CHEM MED CHEM (submitted)

Abstract

Thymidine monophosphate kinase (TMPKmt) is an essential enzyme of nucleotide metabolism of the Mycobacterium tuberculosis and an attractive target for novel antituberculosis agents. In this work, we have explored the chemical space of 2’,3’-bicyclic thymidine derivatives by designing, structure-based focusing and in silico screening of a virtual library with the goal to propose more potent analogs endowed with favorable ADME-related properties. In the library design, we have exchanged the ribose ring of the template inhibitor with a cyclopentane moiety that is less prone to enzymatic degradation. In addition, we have replaced the six-membered 2’,3’-ring by a number of five-membered and six-membered heterocyclic rings containing alternative proton donor and acceptor groups able to interact with the carboxylate group of Asp9, and a number of cationic residues present in the vicinity of the TMPKmt binding site. The three-dimensional structure of the TMPKmt forming a complex with an analog of dTMP, the 5-hydroxymethyl-dUMP inhibitor, was employed to develop a QSAR model, parameterize a scoring function specific for the TMPKmt target and select analogues which display the highest predicted binding to the target. We have derived a small highly focused combinatorial subset of bicyclic thymidine analogues, which contains virtual hits that are predicted to inhibit the mycobacterial TMPK in the submicromolar concentration range and display favorable ADME-related properties.