A myriad of drug-resistant strains of Helicobacter pylori and adverse drug-reactions create a big-barrier in the treatment, thereby demanding novel proof-of-concept inhibitors and breakthrough medicines. Hence, an affinity-centric protocol was devised to implement scaffold-design for 3-dehydroquinate dehydratase-II (AroQ) as a follow-up of our study against beaucoup strains. Herein, the study focuses on preferred the attractive-target methodically due to its salient features include conserving, essential and specific for H. pylori, not present in humans and gut-flora. Structural refinement, energy minimization and optimization of the developed best-model were employed with confirming active site residues around substrate. Published AroQ-inhibitors and substrate were utilized to probe an in-house library of molecules. The prepared dataset was allowed to lead-optimization campaign includes rigid-receptor docking through high-throughput virtual, standard-precision, extra-precision screening filters, quantum-polarized-ligand (quantum mechanical and molecular mechanical (QM/MM)) and induced-fit docking experiments. Convergence threshold (0.05) and Truncated Newton Conjugate Gradient (TNCG) were set in ConfGen's algorithm to produce high-quality bioactive conformations by thoroughly narrowing the conformational space accessible to the leads. ADME/Tox predictions and long-range molecular dynamics simulations were executed after post-docking evaluations. The approach provided seven ranked compounds with better scoring functions, bioactive-conformers and pharmacokinetics profiles than published ligands and substrate. Simulations revealed more consistency of lead1-AroQ complex throughout chemical time than controls in the formulated physiological milieu. The study outcomes showing the good competitive binding propensity for active-tunnel over the substrate and previous ligands, thereby these leads could be ideal for proposing as selective cutting-edge inhibitors to target AroQ specific for H. pylori strains.