Conformational dynamics of kinases implicated in hypertension and finding potent inhibitors : a molecular modeling and simulation study

Abstract

High blood pressure (HBP) or hypertension (HT) is a medical condition with a persistent elevation of the blood pressure in arteries. Hypertension is a serious medical concern that can anticipate the risk factors for various fatal diseases, such as cardiac arrest, kidney failure, brain stroke, and cognitive impairment. It is one of the primary causes of premature death worldwide; 1 in 4 men and 1 in 5 women over a billion people. Throughout the world, ~ 1.13 billion people have been suffering from hypertension. Hypertension is responsible for ~ 45% of death due to heart disease and ~ 51% due to stroke1 . In India, the overall prevalence of hypertension is ~ 30.7%. The currently available therapies have been advantageous in controlling blood pressure; however, the advent of resistance to these drugs, known as resistant hypertension, has imposed a significant challenge in treating hypertension. Furthermore, allergies and intolerance of anti-hypertensive approved medicines have limited their use. Altogether, it is an emerging need in the development of novel anti-hypertensive drugs. Most hypertensive syndromes are from the increased Na+ transport along the aldosterone-sensitive distal nephron in the kidney. The molecular pathogenesis mechanism of hypertension is poorly understood; however, genetic approaches have demonstrated that mutation in many genes regulates renal salt reabsorption and causes variation in blood pressure. The With-No-Lysine (WNK)-signaling cascade is a critical pathway in regulating blood pressure in vivo2 . In 2001, the discovery of renal WNK offered a new insight into sodium, potassium, and blood pressure regulations and body fluid homeostasis. The association between this signaling pathway and hypertension came into the picture when it was reported that mutations in the WNK gene cause hypertension, known as Gordon’s syndrome or Pseudohypoaldosteronism type II (PHAII) or Familial Hyperkalemic Hypertension (FHHt)3 . It causes a paradoxical decrease of aldosterone, suggesting a mechanism of regulating blood pressure independent of the RAAS (renin-angiotensin-aldosterone) system. It has been identified that the WNK kinase interacts, phosphorylates, and activates its downstream tonicity responsive kinases, namely Ste-20 related proline alanine-rich kinase (SPAK) and oxidative stress-response kinase I (OSR1), leading to phosphorylation of various sodium (Na+ ), potassium (K+ ), chloride (Cl- ) ion cotransporters, such as Na+ -K + -Cl- (NKCC1 and NKCC2), Na+ -Cl- (NCC), and K+ -Cl- (KCC)4 . Notably, phosphorylation of these ion cotransporters leads to their activation (NCC) or inhibition (KCC), influencing the electrolyte balance, resulting in changes in blood pressure (Figure 1). Upstream modulators of WNKs comprise Kelch like 3/Cullin-3 (KLHL3/CUL3) E3 ubiquitin ligase complex, which constitutively degrades the WNKs. Hence, WNK kinases have been recognized as a master regulator in WNK-SPAK/OSR1-NCC pathways and may act as a potential target in discovering new anti-hypertensive drugs.