The most potent design based on MD predictions is molecule 2 (∆G = -23 ± 4 kcal/mol, Table ). This molecule -which is the largest one among the designs (Figure ) -engages extensively with the binding pocket of MAPK1 (Figure ), which explains the remarkably favorable predicted affinity. It is important to highlight, however, that the synthetic accessibility of compound 2 might be limited. Design 3 is predicted with the second highest affinity (∆G = -19.6 ± 0.9 kcal/mol), and it differs from compound 13 due to the replacement of the ether and hydroxy moieties with two fluorine atoms, and the addition of a methoxy group (Figure ). Interestingly, this structural modification leads to an improvement of the predicted ∆G value (of approximately -10 kcal/mol), possibly due to the ability to penetrate deeply into the binding pocket thanks to the fluorine atoms (Figure ). Halogens are, in fact, favorable for MAPK1, as evident from the fine-tuning molecules (91% of them containing at least one halogen) and existing literature (e.g., ). Evidence of a favorable positioning of halogens is shown on both the 'top' ) and 'bottom' ) of the binding pocket, further supporting the predicted affinity of compound 3.