Investigation of Drug Interaction Potentials and Binding Modes on Direct Renin Inhibitors: A Computational Modeling Studies

Background: Hypertension is one of the key risk factors for cardiovascular disease, it is regulated through Renin Angiotensin Aldosterone System (RAAS) cascade. Renin catalyzes the initial rate-limiting step in RAAS system, that influences the synthesis of angiotensin I from precursor angiotensin. Renin inhibition could be a potential step for the blood pressure lowering mechanism as well as for organ protection. Methods: In order to understand the structure-activity association of direct renin inhibitors (DRIs), we have carried out three-dimensional quantitative structure activity relationship (3D-QSAR), molecular docking studies and Density Functional Theory (DFT) analysis to identify the attractive compounds. Five-point pharmacophore model of one acceptor, three hydrophobic groups and one aromatic ring was chosen for the dataset of 40 compounds. Results: The generated 3D-QSAR model shows that the alignment has a good correlation coefficient for the training set compounds, which comprise the value of R2 = 0.96, SD = 0.1, and F = 131.3. The test compounds had Q2 = 0.91, RMSE = 0.25, and Pearson-R = 0.97, which describes the predicted model was reliable. Discussion: External validations were carried out to validate the predicted QSAR model. Further, the significant compounds were studied using different in silico approaches in order to explore the difference in the atomic configuration and binding mechanism of the identified compounds. Conclusion: The molecular dynamics simulation of the complex was analyzed and confirmed the stability of the compounds in the protein. The outcome of the result could be useful to improve the safety and efficacy of DRIs that can be projected to clinical trials.

The results of the open observational, international, multicenter, prospective program to assess the efficacy, safety and tolerability of the first direct renin inhibitor RasilezR (aliskiren) in patients with arterial hypertension in ‘real-life’ clinical practice settings (DRIve)

Rasilez® (aliskiren) is the first drug from direct renin inhibitors class (DRI), which is used to treat arterial hypertension. The first aim of the «DRIve» program (Open observational, international, multicenter, prospective study to assess the efficacy, safety and tolerability of the first direct renin inhibitor Rasilez® (aliskiren) in patients with arterial hypertension in a real life setting) is to collect information about the efficacy, safety and tolerability of Rasilez (aliskiren) in monotherapy or in combination with other drugs in a real life setting for 6 months of therapy. Secondary aims were to analyze the patient acceptance of therapy and additional factors determining the outcome of Rasilez treatment. The program had been holding out from October 2009 until July 2011 in 17 cities of Russia.

RISK OF HYPERKALEMIA ASSOCIATED WITH THE USE OF BLOCKERS OF THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM IN THE TREATMENT OF HEART FAILURE: A REVIEW

Heart failure (HF) is the leading cause of hospitalizations for cardiovascular diseases in Brazil. Hyperkalemia is an important adverse effect of therapy for HF. Several factors affect the incidence of hyperkalemia in patients treated for HF, as well as the presence of comorbidities and the use of associated medications. The aim of this study is to gather new evidence regarding the risk of hyperkalemia in patients treated for HF. The well-established therapy for HF involves drugs that may lead to hyperkalemia as inhibitors of angiotensin converting enzyme blockers, angiotensin II receptor blockers, aldosterone receptor blockers and direct renin inhibitors. The high incidence of HF in elderly patients with comorbidities such as diabetes mellitus and renal insufficiency increases the risk of hyperkalemia. Anti-inflammatory drugs, trimethoprim-sulfamethoxazole and heparin may aggravate the situation. Conclusion: Given the risk of hyperkalemia in patients undergoing treatment for HF, cautious monitoring of renal function and serum potassium should be performed.

The dual blockade of the renin-angiotensin system in Internal Medicine: after ONTARGET trial

BACKGROUND In the increasing progress of scientific knowledge, every new discovery is a basis for new problems. In fact, after the success of Angiotensin-Converting Enzyme (ACE)-inhibitors in different cardiovascular diseases, the evidence of the “escape” of ACE and the discovery of Angiotensin- Receptor Blockers (ARBs) became the basis for a new question: is a dual blockade of the Renin-Angiotensin System (RAS) correct? DISCUSSION The different trials carried out (also the latest ONTARGET) didn’t give reliable answers, because differences were found both in the various diseases (hypertension, heart failure, coronary disease, nephropathy, diabetic or not), and between the single drugs of the class. We can say that this combination treatment didn’t show reliable clinical efficacy yet, except in heart failure and in some subgroups of hypertensive patients, checking carefully serum electrolytes and renal function. But even though we haven’t got certain outcomes, the research goes on quickly and some other sites of modulation of RAS were identified, from its first phases (aliskiren as prototype of direct renin inhibitors).