Comprehensive analysis of drugs to treat SARS­CoV­2 infection: Mechanistic insights into current COVID­19 therapies (Review).

The major impact produced by the severe acute respiratory syndrome coronavirus 2 (SARS­CoV­2) focused many researchers attention to find treatments that can suppress transmission or ameliorate the disease. Despite the very fast and large flow of scientific data on possible treatment solutions, none have yet demonstrated unequivocal clinical utility against coronavirus disease 2019 (COVID­19). This work represents an exhaustive and critical review of all available data on potential treatments for COVID­19, highlighting their mechanistic characteristics and the strategy development rationale. Drug repurposing, also known as drug repositioning, and target based methods are the most used strategies to advance therapeutic solutions into clinical practice. Current in silico, in vitro and in vivo evidence regarding proposed treatments are summarized providing strong support for future research efforts.

Intraclass differences among antihypertensive drugs.

The four major classes of antihypertensive drugs­diuretics, ß-blockers, calcium channel blockers, and renin-angiotensin system inhibitors (including angiotensin-converting enzyme inhibitors and angiotensin receptor blockers)­have significant qualitative and quantitative differences in the adverse effects they cause. Structural and chemical differences have been identified within these classes, especially among the calcium channel blockers and, to a lesser extent, among the thiazide/thiazide-like diuretics. However, it has been more difficult to demonstrate that these differences translate into differential effects with respect to either the surrogate endpoint of blood pressure reduction or, more importantly, hypertension-related cardiovascular complications. Based on a hierarchy-of-evidence approach, differences are apparent between hydrochlorothiazide and chlorthalidone based on evidence of moderate quality. Low-quality evidence suggests atenolol is less effective than other ß-blockers. However, no significant intraclass differences have been established among the other classes of antihypertensive drugs.

Review: angiotensin II type 1 receptor blockers: class effects versus molecular effects.

Highly selective angiotensin II (Ang II) type 1 (AT(1)) receptor blockers (ARBs) are now available. The AT(1) receptor is a member of the G protein-coupled receptor (GPCR) superfamily and block the diverse effects of Ang II. Several ARBs are available for clinical use. Most ARBs have common molecular structures (biphenyl-tetrazol and imidazole groups) and it is clear that ARBs have 'class effects'. On the other hand, recent clinical studies have demonstrated that not all ARBs have the same effects, and some benefits conferred by ARBs may not be class effects, and instead may be 'molecular effects'. In addition, each ARB has been clearly shown to have specific molecular effects in basic experimental studies, and these effects may be due to small differences in the molecular structure of each ARB. However, it is controversial whether ARBs have molecular effects in a clinical setting. Although the presence of molecular effects for each ARB based on experimental studies may not directly influence the clinical outcome, this possibility has not been adequately evaluated. This review focuses on the class effects versus molecular effects of ARBs from bench to bedside.

Angiotensin receptor blockers in hypertension and cardiovascular diseases.

Angiotensin receptor blockers are the newest class of antihypertensive agents marketed for the treatment of hypertension. There is now an important amount of evidence indicating that this class of drugs exerts beneficial effects in patients with a variety of cardiovascular disorders. Evidence-based medicine includes well controlled studies with mortality and morbidity endpoints in patients with left ventricular dysfunction after a myocardial infarction, congestive heart failure, cerebrovascular disease, type-2 diabetic subjects with renal dysfunction and high-risk hypertensive patients. In addition to these hard endpoints, treatment with angiotensin receptor blockers prevents the development of type-2 diabetes, promotes a more pronounced regression of left ventricular hypertrophy, decreases microalbuminuria and proteinuria in renal patients, ameliorates coronary and peripheral vascular endothelial dysfunction and decreases plasma levels of several markers of vascular inflammation. In summary, angiotensin receptor blockers are antihypertensive drugs with a very good profile in terms of efficacy, tolerability and cardiovascular protection. They represent an important step in the search for the ideal antihypertensive agent.

CoMFA and CoMSIA studies of angiotensin (AT1) receptor antagonists.

Two 3D-QSAR methods--CoMFA and CoMSIA--were applied to a set of 38 angiotensin receptor (AT1) antagonists. The conformation and alignment of molecules were obtained by a novel method - consensus dynamics. The representation of biological activity, partial charge formalism, absolute orientation of the molecules in the grid, and grid spacing were also studied for their effect on the CoMFA models. The models were thoroughly validated through trials using scrambled activities and bootstrapping. The best CoMFA model had a cross-validated correlation coefficient ( q2) of 0.632, which improved with "region focusing" to 0.680. This model had a "predictive" r2 of 0.436 on a test series that was unique and with little representation in the training set. Although the "predictive" r2 of the best CoMSIA model, which included steric, electrostatic, and hydrogen bond acceptor fields was higher than that of the best CoMFA model, the other statistical parameters like q2, r2, F value, and s were unsatisfactory. The contour maps generated using the best CoMFA model were used to identify the structural features important for biological activity in these compounds.