Docking studies of potential bioactive compounds in the expressive reduction of human type ii 5-alpha-reductase activity

• Grant number: 21/03696-2
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: October 01, 2021
• End date: September 30, 2022
• Field of knowledge: Biological Sciences - Biophysics - Molecular Biophysics
• Principal Investigator: Kathia Maria Honorio
• Grantee: Luis Felipe Marques Ambrogi
• Host Institution: Escola de Artes, Ciências e Humanidades (EACH). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Although there are inhibitors of 5-alpha-reductases activity in the drug market, the search for other compounds with the same attribute is still constant, in particular in the fields of study based on the potentiation of the inhibitory effect for these enzymes. The main focuses of these possible drugs refer to the anti-baldness treatments currently available for the genetic type of this pathology (based on topical and oral medications), and to combat the symptoms of benign prostatic hyperplasia conditioned by the enlarged prostate, damaging the urinary flow and causing bladder stones, infection, and even impairing the function of the kidneys. Besides, it is also possible to mention the fight against prostate cancer, whose causes and the influence of 5-alpha-reductases have been the object of study by specialists from all over the world. The participation of 5-alpha-reductases in metabolic pathways initiates a cascade process that interferes with the regulation of the transcription of certain genes, resulting in the swelling of the prostate gland and/or in the death and atrophy of the hair follicles of the head, in cases of genetic predisposition. To stabilization followed by a possible regression of these conditions, finasteride and dutasteride have been the main synthetic compounds used in the inhibition of isoforms I and II, competing with the substrate for one of the binding sites of these enzymes. However, reports of lasting adverse effects in patients who used these drugs are, even if still controversial in the scientific world, cause for concern among specialists. It is important to mention that there is no satisfactory knowledge on possible interactions of these anti-androgens with other drugs, which does not allow discarding risks to the health of the patient/user both in the short and long term. Therefore, it is essential to understand the mechanisms of action as well as discover new substances with greater inhibitory potential and lesser side effects for these biological targets. Thus, in this project, molecular docking studies and molecular dynamics simulations of these substances with the target of interest will be carried out to understand the mechanisms of recognition and selectivity, as well as assist the design of new drug candidates for such purposes, which may be submitted to experimental tests to prove the desired biological effect. (AU)