Fragment Based Drug Design (FBDD)

The crystal structure of SARS-COV-2 RNA-dependent RNA polymerase in complex with Remdesivir was retrieved from the protein data bank ID (7bv2) (Yin et al., 2020). A cavity surrounding the co-crystalized Remdesivir was constructed by Discovery studio 2016 (Dassault Systèmes BIOVIA, 2016). The cavity was extended to make good use of the entire active site. Then, a fragment-based approach was implemented using the de novo receptor strategy to fetch fragments from a library of fragments that fit properly into the active site of the enzyme (Böhm, 1992). The default Ludi fragments library found in the discovery studio, which contains 1,053 diverse fragments with molecular weights less than (300 KD), was used as the input source of fragments. The strength of binding of the retrieved fragments from the search was evaluated by docking to the receptor cavity using MCSS (Multiple Copy Simultaneous Search) (Caflisch et al., 1993; Evensen et al., 1997). Finally, the successful fragments were linked together with suitable carbon linkers to produce compound MAW-22 ([(2S)-3-[2-amino-5-[(1R)-1-[6-amino-4-(dihydroxymethylene)-1H-pyridin-2-yl]propyl]-4-pyridyl]-2-carboxy-2-[(2-carboxybenzoyl)amino]propyl]-[(1S)-1-carboxypropyl]ammonium). The binding strength of the generated compound was evaluated from the docking stage.