Molecular docking analysis of AGTR1 antagonists

Cardiovascular diseases (CVDs) are the leading cause of death and morbidity globally. The renin-angiotensin system is an important regulatory system for maintaining cardiovascular and renal function. Therefore, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers have emerged as first-line treatments for conditions such as hypertension and heart failure. Currently available synthetic medications used to treat various CVDs have been linked with various adverse effects. Therefore, this study focuses on targeting type-1 angiotensin II receptor (AGTR1) by natural compounds. The ZINC database natural compounds and standard AGTR1 inhibitors have been screened against the AGTR1 active site. The results showed that five compounds, namely ZINC85625504, ZINC62001623, ZINC70666587, ZINC06624086, and ZINC95486187, had similar binding energies to established AGTR1 inhibitors. These compounds were found to interact with crucial AGTR1 residues, indicating their potential as AGTR1 inhibitors. Moreover, the hit compounds demonstrated favorable drug-like characteristics and warrant further investigation for their potential use in managing CVD.

AGTR1 inhibitors have been screened against the AGTR1 active site.The results showed that five compounds, namely ZINC85625504, ZINC62001623, ZINC70666587, ZINC06624086, and ZINC95486187, had similar binding energies to established AGTR1 inhibitors.These compounds were found to interact with crucial AGTR1 residues, indicating their potential as AGTR1 inhibitors.Moreover, the hit compounds demonstrated favorable drug-like characteristics and warrant further investigation for their potential use in managing CVD.

Background:
Cardiovascular diseases (CVDs) are the primary cause of mortality and morbidity worldwide [1].The primary drivers of the rise in CVDs are urbanization and lifestyle changes.CVD mortality, mostly due to ischemic heart disease and stroke, has been declining in high-income nations (Europe, North America, and Australia) since the late twentieth century, and the trend is expected to continue, but the pace of decrease has lately slowed.Nonetheless, the incidence of CVDs is anticipated to rise owing to the prolonged lifespan of individuals with CVDs, while the absolute count of CVD fatalities will also increase due to population aging.Under the assumption of stable major cardiovascular risk factors, a significant increase in the prevalence of heart disease or stroke among middle-aged individuals is expected in the majority of countries, resulting in a significant number of CVD fatalities in the 35-64 age group over the next three decades  There are several known inhibitors/blockers of AGTR1 for example; Losartan, Valsartan, Irbesartan, Candesartan, Telmisartan, Olmesartan medoxomil, and Azilsartan medoxomil .Several currently available synthetic medications used to treat various CVDs have been linked with a number of adverse effects.Consequently, natural compounds have gained popularity in the modern era due to their low cost, easy availability, high effectiveness, and fewer side effects.

Methodology: Preparation of standard inhibitors and natural compounds library preparation:
This study utilized a carefully selected collection of natural compounds sourced from the ZINC database.The compounds were filtered using the 'Lipinski and Veber Rule' and were chosen to have molecular weights within the range of 300 to 500.The resulting curated library contained a total of 350 compounds.These compounds were minimized and prepared in pdbqt format for further docking analysis.ZD7 (co-crystal ligand), candesartan, losartan, and valsartan, all well-known inhibitors of AGTR1, were prepared for docking analysis as a positive control for the screening.

Target protein (AGTR1) preparation for docking analysis:
The 3D structure of AGTR1 was obtained from the RCSB PDB (PDB ID: 4YAY) [9].The structure is asymmetric and monomeric having a co-crystallized ligand ZD7.Water, heteroatoms, and cocrystallized ligands were eliminated, and the protein was cleaned and processed with DS before being saved as a '.pdb' file for virtual screening (VS)/docking purposes.

Structure based virtual screening:
The PyRx program was used to perform VS of prepared natural compounds and standard inhibitors against the active site of prepared target proteins [10].The docked complexes were subsequently assessed using DS Visualizer and Pymol, and the ideal conformation was determined based on the lowest binding energy.
The physicochemical, ADME, and toxicological features of the top 20 natural compounds were investigated.Since the screened library had already been filtered by the 'Lipinski and Veber Rule' and had molecular weights ranging from 300 to 500, most of the screened compounds were nontoxic.According to TOPKAT and ADMET forecasts, few of the chemicals are carcinogenic and the majority of the compounds are not mutagenic (Table 2).

Conclusion:
This study utilized computational methods including structurebased VS, ADME, and interaction analysis to identify compounds (ZINC85625504, ZINC62001623, ZINC70666587, ZINC06624086, and ZINC95486187) that can bind to the AGTR1 protein, a target for therapies for CVDs.These compounds also exhibited favorable drug-like characteristics, indicating their potential as candidates for treating CVDs.
[2,3].The renin-angiotensin system is an important regulatory system for maintaining cardiovascular and renal function.Therefore, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers have emerged as first-line treatments for conditions such as hypertension and heart failure [4].Here in this study, we focus on targeting type-1 angiotensin II receptor (AGTR1) among the several potential druggable targets.The activation of the AGTR1 receptor by angiotensin II results in vasoconstriction, sodium retention, and oxidative stress, all of which contribute to the development of hypertension, heart failure, and other CVDs [5].AGTR1 blockers are a class of drugs that inhibit the activation of AGTR1 selectively, thereby reducing the negative effects of angiotensin II.These medications are commonly used to treat hypertension, heart failure, and other CVDs.Multiple studies have demonstrated that targeting AGTR1 can reduce the incidence of cardiovascular events.Targeting the AGTR1 with drugs such as losartan, valsartan, and irbesartan has been demonstrated to be an effective CVD management strategy [6].Shreds of evidence from literature and protein-protein interaction analysis of AGTR1 with other proteins show that it interacts with several proteins.Numerous protein-protein interaction databases show how AGTR1 interacts with other proteins.For instance, the IntAct database, an open-source molecular interaction database, predicts interactions of AGTR1 with 92 proteins using data either selected from the literature or through direct data depositions [7].The BioGRID database, a freely accessible repository for genetic and protein interaction information from model organisms and people, has 104 interactors [8] (Figure 1).

Figure 1 :
Figure 1: Interaction of AGTR1 with other proteins.Predicted by IntAct database (A), and BioGRID database (B).
have been identified as crucial for binding with inhibitors[11].been observed to bind with these AGTR1 residues.

Figure 2 :
Figure 2: Interaction of best 5 hits with the active site residues of AGTR1.

Figure 3 :
Figure 3: Interaction of positive controls with the active site residues of AGTR1.

Table 1 :
Binding energy of top 20 screened compounds and positive controls.

Table 2 :
Physicochemical, and ADME properties of top 20 hits.