Piecing the Fragments Together: Dynamical Insights into the Enhancement of BRD4-BD1 (BET Protein) Druggability in Cancer Chemotherapy Using Novel 8-methyl-pyrrolo[1,2-a]pyrazin-1(2H)-one Derivatives

Background: Fragment-based drug discovery in recent times has been explored in the design of highly potent therapeutics. Methods: In this study, we explored the inhibitory dynamics of Compound 38 (Cpd38), a newly synthesized Bromodomain-containing protein 4 bromodomain 1 (BRD4-BD1) protein inhibitor derived from the synthetic coupling of Fragment 47 (Fgt47) into ABBV-075 scaffold. Using dynamic simulation methods, we unraveled the augmentative effects of chemical fragmentation on improved BRD4- BD1 inhibition. Results: Findings from this study revealed that although Fgt47 exhibited a considerable ΔGbind, its incorporation into the difluoro-phenoxy pyridine scaffold (Cpd38) notably enhanced the binding affinity. Time-based analyses of interaction dynamics further revealed that the bulkiness of Cpd38 favored its interaction at the BRD4-BD1 active site relative to the fragment. Strikingly, compared to Fgt47, Cpd38 demonstrated high mobility, which could have enabled it to bind optimally and complementarily with key residues of the active site such as Ile146, Asn140, Cys136, Tyr98, Leu94, Val87, Phe83, and Trp81. Discussion: On the contrary, the majority of these interactions were gradually lost in Fgt47, which could further indicate the essence of coupling it with the difluoro-phenoxy pyridine scaffold. Furthermore, Cpd38 had a more altering effect on BRD4-BDI relative to Fgt47, which could also be a result of its higher inhibitory activity. Conclusion: Conclusively, the design of highly potent therapeutics could be facilitated by the incorporation of pharmacologically active small molecule fragments into the scaffold of existing drugs.