P3 scaffolds Compound 5c (Tokyo University)

We report the design and synthesis of a series of dipeptide-type inhibitors with novel P3 scaffolds that display potent inhibitory activity against SARS-CoV 3CLpro. A docking study involving binding between the dipeptidic lead compound 4 and 3CLpro suggested the modification of a structurally flexible P3 N-(3-methoxyphenyl)glycine with various rigid P3 moieties in 4. The modifications led to the identification of several potent derivatives, including 5c-k and 5n with the inhibitory activities (Ki or IC50) in the submicromolar to nanomolar range. Compound 5h, in particular, displayed the most potent inhibitory activity, with a Ki value of 0.006 μM. This potency was 65-fold higher than the potency of the lead compound 4 (Ki=0.39 μM). In addition, the Ki value of 5h was in very good agreement with the binding affinity (16 nM) observed in isothermal titration calorimetry (ITC). A SAR study around the P3 group in the lead 4 led to the identification of a rigid indole-2-carbonyl unit as one of the best P3 moieties (5c). Further optimization showed that a methoxy substitution at the 4-position on the indole unit was highly favorable for enhancing the inhibitory potency.

In the present work, an extensive QSAR (Quant. Structure Activity Relationships) anal. of a series of peptide-type SARS-CoV main protease (MPro) inhibitors following the OECD guidelines has been accomplished.The anal. was aimed to identify salient and concealed structural features that govern the MPro inhibitory activity of peptide-type compoundsThe QSAR anal. is based on a dataset of sixty-two peptide-type compounds which resulted in the generation of statistically robust and highly predictive multiple models.All the developed models were validated extensively and satisfy the threshold values for many statistical parameters (for e.g. R² = 0.80-0.82, Q²_loo = 0.74-0.77, Q²_LMO = 0.66-0.67).The developed QSAR models identified number of sp² hybridized Oxygen atoms within seven bonds from aromatic Carbon atoms, the presence of Carbon and Nitrogen atoms at a topol. distance of 3 and other interrelations of atom pairs as important pharmacophoric features.Hence, the present QSAR models have a good balance of Qual. (Descriptive QSARs) and Quant. (Predictive QSARs) approaches, therefore useful for future modifications of peptide-type compounds for anti- SARS-CoV activity.