Combined Ligand and Structure Based Approaches Towards Developing Novel Renin Inhibitors for the Treatment of Hypertension

<p>Hypertension is considered as the predominant risk factor for the onset of Cardiovascular disease (CVD) in the elder population. The chronic activation of Renin Angiotensin System (RAS) is considered as the primary causative factor for the inception of hypertension in geriatric population. Angiotensin Converting Enzyme (ACE) is a highly explored druggable target in the context of hypertension since this enzyme catalyses the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor. But clinical trials conducted on ACE inhibitors reported their incompetence in the effective treatment of hypertension. Hence, recent studies are focussing on renin, which is a central component of RAS in the regulation of blood pressure. The present study focuses on the elucidation of physicochemical properties of chemical compounds essential for renin inhibition and identification of novel renin inhibitors possessing enhanced potency as well as bioavailability. We have employed Molecular Field Topology Analysis (MFTA) as well as Structure Based Drug Design (SBDD) approaches for the accomplishment of above-mentioned objectives. MFTA approach were piloted on 45 indole-3-carboxamide derivatives by elucidating the significance of charge distribution as well as molecular size of chemical species in eliciting renin inhibition. Optimal model was obtained with Nf = 3, r²= 0.81 , Q² = 0.65. Molecular docking, atom-based binding free energy contributions and bioavailability assessments were carried out to identify most potent lead molecule among 45 compounds reported for renin inhibition. Further, new derivative molecules were predicted for the best lead molecule by employing chemical space exploration. All datasets, descriptor values, QSAR models for predictions usage and plots will be available in <a href="https://github.com/giribio/agingdata">https://github.com/giribio/agingdata</a></p><p></p>

Combined Ligand and Structure Based Approaches Towards Developing Novel Renin Inhibitors for the Treatment of Hypertension

<p>Hypertension is considered as the predominant risk factor for the onset of Cardiovascular disease (CVD) in the elder population. The chronic activation of Renin Angiotensin System (RAS) is considered as the primary causative factor for the inception of hypertension in geriatric population. Angiotensin Converting Enzyme (ACE) is a highly explored druggable target in the context of hypertension since this enzyme catalyses the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor. But clinical trials conducted on ACE inhibitors reported their incompetence in the effective treatment of hypertension. Hence, recent studies are focussing on renin, which is a central component of RAS in the regulation of blood pressure. The present study focuses on the elucidation of physicochemical properties of chemical compounds essential for renin inhibition and identification of novel renin inhibitors possessing enhanced potency as well as bioavailability. We have employed Molecular Field Topology Analysis (MFTA) as well as Structure Based Drug Design (SBDD) approaches for the accomplishment of above-mentioned objectives. MFTA approach were piloted on 45 indole-3-carboxamide derivatives by elucidating the significance of charge distribution as well as molecular size of chemical species in eliciting renin inhibition. Optimal model was obtained with Nf = 3, r²= 0.81 , Q² = 0.65. Molecular docking, atom-based binding free energy contributions and bioavailability assessments were carried out to identify most potent lead molecule among 45 compounds reported for renin inhibition. Further, new derivative molecules were predicted for the best lead molecule by employing chemical space exploration. All datasets, descriptor values, QSAR models for predictions usage and plots will be available in <a href="https://github.com/giribio/agingdata">https://github.com/giribio/agingdata</a></p><p></p>

RENIN-INHIBITORY BIOACTIVE PEPTIDES WITH ANTIHYPERTENSIVE PROPERTY: A REVIEW

Blood pressure is regulated by the renin angiotensin aldosterone system (RAAS). Renin-catalyzed conversion of angiotensinogen to angiotensin I is the rate-limiting step of the RAAS pathway, which arguably makes renin a better target for prevention, treatment and management of hypertension than Angiotensin-Converting Enzyme (ACE). Hydrolysis of food proteins releases bioactive peptides that can interact with receptors, enzymes and molecules in the organism to promote health. Several studies have shown that these bioactive peptides could be exploited for management of hypertension which is a major risk factor for cardiovascular diseases (CVDs). Antihypertensive peptides are bioactive peptides derived from plant and animal sources with inherent potential to ameliorate hypertension by different mechanism including scavenging of free radicals, reduced cholesterol level, inhibit angiotensin-converting enzyme (ACE) activity and renin production. Although there was sufficient information on ACE-inhibitory and antioxidative peptides while information on the potential role of renin-inhibitory peptides against hypertension is limited. Thus, herein the present review primarily used ISI, SCOPUS and PubMed indexed journals containing experimental reports to elucidate the potential role of bioactive peptides against antihypertensive effect via renin inhibition. Key words: Hypertension; Bioactive peptides; Renin inhibition; Mechanism of action.

Molecular Docking Reveals the Potential of Aliskiren, Dipyridamole, Mopidamol, Rosuvastatin, Rolitetracycline and Metamizole to Inhibit COVID-19 Virus Main Protease

<p>Drug repurposing is a fast way to rapidly discover a drug for clinical use. In such circumstances of the spreading of the highly contagious COVID-19, searching for already known drugs is a worldwide demand. In this study, many drugs were evaluated by molecular docking. Among the test compounds, aliskiren (the best), dipyridamole, mopidamol and rosuvastatin showed higher energies of binding than that of the co-crystallized ligand N3 with COVID-19 main protease M^pro. Rolitetracycline showed the best binding with the catalytic center of the protease enzyme through binding with CYS 145 and HIS 41. Metamizole showed about 86 % of the binding energy of the ligand N3 while the protease inhibitor darunavir showed little bit lower binding energy than N3. These results are promising for using these drugs in the treatment and management of the spreading of COVID-19 virus. Also, it could stimulate clinical trials for the use of these drugs by systemic or <b>inhalation</b> route.</p><p></p><p>The results stimulate the evaluation of these drugs as anti COVID-19 especially aliskiren which showed the highest score of binding with the binding site of N3. This will be added to its renin inhibition and advantage of renin inhibition and possibility of the reduced expression of ACE2[12]. Dipyridamole and mopidamol showed a potential to be more M^proinhibitor than ligand N3 and darunavir. Also, dipyridamole has the property of antiviral activity beside its use to decrease the hypercoagulabilty that happens due to COVID infection in addition to the property of promoting type I interferon (IFN) responses and protect mice from viral pneumonia [30]. Rolitetracycling is an amazing in its binding mode in the active site of the protease pocket it seemed as it is tailored to be buried in that pocket. Mopidamol and rosuvastatin are slightly better than the co-crystallized ligand N3 and darunavir in binding mode which nominate the as COVID-19 protease inhibitors. Hopefully this study will help in the repurposing a drug for the treatment of COVID-19.</p><p></p>

Molecular Docking Reveals the Potential of Aliskiren, Dipyridamole, Mopidamol, Rosuvastatin, Rolitetracycline and Metamizole to Inhibit COVID-19 Virus Main Protease

<p>Drug repurposing is a fast way to rapidly discover a drug for clinical use. In such circumstances of the spreading of the highly contagious COVID-19, searching for already known drugs is a worldwide demand. In this study, many drugs were evaluated by molecular docking. Among the test compounds, aliskiren (the best), dipyridamole, mopidamol and rosuvastatin showed higher energies of binding than that of the co-crystallized ligand N3 with COVID-19 main protease M^pro. Rolitetracycline showed the best binding with the catalytic center of the protease enzyme through binding with CYS 145 and HIS 41. Metamizole showed about 86 % of the binding energy of the ligand N3 while the protease inhibitor darunavir showed little bit lower binding energy than N3. These results are promising for using these drugs in the treatment and management of the spreading of COVID-19 virus. Also, it could stimulate clinical trials for the use of these drugs by systemic or <b>inhalation</b> route.</p><p></p><p>The results stimulate the evaluation of these drugs as anti COVID-19 especially aliskiren which showed the highest score of binding with the binding site of N3. This will be added to its renin inhibition and advantage of renin inhibition and possibility of the reduced expression of ACE2[12]. Dipyridamole and mopidamol showed a potential to be more M^proinhibitor than ligand N3 and darunavir. Also, dipyridamole has the property of antiviral activity beside its use to decrease the hypercoagulabilty that happens due to COVID infection in addition to the property of promoting type I interferon (IFN) responses and protect mice from viral pneumonia [30]. Rolitetracycling is an amazing in its binding mode in the active site of the protease pocket it seemed as it is tailored to be buried in that pocket. Mopidamol and rosuvastatin are slightly better than the co-crystallized ligand N3 and darunavir in binding mode which nominate the as COVID-19 protease inhibitors. Hopefully this study will help in the repurposing a drug for the treatment of COVID-19.</p><p></p>