Orthosteric binding site: Orthosteric drugs bind to a protein's active site, competing with the natural substrate or ligand (Figure . Their effects are exerted by outcompeting the native substrate and obstructing the active site when they possess a strong affinity for the site. Most drugs available in the market are traditionally orthosteric ( ). Also, the orthosteric active sites within a protein family exhibit a high degree of conservation, implying that a drug designed to target the active site of one protein can also interact with the active sites of other proteins belonging to the same family ( ). Although extensively employed, orthosteric binding sites and pharmaceuticals also have specific drawbacks in drug design and therapeutic uses ( ). A notable constraint is the possibility of off-target effects caused by the extensive similarity of active sites throughout protein families ( ). This can result in unintentional interactions with proteins that have similar structures, leading to adverse effects and diminishing the selectivity of the medicine. Furthermore, orthosteric medications frequently compete with endogenous ligands or substrates for binding, which might restrict their effectiveness in specific physiological situations or disease states characterised by fluctuating substrate concentrations ( ). Also, the total suppression of protein function by orthosteric medications may not always be preferable, as it can interfere with regular cellular processes that depend on regulated enzyme activity ( ). The significance of taking into account alternative drug design techniques, such as allosteric modulation, is emphasised by these aspects. These strategies aim to obtain more accurate and specific therapeutic results while reducing the possible disadvantages associated with orthosteric binding.