A DFT Study of the Inhibition of the Papain-like Protease (PLpro) from the SARS Coronavirus by a Group of 4-Piperidinecarboxamide Derivatives

Abstract

We present an analysis of the relationships between the electronic structure and the SARS coronavirus papain-like protease inhibitory capacity of a series of 4-piperidinecarboxamide derivatives. The electronic structure of all the molecules was calculated within the Density Functional Theory at the B3LYP/6- 31g(d,p) level with full geometry optimization. We found a statistically significant relationship between the variation of the inhibitory capacity and the variation of the values of local atomic reactivity indices pertaining to five atoms of a common skeleton (n=15, adj R2=0.91, F(5,9)=29.79 (p<0.00002), SD=0.24). Molecular electrostatic potentials and conformational aspects of the molecules are discussed. A partial inhibitory pharmacophore is proposed and discussed. This is another example of the needlessness of using hundreds or thousands of reactivity indices and descriptors to get useful physically-based information from experimental results.