Integration of core hopping, quantum-mechanics, molecular mechanics coupled binding-energy estimations and dynamic simulations for fragment-based novel therapeutic scaffolds against Helicobacter pylori strains

Abstract The cascade of complications by Helicobacter pylori including extra-gastric and peptic ulcers to gastric cancer imposes a salient cause of cancer death globally. Adverse drug reactions and burgeoned genetically diverse resistant strains create a big barrier in the treatment, thereby demanding novel proof-of-concept ligands and breakthrough medicines. Hence, as a follow-up of the previous proteomics study against 53 H. pylori strains, KdsB was identified as a vital conserved-target enzyme. Herein, the rational therapeutic-design strategies exploiting for such a hidden cryptic inhibitor were utilized in lead-optimization campaigns through shape screening, the powerful scaffold-hopping, rigid-receptor, quantum-polarized ligand and induced-fit docking techniques coupled with estimating molecular-mechanics energies (ΔGbind) through generalized-Born and surface-area-continuum solvation. Variable-dielectric-Surface-Generalized Born, a novel energy model and physics-based corrections for bond-interactions and ADME/Tox predictions led to yield improved eight therapeutic chemical entities with positive synthesizability scores (0–1). Long-range molecular dynamics (300 ns) simulations revealed stability of leads. Significant computational findings with better competitive binding-strengths than experimental ligands could pave the best choice for selecting better leads as it warrants and filter false-positives based on the consensus of scaffolds interactions and suggesting that designed novel class of KdsB-antagonist molecules may dysfunction the target and stimulate new insights for developing effectual medical interventions.