Title: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
Volume: 23
Issue: 3
Author(s): Oluwole B. Akawa, Opeyemi S. Soremekun, Fisayo A. Olotu and Mahmoud E.S. Solima*
Affiliation:
- Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal,
Westville Campus, Durban, 4001, South Africa
Keywords:
Fragmentation-based drug discovery, molecular dynamics simulation, prostate cancer, bromodomain and extraterminal proteins (BET), Bromodomain-containing Protein 4 Bromodomain 1 (BRD4-BD1), chemotherapy.
Abstract: 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.
