Background: NS5B polymerase remains an important anti-hepatitis C virus (HCV) drug target.
It has been well reported that ligand binding induces large conformational changes in the receptor.
Several computational models describing polymerase dynamics have been reported. Various conformational
forms have been determined by crystallography and NMR experiments and they suggest the binding
of HCV inhibitors in allosteric sites might affect polymerase flexibility.
Objective: In most of the cases of structure-based drug design (SBDD), only static structures have been
given consideration and most molecular modeling studies have recognized the importance of flexibility.
The standard virtual docking methods using rigid receptor may give misleading results as in reality
many proteins undergo side-chain and/or backbone movements. The importance of HCV NS5B polymerase
receptor flexibility in altering the binding site to complement the shape and binding mode of the
ligand i.e. induced fit docking need to be considered.
Method: The various methodologies were adopted for molecular modeling based on induced-fit docking
at the well-defined inhibitor binding sites i.e. “palm” and “thumb” domain. Some of the well reported
NNIs and NIs are VX-222, ANA598/Setrobuvir, CS01, aureusidin, N,N-disubstituted phenylalanine,
benzothiadiazine, 6-aminoquinoline derivatives, etc.
Results: These assumptions have lead to application of quantum mechanics and induced-fit docking for
the development of various HCV NS5B polymerase inhibitors. This enzyme has proved to be challenging
and therefore potential ligands with structural diversity have been modified to enhance selectivity
and affinity. The flexible nature of HCV polymerase, reveals details about substrate-inhibitor interaction
to its active site within the membrane.
Conclusion: It will help to develop allosteric inhibitors into efficient drugs by understanding their indirect
mode of action and complex structure-activity/kinetic relationship.