Porous materials, such as metal-organic frameworks (MOFs), are an attractive target for bioinspired heterogeneous catalyst design. The well-defined metal sites contained in the secondary building unit (SBU) of the reticular MOF structure have structural and electronic features that are analogous to the metal cofactors in metalloenzymes, including weaker-field ligands that favor high-spin electron configurations that are needed for redox-mediated reactions, as well as pore architectures that resemble an enzyme's binding pocket. Inspired by sMMO, zeolites containing open Fe sites in the square planar geometry and subsequently, MOFs with SBUs containing open Fe sites in the square pyramidal geometry have demonstrated C-H activation activity in light alkanes (i.e., ethane and propane). Additionally, MOFs have been used as scaffolds with metal active sites that are active for alkane hydroxylation incorporated in the pore via post-synthetic functionalization methods. Nevertheless, the discovery of new MOFs capable of C-H activation requires tedious iterative trial and error workflows. There are thousands of candidate MOFs that could be experimentally synthesized and tested for catalytic activity which can be extremely time-consuming. Furthermore, evidence of catalytic activity on candidate MOFs must be accompanied by detailed mechanistic studies that capture fleeting intermediates in the catalytic cycle with in situ spectroscopy which can prove challenging for MOFs. First-principles calculations have thus played a vital role in understanding MOF catalysis, especially in deciphering reaction mechanisms, active site structures, and the roles of the chemical environment in C-H activation by MOFs. While computation has proved valuable in rationalizing the activity of MOFs known to be capable of selective C-H activation, computation can play a leading role by enabling high-throughput virtual screening (HTVS) on the large chemical space of synthesized MOFs. Such HTVS campaigns have been carried out but have typically targeted specific metal-coordination geometries in the MOF SBUs. Notably, most screening efforts overlook MOF stability as a design criteria, which is critical for thermal catalysis. Linear free-energy relationships (LFERs) are often exploited to accelerate catalyst HTVS by drawing correlations between readily computed descriptors and the energetics of individual intermediates or reaction steps. LFERs, however, have shown to be disrupted by changes to the catalyst structure, non-covalent interactions that selectively stabilize specific reaction intermediates or when probing chemical spaces with greater diversity in metal identity, oxidation and spin states. Thus, it is necessary to both expand the search for MOFs beyond those that have been previously studied computationally or experimentally and to identify MOFs that may have been overlooked because of assumed LFERs that may not hold.