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Activation of PKG1α is a compelling strategy for the treatment of cardiovascular diseases. As the main effector of cyclic guanosine monophosphate (cGMP), activation of PKG1α induces smooth muscle relaxation in blood vessels, lowers pulmonary blood pressure, prevents platelet aggregation, and protects against cardiac stress. The development of activators has been mostly limited to cGMP mimetics and synthetic peptides. Described herein is the optimization of a piperidine series of small molecules to yield activators that demonstrate

Ligand efficiency has proven to be a valuable concept for optimization of leads in the early stages of drug design. Taking this one step further, group efficiency (GE) evaluates the binding efficiency of each appendage of a molecule, further fine‐tuning the drug design process. Here, GE analysis is used to systematically improve the potency of inhibitors of Mycobacterium tuberculosis pantothenate synthetase, an important target in tuberculosis therapy. Binding efficiencies were found to be distributed unevenly within a lead molecule derived using a fragment‐based approach. Substitution of the less efficient parts of the molecule allowed systematic development of more potent compounds. This method of dissecting and analyzing different groups within a molecule offers a rational and general way of carrying out lead optimization, with potential broad application within drug discovery.

Fragment-based methods are a new and emerging approach for the discovery of protein binders that are potential new therapeutic agents. Several ways of utilizing structural information to guide the inhibitor assembly have been explored to date. One of the approaches, application of interligand Overhauser effect (ILOE) observations, is of particular interest, as it does not require the availability of a three-dimensional protein structure and is an NMR-based method that can be applied to targets that cannot be observed directly because of their size. Fragments, as small and often hydrophobic molecules, suffer from problems including compound aggregation in an aqueous environment and nonspecific binding contributions, especially when screened at higher concentrations suitable for ILOE observations. Here we report how this problem can be overcome by applying a step-by-step iterative procedure that includes the application of optimized probe molecules with known binding modes to elucidate the unknown binding modes of fragments. An enzyme substrate with well-characterized binding was used as a starting point, and the relative binding modes of modified fragments derived from ILOE observations were used to guide the fragment linking, leading to a potent inhibitor of our model system, Mycobacterium tuberculosis pantothenate synthetase, a potential drug target. We have supported our NMR data with crystal structures, thus establishing the guidelines for optimizing the ILOE observations. This model study should expand the application of the technique in drug discovery.

Herein, we describe a combi-nation of fragment-growing and fragment-linking approachesthat led to the discovery of a new series of inhibitors ofM. tuberculosis PS for the further validation of PS as apotential drug target for TB.We devised a systematic strategy for fragment screening,validation, and characterization