A recursive molecular docking coupled with energy-based pose-rescoring and MD simulations to identify hsGC beta H-NOX allosteric modulators for cardiovascular dysfunctions

Modulating the activity of human soluble guanylate cyclase (hsGC) through allosteric regulation of the beta H-NOX domain has been considered as an immediate treatment for cardiovascular disorder (CVDs). Currently available beta H-NOX domain-specific agonists including cinaciguat are unable to deal with the conundrum raised due to oxidative stress in the case of CVDs and their associated comorbidities. Therefore, the idea of investigating novel compounds for allosteric regulation of hsGC activation has been rekindled to circumvent CVDs. Current study aims to identify novel beta H-NOX domain-specific compounds that can selectively turn on sGC functions by modulating the conformational dynamics of the target protein. Through a comprehensive computational drug-discovery approach, we first executed a target-based performance assessment of multiple docking (PLANTS, QVina, LeDock, Vinardo, Smina) scoring functions based on multiple performance metrices. QVina showed the highest capability of selecting true-positive ligands over false positives thus, used to screen 4.8 million ZINC15 compounds against beta H-NOX domain. The docked ligands were further probed in terms of contact footprint and pose reassessment through clustering analysis and PLANTS docking, respectively. Subsequently, energy-based AMBER rescoring of top 100 low-energy complexes, per-residue energy decomposition analysis, and ADME-Tox analysis yielded the top three compounds i.e. ZINC000098973660, ZINC001354120371, and ZINC000096022607. The impact of three selected ligands on the internal structural dynamics of the beta H-NOX domain was also investigated through molecular dynamics simulations. The study revealed potential electrostatic interactions for better conformational dialogue between beta H-NOX domain and allosteric ligands that are critical for the activation of hsGC as compared to the reference compound.