# _In Silico_ Development of SARS-CoV-2 Non-Covalent Mpro Inhibitors: A Review
## 1 Introduction
### The Role of Drug Repurposing  
Drug repurposing is an efficient strategy for identifying new therapeutic uses for already approved drugs [13]. This approach gained prominence during the COVID-19 pandemic when speed and safety were critical. One of the key advantages of drug repurposing, particularly for identifying SARS-CoV-2 inhibitors, is its potential to accelerate the drug development process significantly. Since these drugs have already undergone extensive testing for safety and efficacy, they can bypass early-phase trials, allowing for faster progression to clinical evaluation for new indications [29].  
Beyond speed, drug repurposing also minimises the financial risks associated with traditional drug discovery. It capitalises on existing pharmacological and toxicological data, which aids in predicting efficacy and side effects in new disease contexts [25]. Moreover, many of these drugs are already in production, facilitating rapid distribution during public health emergencies [30].  
Recent studies indicate that the effects of SARS-CoV-2 extend beyond the respiratory system (RS) to the central nervous system (CNS), intensifying the need for rapid and effective treatments [30; 31]. In this context, drug repurposing has facilitated the identification  
Figure 3: A selection of approved small-molecule COVID-19 therapeutics and investigational antivirals for SARS-CoV-2 in clinical trials [27].  
of promising Mpro inhibitors. For instance, the noncovalent inhibitor ML188, initially developed for SARS-CoV, was successfully adapted for SARS-CoV-2 [32]. Similarly, compounds such as X77, masitimib, and ML300 have emerged through repurposing pipelines as potential SARS-CoV-2 Mpro inhibitors [33]. These examples underscore the strategic value of repositioning existing drugs to accelerate antiviral drug discovery.  
While several reviews have broadly explored SARS-CoV-2 Mpro inhibitors, many of these articles either conflate covalent and non-covalent classes or lack a detailed analysis of the computational strategies specifically tailored to non-covalent inhibitors. The present review addresses this gap by critically highlighting representative structure-based _in silico_ approaches--including molecular docking, molecular dynamics (MD) simulations, and virtual screening--used in the discovery and optimisation of non-covalent Mpro inhibitors, with a particular emphasis on role of repurposed drug scaffolds, and the increasing importance of robust, high-fidelity MD simulations in elucidating binding mechanisms, and refining lead compounds. Rather than providing an exhaustive survey, this work offers a focused and critical perspective on recent computational advancements that have contributed to the development of these promising compounds, a topic that remains under-discussed in the current literature.  
Importantly, the review also underscores the essential role of in vitro validation to confirm biological relevance and the value of integrated in vitro and in vivo strategies in progressing potential Mpro inhibitors from computational hits to clinically viable candidates. This reinforces the notion that while _in silico_ techniques are powerful and widely used in early-stage drug discovery, they must be complemented by experimental studies to ensure translational impact.