Kenno Vanommeslaeghe

The chromatographic separation of pharmaceutically relevant enantiomers is an important clinical and economical issue. A popular class of chiral stationary phases used for this purpose employs polysaccharide-based chiral selectors. In the present work, the structure and dynamics of two representative polysaccharide-based chiral selectors, amylose tris(3,5-dimethylphenylcarbamate) and cellulose tris(3,5-dimethylphenylcarbamate) were studied, using explicit solvent molecular dynamics. The conformational ensemble emerging from this work is substantially more disordered than what is often assumed in the literature. We show that existing nuclear Overhauser effect spectroscopy (NOESY) results on an amylose tris(3,5-dimethylphenylcarbamate) substituted disaccharide are compatible with an equilibrium between two major conformations. While longer oligomers are substantially more constrained due to steric crowding, there is still considerable conformational flexibility in our simulations, even more so in more polar solvent mixtures that are representative for reversed-phase liquid chromatography conditions. Either way, we conclude that explicitly accounting for the conformational freedom of polysaccharide-based selectors will be important for future studies aimed at predicting enantioselectivity.

In this work, chiral molecular descriptors were defined using 2 distinct approaches: (1) scalar triple products of vectorial molecular properties, and (2) descriptors that attempt to quantify the amount of twist in the overall molecular shape. Because both approaches give rise to conformation dependence, descriptor values were averaged over a conformational ensemble obtained by Molecular Dynamics. In addition, a method is introduced that attempts to quantify the asymmetry of the distribution of the descriptor values over the conformational ensemble. The totality of the resulting descriptors were named “Ensemble Steric and Electrostatic Chirality (ESEC) descriptors”. A pilot validation study was performed by building Quantitative Structure-Enantioselectivity Relationships (QSER), i.e. mathematical models to predict the chromatographic separation of enantiomers, using a test set of 43 structurally diverse pharmaceuticals analyzed on a polysaccharide-based chiral stationary phase. The best linear regression model (7 descriptors) for the chiral separation (expressed as selectivity factor) featured a low leave-one-out cross validation error (0.0814), a well-predicted elution sequence of the separated enantiomers (21 out of 23 molecules) and a well-predicted α _RS for 27 out of 42 molecules. To the best of our knowledge, this is the first time that acceptable linear QSER models were obtained for chiral chromatographic separations of such a chemically diverse set of pharmaceuticals.

The serotonin-2A receptor (5-HT_2AR) is an interesting target for drug design in the context of antidepressants that might have a rapid onset of action and/or be effective in treatment-resistant cases. The main challenge, however, is that the activation of this receptor can provoke hallucinations. Recent studies have shown that activating the receptor with certain (partial) agonists could potentially give rise to antidepressant effect without hallucinogenic side effects. Although substantial research has been done in this area, the atomistic details of this differential activation of the serotonin-2A receptor are not fully understood. In the present study we performed multiple atomistic molecular dynamics (MD) simulations on 5-HT_2AR bound with two antipsychotics, three different potential non-hallucinogens and two hallucinogens to identify the receptor’s ligand dependent conformations. Overall, our findings suggest that modest 5-HT_2AR activation would only yield antidepressant effects and hallucinations result from excessive activation. While modest activation through microdosing may be problematic on account of abuse potential as well as possibly narrow and patient-dependent therapeutic windows, modest activation through administration of a sufficiently weak partial agonist may offer a viable drug development pathway.

The serotonin-2A receptor (5-HT _2A R) is an interesting target for drug design in the context of antidepressants that might have a rapid onset of action and/or be effective in treatment-resistant cases. The main challenge, however, is that the activation of this receptor can provoke hallucinations. Recent studies have shown that activating the receptor with certain (partial) agonists could potentially give rise to antidepressant effect without hallucinogenic side effects. Although substantial research has been done in this area, the atomistic details of this differential activation of the serotonin-2A receptor are not fully understood. In the present study we performed multiple atomistic molecular dynamics (MD) simulations on 5-HT _2A R bound with an antipsychotic, two different potential non-hallucinogenic antidepressants and a hallucinogen to identify the receptor’s ligand dependent conformations. Overall, our findings suggest that modest 5-HT _2A R activation would only yield antidepressant effects and hallucinations result from excessive activation. While modest activation through microdosing may be problematic on account of abuse potential as well as possibly narrow and patient-dependent therapeutic windows, modest activation through administration of a sufficiently weak partial agonist may offer a viable drug development pathway. Author Summary: Activating the serotonin-2A receptor (5-HT2AR) with specific agonists is a promising strategy for the development of a new class of antidepressants. However, potent agonists such as LSD, DMT or psylocibin generally cause hallucinations. To aid the development of 5-HT2AR-targeted antidepressants that do not cause this side effect, we seek to gain a better understanding of the receptor by studying its activation mechanism. Specifically, we performed molecular dynamics simulations to explore how different drugs interact with 5-HT2AR, both in the absence and presence of an intracellular binding partner. This led to the identification of tentative intermediate states along the activation pathway, which could be linked to the ligands’ pharmacological properties. Our findings suggest that hallucinogens cause an excessive build-up of activated receptors, whereas carefully designed mild activators could lead to a new generation of antidepressants that do not induce hallucinations.

The Pauli repulsion is the intermolecular force responsible for the volume and low compressibility of condensed-phase matter at normal conditions. A simple model for this force is presented, wherein per-atom electron densities are represented as spherical charge distributions that are prevented from significantly overlapping. In the example of two noble gas atoms approaching one another beyond their van der Waals radii, the distance between the centers of the electronic charge distributions becomes larger than the distance between the nuclei, giving rise to an unfavorable electrostatic interaction. For the purpose of calculating this interaction, the model is further simplified by representing the per-atom electron density as a negative point charge, loosely inspired by the classical Drude oscillator. The dispersion interaction is simplified to an R-6 term, centered on the aforementioned point charges. Despite the gross simplicity of the resulting formalism, near-quantitative agreement with high-level QM interaction energies of noble gas dimers is achieved. Accordingly, the present model is thought to have utility in force fields, in post-HF and post-DFT dispersion corrections, and in chemical education.

The Pauli repulsion is the intermolecular force responsible for the volume and low compressibility of condensed-phase matter at normal conditions. A simple model for this force is presented, in which per-atom electron densities are represented as spherical charge distributions that are prevented from significantly overlapping. In the example of two noble gas atoms approaching one another beyond their van der Waals radii, the distance between the centers of the electronic charge distributions becomes larger than the distance between the nuclei, giving rise to an unfavorable electrostatic interaction. For the purpose of calculating this interaction, the model is further simplified by representing the per-atom electron density as a negative point charge, inspired by the classical Drude oscillator. The dispersion interaction is simplified to an R^-6term, centered on the aforementioned point charges. Despite the gross simplicity of the resulting formalism, near-quantitative agreement with high-level QM interaction energies of noble gas dimers is achieved. Accordingly, the present model is thought to have utility in force fields, in post-HF and post-DFT dispersion corrections and in chemical education.

The cystine/glutamate antiporter system x_c⁻(Sx_c⁻) belongs to the SLC7 family of plasma membrane transporters. It exports intracellular glutamate along the latter’s concentration gradient as a driving force for cellular uptake of cystine. Once imported, cystine is mainly used for the production of glutathione, a tripeptide thiol crucial in maintenance of redox homeostasis and protection of cells against oxidative stress. Overexpression of Sx_c⁻has been found in several cancer cells, where it is thought to counteract the increased oxidative stress. In addition, Sx_c⁻is important in the central nervous system, playing a complex role in regulating glutamatergic neurotransmission and glutamate toxicity. Accordingly, this transporter is considered a potential target for the treatment of cancer as well as neurodegenerative diseases. Till now, no specific inhibitors are available. We herein present four conformations of Sx_c⁻along its transport pathway, obtained using multi-template homology modeling and refined by means of Molecular Dynamics. Comparison with a very recently released cryo-EM structure revealed an excellent agreement with our inward-open conformation. Intriguingly, our models contain a structured N-terminal domain that is unresolved in the experimental structures and is thought to play a gating role in the transport mechanism of other SLC7 family members. In contrast to the inward-open model, there is no direct experimental counterpart for the other three conformations we obtained, although they are in fair agreement with the other stages of the transport mechanism seen in other SLC7 transporters. Therefore, our models open the prospect for targeting alternative Sx_c⁻conformations in structure-based drug design efforts.

Rationale: The BCL6 oncogene is constitutively activated by chromosomal translocations and amplification in ABC-DLBCLs, a class of DLBCLs that respond poorly to current therapies. Yet the role of BCL6 in maintaining these lymphomas has not been investigated. BCL6 mediates its effects by recruiting corepressors to an extended groove motif. Development of effective BCL6 inhibitors requires compounds exceeding the binding affinity of these corepressors. Objectives: To design small molecule inhibitors with superior potency vs. endogenous BCL6 ligands for unmet putative therapeutic needs such as targeting ABC-DLBCL. Findings: We used an in silico drug design functional-group mapping approach called SILCS to create a specific BCL6 inhibitor with 10-fold greater potency than endogenous corepressors. The compound, called FX1, binds in such a way as to occupy an essential region of the BCL6 lateral groove. FX1 disrupts BCL6 repression complex formation, reactivates BCL6 target genes, and mimics the phenotype of mice engineered to express BCL6 with lateral groove mutations. This compound eradicated established DLBCLs xenografts at low doses. Most strikingly, FX1 suppressed ABC-DLBCL cells as well as primary human ABC-DLBCL specimens ex vivo. Conclusions: ABC-DLBCL is a BCL6 dependent disease that can be targeted by novel inhibitors able to exceed the binding affinity of natural BCL6 ligands. Citation Format: Mariano Gonzalo Cardenas, Wenbo Yu, Wendy Beguelin, Teater R. Matthew, Huimin Geng, Rebecca Goldstein, Erin Oswald, Katerina Hatzi, Shao-Ning Yang, Joanna Cohen, Rita Shaknovich, Kenno Vanommeslaeghe, Huimin Cheng, Dongdong Liang, Hyoje Cho, Joshua Abbott, Wayne Tam, John P. Leonard, Leandro Cerchietti, Tomasz Cierpicki, Fengtian Xue, Alexander D. MacKerell, Jr., Ari Melnick. Therapeutic targeting of GCB- and ABC-DLBCLS by rationally designed BCL6 inhibitors. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr A11.