydrofolate into tetrahydrofolate. This metabolite is essential to the biosynthesis of DNA and proteins. Therefore, the development of new antagonist of dihydrofolate reductase have been considered a good strategy to optimize the treatment of infectious diseases. On this perspective, the present work aimed to analyze the molecular anchoring of the protein dihydrofolate reductase of Candida albicans with the ligand azadiractine in order to study its inhibitory potential facing said protein,

exploring a possible new interaction or specific molecular target. On this wise, in silico protein- ligand experiments were done on Autodock 4.6, resulting in a direct interaction of Azadiractine

with the active site of DHFR. The estimated data in the calculations revealed expressively negative values, for the free energy of binding, they ranged from -1.21 kcal/mol, on complex 1, to -1.45 kcal/mol, on complex 10, while for the intermolecular energy they ranged from -5.08 to -9.43. In sequence, the inhibition constants (KI) ranged from 80,35 uM to 894,54 μM. Azadirachtin is a weak inhibitor due to KI values, even if it binds directly to the active site of the protein.