IMP-1088

The pharmacological inhibition of human N‐myristoyltransferase (HsNMT) has emerged as an efficient strategy to completely prevent the replication process of rhinoviruses, a potential treatment for the common cold. This was corroborated by the recent discovery of compound IMP‐1088, a novel inhibitor that demonstrated a dual‐inhibitory activity against the two HsNMT subtypes 1 and 2 without inducing cytotoxicity. However, the molecular and structural basis for the dual‐inhibitory potential of IMP‐1088 has not been investigated. As such, we employ molecular modelling techniques to resolve the structural mechanisms that account for the dual‐inhibitory prowess of IMP‐1088. Sequence and nanosecond‐based analyses identified Tyr296, Phe190, Tyr420, Leu453, Gln496, Val181, Leu474, Glu182, and Asn246 as residues common within the binding pockets of both HsNMT1 and HsNMT2 subtypes whose consistent interactions with IMP‐1088 underpin the basis for its dual inhibitory potency. Nano‐second‐based assessment of interaction dynamics revealed that Tyr296 consistently elicited high‐affinity π‐π stacked interaction with IMP‐1088, thus further highlighting its cruciality corroborating previous report. An exploration of resulting structural changes upon IMP‐1088 binding further revealed a characteristic impeding of residue fluctuations, structural compactness, and a consequential burial of crucial hydrophobic residues, features required for HsNMT1/2 functionality. Findings present essential structural perspectives that augment previous experimental efforts and could also advance drug development for treating respiratory tract infections, especially those mediated by rhinoviruses.