Irreversible bimolecular complexes are highly desirable because (1) the residence of one molecule inside the cavity of another molecule is permanent until the breakdown of the cavity-containing molecule, (2) the complex formation is one-to-one stoichiometric, and (3) for drug therapy the permanent residence and 1:1 stoichiometry confer the cavity-residing molecule with desired high metabolic stability, high potency-to-mass ratio, low acting dose, and low off-target activity . These complexes generally refer to covalent irreversible complexes that are self-assembled by two molecules between which there is a covalent bond resulting from the self-assembly process. The desirability of covalent irreversible complexes is apparent from the drug action mechanisms of aspirin , penicillin , and sotorasib all of which involve a covalent irreversible complex. Notably, sotorasib was approved in May 2021 (lung-cancer-mutation-previously-considered-resistant-drug) as the first-in-class personalized treatment for a lung cancer mutation previously considered resistant to drug therapy due to sotorasib's unique capability to clinically block the function of KRAS G12C (an enzyme mutant responsible for ~13% nonsmall-cell lung cancers) via irreversible complexation. However, the covalent irreversible complexes from in situ cysteine conjugation are limited by the infrequent presence of the noncatalytic cysteine in a protein cavity, and inhibiting KRAS G12C offers treatment for only a subset of cancer patients. A paradigm shift is needed for the design of irreversible bimolecular complexes.