Prediction of pKa Values for Druglike Molecules Using Semiempirical Quantum Chemical Methods.

Rapid yet accurate pKa prediction for druglike molecules is a key challenge in computational chemistry. This study uses PM6-DH+/COSMO, PM6/COSMO, PM7/COSMO, PM3/COSMO, AM1/COSMO, PM3/SMD, AM1/SMD, and DFTB3/SMD to predict the pKa values of 53 amine groups in 48 druglike compounds. The approach uses an isodesmic reaction where the pKa value is computed relative to a chemically related reference compound for which the pKa value has been measured experimentally or estimated using a standard empirical approach. The AM1- and PM3-based methods perform best with RMSE values of 1.4-1.6 pH units that have uncertainties of ±0.2-0.3 pH units, which make them statistically equivalent. However, for all but PM3/SMD and AM1/SMD the RMSEs are dominated by a single outlier, cefadroxil, caused by proton transfer in the zwitterionic protonation state. If this outlier is removed, the RMSE values for PM3/COSMO and AM1/COSMO drop to 1.0 ± 0.2 and 1.1 ± 0.3, whereas PM3/SMD and AM1/SMD remain at 1.5 ± 0.3 and 1.6 ± 0.3/0.4 pH units, making the COSMO-based predictions statistically better than the SMD-based predictions. For pKa calculations where a zwitterionic state is not involved or proton transfer in a zwitterionic state is not observed, PM3/COSMO or AM1/COSMO is the best pKa prediction method; otherwise PM3/SMD or AM1/SMD should be used. Thus, fast and relatively accurate pKa prediction for 100-1000s of druglike amines is feasible with the current setup and relatively modest computational resources.

Open Source Antibiotics: Simple Diarylimidazoles Are Potent against Methicillin-Resistant Staphylococcus aureus.

Antimicrobial resistance (AMR) is widely acknowledged as one of the most serious public health threats facing the world, yet the private sector finds it challenging to generate much-needed medicines. As an alternative discovery approach, a small array of diarylimidazoles was screened against the ESKAPE pathogens, and the results were made publicly available through the Open Source Antibiotics (OSA) consortium (https://github.com/opensourceantibiotics). Of the 18 compounds tested (at 32 µg/mL), 15 showed >90% growth inhibition activity against methicillin-resistant Staphylococcus aureus (MRSA) alone. In the subsequent hit-to-lead optimization of this chemotype, 147 new heterocyclic compounds containing the diarylimidazole and other core motifs were synthesized and tested against MRSA, and their structure-activity relationships were identified. While potent, these compounds have moderate to high intrinsic clearance and some associated toxicity. The best overall balance of parameters was found with OSA_975, a compound with good potency, good solubility, and reduced intrinsic clearance in rat hepatocytes. We have progressed toward the knowledge of the molecular target of these phenotypically active compounds, with proteomic techniques suggesting TGFBR1 is potentially involved in the mechanism of action. Further development of these compounds toward antimicrobial medicines is available to anyone under the licensing terms of the project.

Escaping from Flatland: Antimalarial Activity of sp3-Rich Bridged Pyrrolidine Derivatives.

We utilized synthetic photochemistry to generate novel sp3-rich scaffolds and report the design, synthesis, and biological testing of a diverse series of amides based on the 1-(amino-methyl)-2-benzyl-2-aza-bicyclo[2.1.1]hexane scaffold. Preliminary antimalarial screening of the library provided promising compounds with activity in the 1-5 µM range with an enhanced hit rate. Further evaluation (solubility, drug metabolism and pharmacokinetics (DMPK), and toxicity) of a selected compound (9) suggested that this series represents an excellent opportunity for further optimization with the framework offering multiple opportunities for the addition of uniquely vectorally positioned extra functionality.

Bifunctional crosslinking ligands for transthyretin.

Wild-type and variant forms of transthyretin (TTR), a normal plasma protein, are amyloidogenic and can be deposited in the tissues as amyloid fibrils causing acquired and hereditary systemic TTR amyloidosis, a debilitating and usually fatal disease. Reduction in the abundance of amyloid fibril precursor proteins arrests amyloid deposition and halts disease progression in all forms of amyloidosis including TTR type. Our previous demonstration that circulating serum amyloid P component (SAP) is efficiently depleted by administration of a specific small molecule ligand compound, that non-covalently crosslinks pairs of SAP molecules, suggested that TTR may be also amenable to this approach. We first confirmed that chemically crosslinked human TTR is rapidly cleared from the circulation in mice. In order to crosslink pairs of TTR molecules, promote their accelerated clearance and thus therapeutically deplete plasma TTR, we prepared a range of bivalent specific ligands for the thyroxine binding sites of TTR. Non-covalently bound human TTR-ligand complexes were formed that were stable in vitro and in vivo, but they were not cleared from the plasma of mice in vivo more rapidly than native uncomplexed TTR. Therapeutic depletion of circulating TTR will require additional mechanisms.

Evidence for an enhancement of excitatory transmission in adult CNS by Wnt signaling pathway modulation.

The role for Wnt signaling modulation during synaptogenesis, neurogenesis and cell fate specification have been well characterized. In contrast, the roles for Wnt signaling pathways in the regulation of synaptic plasticity and adult physiology are only starting to be elucidated. Here, we have identified a novel series of Wnt pathway small molecule modulators, and report that these and other small molecules targeting the Wnt pathway acutely enhance excitatory transmission in adult hippocampal preparations. Our findings are consistent with a pre- and postsynaptic site of action, leading to both increased spontaneous and evoked neurotransmission that occurs in a transcription-independent fashion.

Identification and optimisation of 5-amino-7-aryldihydro-1,4-diazepines as 5-HT2A ligands.

A several series of low molecular weight 5-HT(2A) leads were identified from an analysis of HTS data, the exploration of SAR and optimization of one series using parallel synthesis are described, affording compound 22 (5-HT(2A) IC(50) 1.1 nM).

Synthesis and structure-activity relationships of 8-azabicyclo[3.2.1]octane benzylamine NK1 antagonists.

A series of 8-azabicyclo[3.2.1]octane amine hNK1 antagonists has been investigated and structure-activity relationships of the benzylamine and 6-exo substituents described. Acidic substituents at C6 give a series of high affinity compounds for hNK1 with selectivity over the hERG channel.

Novel lactam NK1 antagonists with anti-emetic activity.

A series of 4,4-disubstituted cyclohexylamine NK(1) antagonists containing a lactam ring is described. The compounds are brain penetrant and activity is demonstrated in a ferret emesis model.

Spirocyclic NK(1) antagonists II: [4.5]-spiroethers.

A series of novel spiroether-based neurokinin-1 (NK(1)) antagonists is described. The effect of modifications to the spiroether ring and aromatic substituents are discussed, leading to the identification of compounds with high affinity and excellent CNS penetration.

4,4-Disubstituted cyclohexylamine NK(1) receptor antagonists I.

A series of novel 4,4-disubstituted cyclohexylamine based NK(1) antagonists is described. The effect of changes to the C(1)-C(4) relative stereochemistry on the cyclohexane ring and replacements for the flexible linker are discussed, leading to the identification of compounds with high affinity and good in vivo duration of action.

Spirocyclic NK(1) antagonists I: [4.5] and [5.5]-spiroketals.

A series of novel spiroketal-based NK(1) antagonists is described. The effect of modifications to the spiroether ring and aromatic substituents are discussed, leading to the identification of compounds with high affinity and excellent CNS penetration.

4,4-Disubstituted cyclohexylamine NK(1) receptor antagonists II.

A series of novel 4,4-disubstituted cyclohexylamines as NK(1) receptor antagonists is described: modifications to the amine moiety retain NK(1) receptor binding affinity whilst disrupting I(Kr) affinity.