## 3 Discussion
### Benefit-Risk Balance of MTDL  
Thus, the efficacy of the drug can be multiplied as an MTDL rather than a single molecule. Indeed, MTDL mimics drug combinations, including additive or synergistic effects. With well-associated combinations, synergy can increase benefit-risk balance and favor the success of clinical trial studies. Research on this topic spans various disease applications, including Alzheimer's [157; 158], cancer, and infectious diseases. Understanding drug resistance in cancer supports the development of MTDLs, coupled with clinical experience, which has revealed a multi-target strategy to enhance anticancer activity [159]. This approach holds significant potential in fighting infectious diseases [160; 161; 162; 163; 164; 165; 166]. In virology, multi-target compounds have been developed for pulmonary diseases targeting F508 del-CFTR and P14 KIII\(\beta\)[167]. This approach is fascinating as it simultaneously inhibits viral replication and reduces the intensity of symptoms [168]. Virtual screening was recently performed in SARS-CoV-2, CVB1, CVB3, and E1 treatment research with the goal of designing multi-target compounds [169; 102; 118]. Many projects described above were designated for in silico evaluation of the interest of linked, merged, or fused compounds to produce an effective compound library [170; 171]. Several combinations can increase the potency of enterovirus inhibitors to achieve a broad-spectrum effect against non-polio enteroviruses (NPEVs) or enhance antiviral potency. A broad-spectrum approach is interesting because most NPEVs have similar mild clinical manifestations with different complications. Having a single compound for every NPEV eliminates the need for virus identification, leading to more effective patient management. This advantage is crucial for the patient, as therapy initiation can be prompt without the time-consuming process of viral typing, which requires specialized equipment. Fusing, merging, or linking several inhibitors in one MTDL leads to a need for a balance between the affinity of the MTDL with its different targets and its pharmacokinetic parameters. The single-chemical approach utilized by MTDLs can reduce adverse effects and enhance pharmacokinetic/pharmacodynamics parameters compared to combinations of individual single-target drugs [157; 158]. However, MTDLs based on a linker to bind selected candidates can have a high molecular weight. Formulation or transport studies must be performed to evaluate the bioavailability of synthesized new MTDLs. Macromolecules, polymers, or pharmacokinetic enhancers can be added to improve the passage through the intestine barrier. This approach may also lead to a more effective treatment, having additive or synergistic effects by targeting several viral proteins. Compounds, before linking, fusion, or merging must have synergistic effects between them. Some bindings can be modified for fused or merged MTDLs. Indeed, including partial structure or pharmacophore of initial inhibitor in one compound could lead to adverse interactions or steric hindrance with the targeted viral proteins. These effects could decrease the absolute efficacy of MTDL without considering synergistic effects. Thus, MTDL should modify only the structure without affecting the binding mode of the initial inhibitor. MTDLs, gathering several initial inhibitors, generally have a higher molecule weight that implies a better specificity to target considered viralproteins. MTDLs try to maintain the same binding mode with the target but do not have the same interactions with unintentional cell metabolism steps. Consequently, it automatically decreases the adverse effects linked with these steps [157; 158]. Moreover, the MTDL strategy delayed the emergence of drug-related resistance. Viruses can develop lower sensitivity due to multiple contacts with the drug in monotherapy or lower doses of inhibitors in combinations [146].