Inhibitors for matrix metalloproteinases (MMPs) are under investigation for the treatment of cancer, arthritis, and cardiovascular disease. Here, we report a class of highly selective MMP-13 inhibitors (pyrimidine dicarboxamides) that exhibit no detectable activity against other MMPs. The high-resolution X-ray structures of three molecules of this series bound to MMP-13 reveal a novel binding mode characterized by the absence of interactions between the inhibitors and the catalytic zinc. The inhibitors bind in the S1' pocket and extend into an additional S1' side pocket, which is unique to MMP-13. We analyze the determinants for selectivity and describe the rational design of improved compounds with low nanomolar affinity.

Kv1.5 channel blockers prolong atrial action potentials and may prevent atrial flutter or fibrillation without affecting ventricular repolarization. Here we characterize the mechanisms of action of 2Ј-{[2-(4-methoxy-phenyl)-acetylamino]-methyl}-biphenyl-2-carboxylic acid (2-pyridin-3-yl-ethyl)-amide (AVE0118) on Kv1.5 channels heterologously expressed in Xenopus laevis oocytes. Whole cell currents in oocytes were recorded using the two-microelectrode voltage clamp technique. AVE0118 blocked Kv1.5 current in oocytes with an IC 50 of 5.6 M. Block was enhanced by higher rates of stimulation, consistent with preferential binding of the drug to the open state of the channel. Ala-scanning mutagenesis of the pore domain of Kv1.5 identified the amino acids Thr479, Thr480, Val505, Ile508, Val512, and Val516 as important residues for block by AVE0118. A homology model of the pore region of Kv1.5 predicts that these six residues face toward the central cavity of the channel. In addition, mutation of two other S6 residues (Ile502 and Leu510) that are predicted to face away from the central cavity also diminished drug block. All these putative drug-binding residues are highly conserved in other Kv channels, explaining our finding that AVE0118 also blocked Kv1.3, Kv2.1, Kv3.1, and Kv4.3 channels with similar potency. Docking of AVE0118 into the inner cavity of a Kv1.5 pore homology model predicted an unusual binding mode. The drug aligned with the inner S6 ␣-helical domain in a manner predicted to block the putative activation gate. This "foot-in-the-door" binding mode is consistent with the observation that the drug slowed the rate of current deactivation, causing a crossover of tail current traces recorded before and after drug treatment.

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The voltage-gated potassium channel Kv1.5 is regarded as a promising target for the development of new atrial selective drugs with fewer side effects. In the present study the discovery of ortho,ortho-disubstituted bisaryl compounds as blockers of the Kv1.5 channel is presented. Several compounds of this new class were synthesized and screened for their ability to block Kv1.5 channels expressed in Xenopus oocytes. The observed structure-activity relationship (SAR) is described by a pharmacophore model that consists of three hydrophobic centers in a triangular arrangement. The hydrophobic centers are matched by a phenyl or pyridyl ring of the bisaryl core and both ends of the side chains. The most potent compounds (e.g., 17c and 17o) inhibited the Kv1.5 channel with sub-micromolar half-blocking concentrations and displayed 3-fold selectivity over Kv1.3 and no significant effect on the HERG channel and sodium currents. In addition, compounds 17c and 17m have already shown antiarrhythmic effects in a pig model.

During the practice of combinatorial chemistry, it has been realized that molecular diversity is not the only essential feature in a synthetically feasible library. In addition, it is of utmost importance to enrich potential libraries with those molecules which could be converted to viable drug candidates. Given the enormous number of potentially synthesizable compounds, there is a need to design a subset of true "drug-like" compounds. In addition, a paradigm shift in drug discovery has resulted in the integration of pharmacokinetic and drug development activities into early stages of lead discovery. In particular, in silico filters are being developed and used to help identify and screen out compounds that are unlikely to become drugs. This paper highlights recent computational approaches towards the design of drug-like compound libraries, in particular, the prediction of drug-likeness in a more general sense as well as intestinal absorption through passive transport, the permeation of the blood-brain barrier and recent developments towards identification of potentially metabolically unstable molecules. Current computational tools for library design allow the incorporation of medicinal chemistry knowledge into library planning by a variety of methods, ranging from the use of privileged building blocks and simple counting of structural properties (e.g. number of hydrogen bonding partners) to relatively complex regression or neural network-based models to explain oral bioavailability and other pharmacokinetic properties by structural features. These tools are being incorporated more frequently into drug design according to the "rule-of-five" which refers to simple descriptors correlated to oral drug absorption. Combining experimental knowledge with effective computational filtering and prediction of various aspects of drug-likeness thus facilitates the rapid and cost-effective elimination of poor candidates prior to synthesis and helps focus attention on interesting molecules.

BCUTs are an interesting class of molecular descriptor which have been proposed for a number of design and QSAR type tasks. It is important to understand what kind of information any particular descriptor encodes and to be able to relate this to the biological properties of the molecules. In this paper we present studies with BCUTs for the classification of ATP site directed kinase inhibitors active against five different protein kinases: three from the serine/threonine family and two from the tyrosine kinase family. In combination with a chemometric method, PLS discriminant analysis, the BCUTs are able to correctly classify the ligands according to their target. A novel class of kinase inhibitors is correctly predicted as inhibitors of the EGFR tyrosine kinase. Comparison with other descriptor types such as two-dimensional fingerprints and three-dimensional pharmacophore-based descriptors allows us to gain an insight into the level of information contained within the BCUTs.

Kv1.5 channels conduct the ultrarapid delayed rectifier current (I Kur ) that contributes to action potential repolarization of human atrial myocytes. Block of these channels has been proposed as a treatment for atrial arrhythmias. Here we report a novel and potent inhibitor of Kv1.5 potassium channels, N-benzyl-N-pyridin-3-yl-methyl-2-(toluene-4-sulfonylamino)-benzamide hydrochloride (S0100176), which exhibits features consistent with preferential block of the open state. The IC 50 of S0100176 for Kv1.5 expressed in Xenopus oocytes was 0.7 M. Ala-scanning mutagenesis within the pore helix and the S6 segment, regions that form the walls of the central cavity, was combined with voltage clamp analysis to identify point mutations that altered drug affinity. This approach identified Thr-479, Thr-480, Val-505, Ile-508, and Val-512 as the most important residues for block by S0100176. Mutations of these key residues to Ala or other amino acids caused marked changes in the IC 50 of S0100176 (p < 0.01). For example, the IC 50 of S0100176 increased 362-fold for T480A, 26-fold for V505A, 150-fold for I508A, and 99-fold for V512A. We used modeling to dock S0100176 into the inner cavity of a Kv1.5 pore homology model that was generated based on the crystal structure of KcsA. The docking predicted that the five residues identified by the Ala scan were positioned less than 4.5 Å from the compound. Based on the homology models, the positions of the five amino acids identified to interact with S0100176 face toward the central cavity and overlap with putative binding sites for other blockers and voltage-gated potassium channels.

To gain insight into the structural determinants for the matrix metalloproteinase (MMP) family, we characterized the binding sites of 56 MMP structures and one TACE (tumor necrosis factor alpha converting enzyme) structure using molecular interaction fields (MIFs). These MIFs were produced by two approaches: the GRID force field and the knowledge-based potential DrugScore. The subsequent statistical analysis using consensus principal component analysis (CPCA) for the entire binding site and each subpockets revealed both approaches to encode similar information about discriminating regions. However, the relative importance of the probes varied between both approaches. The CPCA models provided the following ranking of the six subpockets based on the opportunity for selective interactions with different MMPs: S1' > S2, S3, S3' > S1, S2'. The interpretation of these models agreed with experimental binding modes inferred from crystal structures or docking.