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A Molecular Docking Approach to Evaluate the Pharmacological Properties of Natural and Synthetic Treatment Candidates for Use against Hypertension.

ABSTRACT: Cardiovascular diseases (CVDs) have become the leading cause of disability and death worldwide, particularly in low- and middle-income countries. Hypertension, a major cause of CVD progression, is widely attributable to genetic, behavioral, and environmental risk factors. Among the genetic reasons, angiotensin II enzyme, produced as a result of abnormal functioning of the renin?angiotensin system, is reported as the foremost cause of hypertension. A cascade of genes, including those encoding for WNK kinases (WNK1 and WNK4), Bp1, Bp2, angiotensinogen, and other enzymes, is involved in the conversion of angiotensin I to angiotensin II. However, the angiotensin-converting enzyme (ACE) plays a crucial role in this pathway. Therefore, ACE could be a potential therapeutic target in regulating the conversion of angiotensin I to angiotensin II and eventually controlling hypertension. In this study, a molecular docking-based approach was utilized for identifying and evaluating potential inhibitors of ACE present in herbs, other natural sources, and synthetic sources, on the basis of these compounds' binding affinities and other physicochemical features. In addition, the suitability of these inhibitors as drugs for biological systems, considering their adsorption, distribution, metabolism, and excretion (ADME), was predicted using Lipinski's rule. In conclusion, our study provides a novel and clearer insight into the interaction properties of known putative inhibitors of ACE.

SUBMITTER: Attique SA

PROVIDER: S-EPMC6466102 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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A Molecular Docking Approach to Evaluate the Pharmacological Properties of Natural and Synthetic Treatment Candidates for Use against Hypertension.

Attique Syed Awais SA Hassan Muhammad M Usman Muhammad M Atif Rana Muhammad RM Mahboob Shahid S Al-Ghanim Khalid A KA Bilal Muhammad M Nawaz Muhammad Zohaib MZ

International journal of environmental research and public health 20190314 6

Cardiovascular diseases (CVDs) have become the leading cause of disability and death worldwide, particularly in low- and middle-income countries. Hypertension, a major cause of CVD progression, is widely attributable to genetic, behavioral, and environmental risk factors. Among the genetic reasons, angiotensin II enzyme, produced as a result of abnormal functioning of the renin⁻angiotensin system, is reported as the foremost cause of hypertension. A cascade of genes, including those encoding for ...[more]

PMID: 30875817

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Project description:Hypertension (HTN) is a major risk factor for cardiovascular and renal diseases, cerebrovascular accidents (CVA) and a prime underlying cause of worldwide morbidity and mortality. Hypertension is a complex condition and a strong interplay of multiple genetic, epigenetic and environmental factors is involved in its etiology. Previous studies showed an association of overexpression of genes with hypertension. Satisfactory control of Blood Pressure (BP) levels is not achieved in a major portion of hypertensive patients who take antihypertensive drugs. Since existing antihypertensive drugs have many severe or irreversible side effects and give rise to further complications like frequent micturition and headaches, dizziness, dry irritating cough, hypoglycemia, GI hemorrhage, impaired left ventricular function, hyperkalemia, Anemia, angioedema and azotemia. There is a need to identify new antihypertensive agents that can inhibit the expression of these overexpressed genes contributing to hypertension. The study was designed to identify drug-able targets against overexpressed genes involved in hypertension to intervene the disease. The structure of the protein encoded by an overexpressed gene Endothelin-1 was retrieved from Protein Database (PDB). A library of five thousand phytochemicals was docked against Endothelin-1. The top four hits against Endothelin-1 protein were selected based on S score and Root Mean Square Deviation (RMSD). S score is a molecular docking score which is used to determine the preferred orientation, binding mode, site of the ligand and binding affinity. RMSD refines value for drug target identification. Absorption, distribution, metabolism, excretion, and toxicity profiling (ADMET) was done. The study provides novel insights into HTN etiology and improves our understanding of BP pathophysiology. These findings help to understand the impact of gene expression on BP regulation. This study might be helpful to develop an antihypertensive drug with a better therapeutic profile and least side effects.

Project description:The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), possesses an important bifunctional nonstructural protein (nsp14) with a C-terminal N7-methyltransferase (N7-MTase) domain and an N-terminal domain with exoribonuclease (ExoN) activity that is required for maintaining high-fidelity viral replication. Viruses use the error-prone replication mechanism, which results in high mutation rates, to adapt quickly to stressful situations. The efficiency with which nsp14 removes mismatched nucleotides due to the presence of ExoN activity protects viruses from mutagenesis. We investigated the pharmacological role of the phytochemicals (Baicalein, Bavachinin, Emodin, Kazinol F, Lycorine, Sinigrin, Procyanidin A2, Tanshinone IIA, Tanshinone IIB, Tomentin A, and Tomentin E) against the highly conserved nsp14 protein using docking-based computational analyses in search of new potential natural drug targets. The selected eleven phytochemicals failed to bind the active site of N7-Mtase in the global docking study, while the local docking study identified the top five phytochemicals with high binding energy scores ranging from - 9.0 to - 6.4 kcal/mol. Procyanidin A2 and Tomentin A showed the highest docking score of - 9.0 and - 8.1 kcal/mol, respectively. Local docking of isoform variants was also conducted, yielding the top five phytochemicals, with Procyanidin A1 having the highest binding energy value of - 9.1 kcal/mol. The phytochemicals were later tested for pharmacokinetics and pharmacodynamics analysis for Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) which resulted in choosing Tomentin A as a potential candidate. The molecular dynamics simulations studies of nsp14 revealed significant conformational changes upon complex formation with the identified compound, implying that these phytochemicals could be used as safe nutraceuticals which will impart long-term immunological competence in the human population against CoVs.Graphical abstractSupplementary informationThe online version contains supplementary material available at 10.1007/s40203-023-00143-7.

Dataset Information

A Molecular Docking Approach to Evaluate the Pharmacological Properties of Natural and Synthetic Treatment Candidates for Use against Hypertension.

Publications

A Molecular Docking Approach to Evaluate the Pharmacological Properties of Natural and Synthetic Treatment Candidates for Use against Hypertension.

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