Cheminformatics approach for identification of N-HyMenatPimeMelly as a novel potential ligand against RAS and renal chloride channel

Abstract

Some angiotensin receptor (AR) blockers interfere with the renal chloride channel (ClC-K), which plays an important role in urine concentration. Identifying ligands targeting this channel, whether activating or blocking, is highly desirable because it could open the way for interventions that modulate their activity. In this study, the Asinex (BioDesign) complete library was screened to identify a compound with favorable physicochemical and pharmacokinetic properties, which have both AR blocking and ClC‐Ka-modulating activities to present it as a novel potential oral candidate which could be useful for treatment of salt-sensitive hypertension without major ClC‐K affection. A compound, N-{[4-Hydroxy-1-(2-methyl-1,6-naphthyridin-4-yl)-4-piperidinyl]methyl}-N-methyl-L-lysinamide (N-HyMenatPimeMelly) (Chem Spider ID 68416221), was identified as a potent potential oral ligand of the renin-angiotensin system (RAS) and ClC-Ka with docking scores ranging from −10.978 to −7.324 with the four selected proteins (4YAY: AR type 1, 2PFI: Cytoplasmic domain of ClC-Ka, 6JOD: AR type 2 and 6M0J: Angiotensin-converting enzyme 2). The protein-ligand complex was used to perform molecular dynamics (MD) simulation for 100 ns. The QikProp and SwissADME tools’ results showed that the compound has ADME/T and drug-likeness properties, which are within the permissible ranges for 95% of known drugs. The density functional theory (DFT) analysis and MD simulation extended the study toward computational validation. Throughout the study, N-HyMenatPimeMelly has shown good interactions and stable performance in MD simulation and DFT analysis. The whole analysis has produced promising results, and N-HyMenatPimeMelly can be treated as a novel potential RAS and ClC-K oral ligand, however, experimental validation is needed before human use.

Communicated by Ramaswamy H. Sarma

Keywords:

• Renin-Angiotensin system
• N-HyMenatPimeMelly
• ADME/T
• molecular dynamics simulation
• Density functional theory (DFT)

Disclosure statement

The authors reported no potential conflict of interest.

Data availability statement

Data may be requested via the authors.

Additional information

Funding

Institutional Fund Projects funded this research under grant no: (IFPIP: 64-828-1443). The authors gratefully acknowledge the technical and financial support from the Ministry of Education and King Abdulaziz University, DSR, Jeddah, Saudi Arabia.