Structure-Based Design of a Benzodiazepine Scaffold Yields a Potent Allosteric Inhibitor of Hepatitis C NS5B RNA Polymerase

Abstract

HCV NS5B polymerase, an essential and virus-specific enzyme, is an important target for drug discovery. Using structure-based design, we optimized a 1,5-benzodiazepine NS5B polymerase inhibitor chemotype into a new sulfone-containing scaffold. The design yielded potent inhibitor (S)-4c (K(D) = 0.79 nM), which has approximately 20-fold greater affinity for NS5B than its carbonyl analogue (R)-2c.

1a/1b Subtype Profiling of Nonnucleoside Polymerase Inhibitors of Hepatitis C Virus

“…On the basis of our earlier studies, we previously concluded that binding of 1,5-BZDs did not lead to a significant conformational change in NS5B (32,36,47). Our present results are consistent with those of our earlier study and allow us to tentatively extend this conclusion to include the 1a enzyme.…”

“…Similar to previous 1b-1,5-BZD complexes, we have described (32,36,47), the NS5B-4 complex is observed in the closed active conformation for both genotypes 1a and 1b. On the basis of our earlier studies, we previously concluded that binding of 1,5-BZDs did not lead to a significant conformational change in NS5B (32,36,47).…”

“…The characteristic right-hand shape with finger, palm, and thumb domains encircling the active site is strictly conserved in the new structure (Fig. 3A), and various structural superimpositions establish that the 1a and 1b structures reported here are similar to previous 1b structures (6,26,32,36,37,47). The three monomers of the asymmetric unit of the new 1a structure are fully consistent, with pairwise C ␣ root mean square deviations (RMSDs) of Յ0.23 Å.…”

“…3A). Another useful frame of reference is comparison to our previous 1b structures with inhibitors of the same 1,5-BZD chemotype (compounds 1 and 2) bound at the same site (32,47). The various monomer-monomer superimpositions of these two previous structures with the new 1b structure are within the RMSD range of 0.31 to 0.65 Å.…”

“…Based on the results in the 1,5-BZD O-benzyl series, structure-based design was used to guide medicinal chemistry and improve upon the potency of the initial leads (47). These efforts resulted in the identification of the 1,1-dioxo-1-thia-5,10-diazadibenzocycloheptene analogs compounds 3 and 4 ( Fig.…”