Among the many MOFs experimentally synthesized and tested for noble gas separation and capture [ , , -], Ni(PyC) 2 (PyC " pyridine--carboxylate) is a formidable contender for Xe/Kr separations, exhibiting a higher Xe/Kr selectivity ( at K in the dilute limit) than SBMOF-[ ]. Akin to lead-optimization in drug discovery, here we aim to leverage the tunability of MOFs to optimize the chemistry of the "lead", parent Ni(PyC) 2 MOF for Xe/Kr selectivity. In particular, we wish to determine which functional group X is optimal to append to the PyC linker to give the new Ni(PyC-X) 2 MOF the highest Xe/Kr selectivity. To guide experimental pursuits, we conduct a virtual screening of Ni(PyC-X) 2 structures for noble gas separations. First, we show that molecular models and simulations accurately reproduce the experimentally measured [ ] Xe, Kr, and Ar adsorption isotherms in the parent Ni(PyC) 2 MOF. Then, we construct a library of Ni(PyC-X) 2 crystal structure models and use molecular simulations to predict their Xe, Kr, and Ar Henry coefficients and selectivities at room temperature. The virtual screening predicts that several Ni(PyC-X) 2 MOFs will exhibit a higher Xe/Kr selectivity and Xe Henry coefficient than the parent Ni(PyC) 2 MOF. Among them, we targeted Ni(PyCm-NH 2 ) 2 for synthesis in the lab owing to the commercial availability of the PyC-m-NH 2 ligand. We synthesized Ni(PyC-m-NH 2 ) 2 (solvothermal, de novo), determined its crystal structure by X-ray powder diffraction (XRPD), and measured its Xe, Kr, and Ar adsorption isotherms. In agreement with our molecular simulations, the experimentally measured (dilute) Xe/Kr selectivity and Xe Henry coefficient ( , mmol/(g-bar)) of Ni(PyC-m-NH 2 ) 2 are greater than those of the parent Ni(PyC) 2 MOF ( , mmol/(g-bar)). More, based on changes in the XRPD pattern of the samples upon exposure to air, Ni(PyC-m-NH 2 ) 2 shows greater stability to air exposure than the parent Ni(PyC) 2 MOF. In situ X-ray diffraction studies elucidate the well-defined Xe adsorption pockets in Ni(PyC-m-NH 2 ) 2 , corroborated by molecular modeling. In addition to discovering Ni(PyC-m-NH 2 ) 2 for enhanced noble gas separations, our study illustrates the computation-informed optimization of the chemistry of a "lead", parent MOF to enhance its selectivity for an adsorbate.