Albeit considerate of SASA around the target residue, the DeepCoSI platform was able to capture at least 28% (high accuracy ranked) and at most 76% of the ligandable cysteines (the total of high and medium accuracy predictions using ranking-based scores). In contrast to ranking-based score, the proportion of top predicted ligandable cystines based on probability score of the algorithm matched that of the empirical data at least 19% and at most 40% of the time. (Figure ). Treating the same apo-covPDB samples as empirical cysteine chemoproteomics data points and assessing them for ligandability using the simplistic and advanced approaches correctly assessed 78% and 92% of the ligandable cysteines, respectively. As exemplified, covalent ligandability evaluation techniques purely dependent on computational methods may misrepresent a real ligandable site whereas that which uses the simplistic rigid protein models for site ligandability evaluation may fail to detect hidden or novel sites. By maximizing the number of correct predictions, the advanced ligandability approach which considers protein conformational fluctuations in assessing ligandable cavities around experimental sites is an ideal method to be adopted in site-directed and covalent drug discovery pipelines.