Computational characteristics of the structure-activity relationship of inhibitors targeting Pks13-TE domain

Multiple studies have established the Pks13-TE domain as a promising target for anti-tuberculosis drug development. However, recent findings have revealed that the lead compound currently in the pipeline for Pks13-TE has significant cardiotoxicity issues. Given the pressing need for new chemical structures for Pks13-TE inhibitors, this study aims to provide a detailed understanding of the Pks13-TE domain binding site through the application of computational chemical biology techniques. Our results highlight the size and shape of the Pks13-TE domain binding pocket, key residues including Asp1644, Asn1640, Phe1670, and Tyr1674 within the pocket, and inhibitor pharmacophore characteristics such as aromatic ring sites, positively charged sites, and hydrogen bond donors. To our knowledge, these simulation results are novel and contribute to the discovery of next-generation Pks13-TE inhibitors without similar prior studies. [Display omitted] •The binding site of the Pks13-TE domain was adequately investigated through multiple simulations.•Molecular docking and BPMD precisely model the binding modes of inhibitors, uncovering key residues and SAR.•Unbiased MD confirms key residue interactions and stabilities, highly consistent with molecular docking.•Various of analysis methods, such as MM/GBSA, ASM, FEP, confirm our conclusions, and the outcomes are as expected.