Application of EMBM to Structure‐Based Design of Warheads for Protease Inhibitors

Abstract

Most CADD tools handle non-covalent enzyme inhibitors, despite the growing interest of the pharma industry in covalent inhibitors. We have recently introduced an enzyme mechanism-based method, EMBM, as a computational tool for binding trend analysis and prediction of chemical sites (CS) of reversible covalent enzyme inhibitors. In the current study we demonstrate the utility of EMBM to structure-based applications. In this mode, the energy of the enzyme-inhibitor covalent bond is accounted for by the W1 and W2 covalent descriptors we have developed, whereas the non-covalent interactions between the inhibitor CS and the enzyme active site can be estimated directly on the 3D structure of the enzyme-inhibitor complex.

From Catalytic Mechanism to Rational Design of Reversible Covalent Inhibitors of Serine and Cysteine Hydrolases

“…[113,114] The electrophilicity of the carbon atom and the PA of the oxygen atom of the carbonyl group have the opposite influence on the binding trend of a series of warheads. It was applied for both ligand-( Figure 6) [114] and structure-based (Figure 7) [118] rational design of RCA inhibitors. Detailed physical reasons for the different role of W1 and W2 in the CS reactivity trend can be found in ref.…”

“…When the covalent descriptor did not contribute to the correlation due to either poor alignment of the inhibitors RS fragments in the AS or because the varied substituent in CS was not conjugated with the electrophilic carbonyl, and therefore, had no influence on its electrophilicity. [113,114,118] The first is the energy of reorganization of covalent bonds of the CS during the chemical transformation in the enzyme AS, accounted for by the W1 and W2 covalent descriptors. On the contrary, only W2, but not W1, gave good correlations for the cysteine proteases studied.…”