Introduction:
Blocking Human Immunodeficiency Virus type 1 (HIV-1) entry via C-C chemokine receptor 5
(CCR5) inhibition has remained an essential strategy in HIV drug discovery. This underlies the development of CCR5
blockers, such as Maraviroc, which, however, elicits undesirable side effects despite its potency.
Background:
Recent lead optimization efforts led to the discovery of novel 1-heteroaryl-1,3-propanediamine derivatives;
Compd-21 and -34, which were ~3 times more potent than Maraviroc, with improved pharmacokinetics. However, atomistic
molecular interaction mechanism of how slight structural variance between these inhibitors significantly affects their binding profiles have not been elucidated.
Method:
This study employed explicit lipid bilayer molecular dynamics (MD) simulations, and advance analyses to explore
these inhibitory discrepancies.
Results:
Findings revealed that the thiophene moiety substitution common to Compd-21 and -34 enhanced their CCR5-
inhibitory activities due to complementary high-affinity interactions with Trp862.60, Tyr1083.32, Tyr2516.51, Glu2837.39. These
cumulatively accounted for their ΔGbind which were higher than Maraviroc. Binding dynamics further revealed that the
compounds mediated direct competitive inhibition at CCR5 by blocking the gp120 V3 loop. Furthermore, constituent tropane and triazole moieties in the compounds commonly engaged in interactions with Glu2837.39 and Trp862.60, respectively.
Structural analyses also revealed that both Compd-21 and -34 elicited distinct internal dynamic effect on CCR5 relative to
Maraviroc.
Conclusion:
Structural modifications at the thiophene substituent and the addition of new functional groups to the triazole
ring may enhance inhibitor competition with gp120 V3-loop. Findings herein highlighted would contribute to future structure-based design of inhibitors of HIV-1 CCR5 with improved potencies.
Temperature chaos is present in off-equilibrium spin-glass dynamics