KRAS is vulnerable to reversible switch-II pocket engagement in cells.

Current small-molecule inhibitors of KRAS(G12C) bind irreversibly in the switch-II pocket (SII-P), exploiting the strong nucleophilicity of the acquired cysteine as well as the preponderance of the GDP-bound form of this mutant. Nevertheless, many oncogenic KRAS mutants lack these two features, and it remains unknown whether targeting the SII-P is a practical therapeutic approach for KRAS mutants beyond G12C. Here we use NMR spectroscopy and a cellular KRAS engagement assay to address this question by examining a collection of SII-P ligands from the literature and from our own laboratory. We show that the SII-Ps of many KRAS hotspot (G12, G13, Q61) mutants are accessible using noncovalent ligands, and that this accessibility is not necessarily coupled to the GDP state of KRAS. The results we describe here emphasize the SII-P as a privileged drug-binding site on KRAS and unveil new therapeutic opportunities in RAS-driven cancer.

Development of an effective two-equation turbulence modeling approach for simulating aerosol deposition across a range of turbulence levels.

Pharmaceutical aerosol systems present a significant challenge to computational fluid dynamics (CFD) modeling based on the need to capture multiple levels of turbulence, frequent transition between laminar and turbulent flows, anisotropic turbulent particle dispersion, and near-wall particle transport phenomena often within geometrically complex systems over multiple time scales. Two-equation turbulence models, such as the k-ω family of approximations, offer a computationally efficient solution approach, but are known to require the use of near-wall (NW) corrections and eddy interaction model (EIM) modifications for accurate predictions of aerosol deposition. The objective of this study was to develop an efficient and effective two-equation turbulence modeling approach that enables accurate predictions of pharmaceutical aerosol deposition across a range of turbulence levels. Key systems considered were the traditional aerosol deposition benchmark cases of a 90-degree bend (Re=6,000) and a vertical straight section of pipe (Re=10,000), as well as a highly complex case of direct-to-infant (D2I) nose-to-lung pharmaceutical aerosol delivery from an air-jet dry powder inhaler (DPI) including a patient interface and infant nasal geometry through mid-trachea (500

Novel Compound Heterozygous ZAP70 R37G A507T Mutations in Infant with Severe Immunodeficiency.

Zeta-chain associated protein kinase 70 kDa (ZAP70) combined immunodeficiency (CID) is an autosomal recessive severe immunodeficiency that is characterized by abnormal T-cell receptor signaling. Children with the disorder typically present during the first year of life with diarrhea, failure to thrive, and recurrent bacterial, viral, or opportunistic infections. To date, the only potential cure is hematopoietic stem cell transplant (HSCT). The majority of described mutations causing disease occur in the homozygous state, though heterozygotes are reported without a clear understanding as to how the individual mutations interact to cause disease. This case describes an infant with novel ZAP-70 deficiency mutations involving the SH2 and kinase domains cured with allogeneic HSCT utilizing a reduced-intensity conditioning regimen and graft manipulation. We then were able to further elucidate the molecular signaling alterations imparted by these mutations that lead to altered immune function. In order to examine the effect of these novel compound ZAP70 heterozygous mutations on T cells, Jurkat CD4+ T cells were transfected with either wild type, or with individual ZAP70 R37G and A507T mutant constructs. Downstream TCR signaling events and protein localization results link these novel mutations to the expected immunological outcome as seen in the patient's primary cells. This study further characterizes mutations in the ZAP70 gene as combined immunodeficiency and the clinical phenotype.

Near Elimination of In Vitro Predicted Extrathoracic Aerosol Deposition in Children Using a Spray-Dried Antibiotic Formulation and Pediatric Air-Jet DPI.

PURPOSE: This study evaluated the in vitro aerosol performance of a dry powder antibiotic product that combined a highly dispersible tobramycin powder with a previously optimized pediatric air-jet dry powder inhaler (DPI) across a subject age range of 2-10 years. METHODS: An excipient enhanced growth (EEG) formulation of the antibiotic tobramycin (Tobi) was prepared using a small particle spray drying technique that included mannitol as the hygroscopic excipient and trileucine as the dispersion enhancer. The Tobi-EEG formulation was aerosolized using a positive-pressure pediatric air-jet DPI that included a 3D rod array. Realistic in vitro experiments were conducted in representative airway models consistent with children in the age ranges of 2-3, 5-6 and 9-10 years using oral or nose-to-lung administration, non-humidified or humidified airway conditions, and constant or age-specific air volumes. RESULTS: Across all conditions tested, mouth-throat depositional loss was < 1% and nose-throat depositional loss was < 3% of loaded dose. Lung delivery efficiency was in the range of 77.3-85.1% of loaded dose with minor variations based on subject age (~ 8% absolute difference), oral or nasal administration (< 2%), and delivered air volume (< 2%). Humidified airway conditions had an insignificant impact on extrathoracic depositional loss and significantly increased aerosol size at the exit of a representative lung chamber. CONCLUSIONS: In conclusion, the inhaled antibiotic product nearly eliminated extrathoracic depositional loss, demonstrated high efficiency nose-to-lung antibiotic aerosol delivery in pediatric airway models for the first time, and provided ~ 80% lung delivery efficiency with little variability across subject age and administered air volume.

Defective Mitochondrial Dynamics and Protein Degradation Pathways Underlie Cadmium-Induced Neurotoxicity and Cell Death in Huntington's Disease Striatal Cells.

Exposure to heavy metals, including cadmium (Cd), can induce neurotoxicity and cell death. Cd is abundant in the environment and accumulates in the striatum, the primary brain region selectively affected by Huntington's disease (HD). We have previously reported that mutant huntingtin protein (mHTT) combined with chronic Cd exposure induces oxidative stress and promotes metal dyshomeostasis, resulting in cell death in a striatal cell model of HD. To understand the effect of acute Cd exposure on mitochondrial health and protein degradation pathways, we hypothesized that expression of mHTT coupled with acute Cd exposure would cooperatively alter mitochondrial bioenergetics and protein degradation mechanisms in striatal STHdh cells to reveal novel pathways that augment Cd cytotoxicity and HD pathogenicity. We report that mHTT cells are significantly more susceptible to acute Cd-induced cell death as early as 6 h after 40 µM CdCl2 exposure compared with wild-type (WT). Confocal microscopy, biochemical assays, and immunoblotting analysis revealed that mHTT and acute Cd exposure synergistically impair mitochondrial bioenergetics by reducing mitochondrial potential and cellular ATP levels and down-regulating the essential pro-fusion proteins MFN1 and MFN2. These pathogenic effects triggered cell death. Furthermore, Cd exposure increases the expression of autophagic markers, such as p62, LC3, and ATG5, and reduces the activity of the ubiquitin-proteasome system to promote neurodegeneration in HD striatal cells. Overall, these results reveal a novel mechanism to further establish Cd as a pathogenic neuromodulator in striatal HD cells via Cd-triggered neurotoxicity and cell death mediated by an impairment in mitochondrial bioenergetics and autophagy with subsequent alteration in protein degradation pathways.

Structural mapping of GABRB3 variants reveals genotype-phenotype correlations.

PURPOSE: Pathogenic variants in GABRB3 have been associated with a spectrum of phenotypes from severe developmental disorders and epileptic encephalopathies to milder epilepsy syndromes and mild intellectual disability (ID). In this study, we analyzed a large cohort of individuals with GABRB3 variants to deepen the phenotypic understanding and investigate genotype-phenotype correlations. METHODS: Through an international collaboration, we analyzed electro-clinical data of unpublished individuals with variants in GABRB3, and we reviewed previously published cases. All missense variants were mapped onto the 3-dimensional structure of the GABRB3 subunit, and clinical phenotypes associated with the different key structural domains were investigated. RESULTS: We characterized 71 individuals with GABRB3 variants, including 22 novel subjects, expressing a wide spectrum of phenotypes. Interestingly, phenotypes correlated with structural locations of the variants. Generalized epilepsy, with a median age at onset of 12 months, and mild-to-moderate ID were associated with variants in the extracellular domain. Focal epilepsy with earlier onset (median: age 4 months) and severe ID were associated with variants in both the pore-lining helical transmembrane domain and the extracellular domain. CONCLUSION: These genotype-phenotype correlations will aid the genetic counseling and treatment of individuals affected by GABRB3-related disorders. Future studies may reveal whether functional differences underlie the phenotypic differences.

Evaluation of the Polyhedral Mesh Style for Predicting Aerosol Deposition in Representative Models of the Conducting Airways.

A critical factor affecting the accuracy of Computational Fluid Dynamic (CFD) simulations and the time required to conduct them is construction of the computational mesh. This study aimed to evaluate the relatively new polyhedral mesh style for simulating aerosol deposition in the upper conducting airways compared with established meshing techniques and experimental data. Hexahedral and polyhedral mesh solutions were compared in two benchmark geometries: 1) a 90°-bend with flow characteristics similar to the extrathoracic airways of an adolescent child, and 2) a double bifurcation representing bifurcations B3-B5 in an adult. Both 4-block and 5-block hexahedral meshes were used in the 90°-bend to capture the potential of fully-structured hexahedral meshes. In the 90°-bend, polyhedral elements matched polydisperse in vitro deposition data with 20% relative error (RE; averaged across the particle sizes considered), which is an improvement on the accuracy of the 4-block hexahedral mesh (35% RE) and is similar to the accuracy of the 5-block hexahedral mesh (19% RE). In the double bifurcation, deposition fraction relative differences evaluated between polyhedral and hexahedral meshes ranged from 0.3% to 28.6% for the different particle sizes assessed, which is an order of magnitude improvement compared with previous studies that considered hexahedral vs. hybrid tetrahedral-prism meshes for the same flow field. Solution convergence time with polyhedral elements was found to be 50% to 140% higher than with hexahedral meshes of comparable size. While application dependent, the increase in simulation time observed with polyhedral meshes will likely be outweighed by the ease and convenience of polyhedral mesh construction. It was concluded that the polyhedral mesh style, with sufficient resolution especially near the walls, is an excellent alternative to the highly regarded hexahedral mesh style for predicting upper airway aerosol transport and deposition and provides a powerful new tool in the assessment of respiratory aerosol dosimetry.

Patient-Centered Discussion on End-of-Life Care for Patients with Advanced COPD.

Exacerbations of chronic obstructive pulmonary disease (COPD) may lead to a rapid decline in health and subsequent death, an unfortunate tyranny of having COPD-an irreversible health condition of 16 million individuals in the USA totaling 60 million in the world. While COPD is the third largest leading cause of death, causing 3.23 million deaths worldwide in 2019 (according to the WHO), most patients with COPD do not receive adequate treatment at the end stages of life. Although death is inevitable, the trajectory towards end-of-life is less predictable in severe COPD. Thus, clinician-patient discussion for end-of-life and palliative care could bring a meaningful life-prospective to patients with advanced COPD. Here, we summarized the current understanding and treatment of COPD. This review also highlights the importance of patient-centered discussion and summarizes current status of managing patients with advanced COPD.

Discovery of a heme-binding domain in a neuronal voltage-gated potassium channel.

The EAG (ether-à-go-go) family of voltage-gated K+ channels are important regulators of neuronal and cardiac action potential firing (excitability) and have major roles in human diseases such as epilepsy, schizophrenia, cancer, and sudden cardiac death. A defining feature of EAG (Kv10-12) channels is a highly conserved domain on the N terminus, known as the eag domain, consisting of a Per-ARNT-Sim (PAS) domain capped by a short sequence containing an amphipathic helix (Cap domain). The PAS and Cap domains are both vital for the normal function of EAG channels. Using heme-affinity pulldown assays and proteomics of lysates from primary cortical neurons, we identified that an EAG channel, hERG3 (Kv11.3), binds to heme. In whole-cell electrophysiology experiments, we identified that heme inhibits hERG3 channel activity. In addition, we expressed the Cap and PAS domain of hERG3 in Escherichia coli and, using spectroscopy and kinetics, identified the PAS domain as the location for heme binding. The results identify heme as a regulator of hERG3 channel activity. These observations are discussed in the context of the emerging role for heme as a regulator of ion channel activity in cells.

Novel genetic testing model: A collaboration between genetic counselors and nephrology.

Many barriers to genetic testing currently exist which delay or prevent diagnosis. These barriers include wait times, staffing, education, and cost. Specialists are able to identify patients with disease that may need genetic testing, but lack the genetics support to facilitate that testing in the most cost, time, and medically effective manner. The Nephrology Division and the Genetic Testing Stewardship Program at Nemours A.I. duPont Hospital for Children created a novel service delivery model in which nephrologists and genetic counselors collaborate in order to highlight their complementary strengths (clinical expertise of nephrologists and genetics and counseling skills of genetic counselors). This collaboration has reduced many barriers to care for our patients. This workflow facilitated the offering of genetic testing to 76 patients, with 86 tests completed over a 20-month period. Thirty-two tests were deferred. Twenty-seven patients received a diagnosis, which lead to a change in their medical management, three of whom were diagnosed by cascade family testing. Forty-two patients had a negative result and 16 patients had one or more variants of uncertain significance on testing. The inclusion of genetic counselors in the workflow is integral toward choosing the most cost and time effective genetic testing strategy, as well as providing psychosocial support to families. The genetic counselors obtain informed consent, and review genetic test results and recommendations with the patient and their family. The availability of this program to our patients increased access to genetic testing and helps to provide diagnoses and supportive care.

Diversity-orientated synthesis of macrocyclic heterocycles using a double SNAr approach.

An efficient macrocyclisation approach based on the double aromatic nucleophilic substitution (SNACK) was developed. This methodology allows a facile incorporation of heterocyclic motifs into macrocyclic rings and rapid synthesis of a significant number of structurally diverse macrocycles. SNACK macrocyclisation enables preparation of stable diastereoisomers of conformationally restricted macrocycles (atropisomers). Practical application of SNACK macrocyclisation in a drug discovery project was exemplified by the identification of high affinity macrocyclic binders of B-cell lymphoma 6 (BCL6).

Identification of Three Small Molecules That Can Selectively Influence Cellular Manganese Levels in a Mouse Striatal Cell Model.

Manganese (Mn) is a biologically essential metal, critical as a cofactor for numerous enzymes such a glutamine synthetase and kinases such as ataxia-telangiectasia mutated (ATM). Similar to other essential metals such as iron and zinc, proper levels of Mn need to be achieved while simultaneously being careful to avoid excess levels of Mn that can be neurotoxic. A lifetime of occupational exposure to Mn can often lead to a Parkinsonian condition, also known as "manganism", characterized by impaired gait, muscle spasms, and tremors. Despite the importance of its regulation, the mechanisms underlying the transport and homeostasis of Mn are poorly understood. Rather than taking a protein or gene-targeted approach, our lab recently took a high-throughput-screening approach to identify 41 small molecules that could significantly increase or decrease intracellular Mn in a neuronal cell model. Here, we report characterization of these small molecules, which we refer to as the "Mn toolbox". We adapted a Fura-2-based assay for measuring Mn concentration and for measuring relative concentrations of other divalent metals: nickel, copper, cobalt, and zinc. Of these 41 small molecules, we report here the identification of three that selectively influence cellular Mn but do not influence the other divalent metals tested. The patterns of activity across divalent metals and the discovery of Mn-selective small molecules has potential pharmacological and scientific utility.

Alkynyl Benzoxazines and Dihydroquinazolines as Cysteine Targeting Covalent Warheads and Their Application in Identification of Selective Irreversible Kinase Inhibitors.

With a resurgence in interest in covalent drugs, there is a need to identify new moieties capable of cysteine bond formation that are differentiated from commonly employed systems such as acrylamide. Herein, we report on the discovery of new alkynyl benzoxazine and dihydroquinazoline moieties capable of covalent reaction with cysteine. Their utility as alternative electrophilic warheads for chemical biological probes and drug molecules is demonstrated through site-selective protein modification and incorporation into kinase drug scaffolds. A potent covalent inhibitor of JAK3 kinase was identified with superior selectivity across the kinome and improvements in in vitro pharmacokinetic profile relative to the related acrylamide-based inhibitor. In addition, the use of a novel heterocycle as a cysteine reactive warhead is employed to target Cys788 in c-KIT, where acrylamide has previously failed to form covalent interactions. These new reactive and selective heterocyclic warheads supplement the current repertoire for cysteine covalent modification while avoiding some of the limitations generally associated with established moieties.

Rheological and Ionic Transport Properties of Nanocomposite Electrolytes Based on Protic Ionic Liquids and Silica Nanoparticles.

In this study, the effect of hydrophilic silica nanoparticle (AEROSIL 200) addition on the rheological and transport properties of several protic ionic liquids (PILs) consisting of protonated 1,8-diazabicyclo[5.4.0]undec-7-ene cation (DBU) was studied. Interactions between the surface silanol groups of the silica nanoparticles and the ions of these PILs affected the nature of particle aggregation and the hydrogen bonding environment, which was reflected in the nonlinear rheological behaviors and transport properties of their colloidal suspensions. In contrast to shear-thinning gels formed by colloidal suspensions of the silica nanoparticles in [DBU][TFSA] ([TFSA] = [N(SO2CF3)2]), [DBU][TfO] ([TfO] = [CF3SO3]), and [DBU][TFA] ([TFA] = [CF3CO2]), a shear-thickening stable suspension was formed in the [DBU][MSA] ([MSA] = [CH3SO3]) system. A relatively strong interaction between the silanol groups and the ions of [DBU][MSA] and the ability of this PIL to form a thicker solvation layer through hydrogen bonding were assumed to be responsible for this unique behavior. Moreover, the [DBU][MSA]-silica system showed a large enhancement in the conductivity at a certain silica concentration. This enhancement was not observed in the other PIL-silica composites that exhibited shear-thinning behavior. Even though diffusion of ions was found to be restricted in the presence of silica, a preferentially stronger interaction between [MSA] anions and the silica surface resulted in an increase in the number of charge carriers.

Application of Ionic Liquids to Energy Storage and Conversion Materials and Devices.

Ionic liquids (ILs) are liquids consisting entirely of ions and can be further defined as molten salts having melting points lower than 100 °C. One of the most important research areas for IL utilization is undoubtedly their energy application, especially for energy storage and conversion materials and devices, because there is a continuously increasing demand for clean and sustainable energy. In this article, various application of ILs are reviewed by focusing on their use as electrolyte materials for Li/Na ion batteries, Li-sulfur batteries, Li-oxygen batteries, and nonhumidified fuel cells and as carbon precursors for electrode catalysts of fuel cells and electrode materials for batteries and supercapacitors. Due to their characteristic properties such as nonvolatility, high thermal stability, and high ionic conductivity, ILs appear to meet the rigorous demands/criteria of these various applications. However, for further development, specific applications for which these characteristic properties become unique (i.e., not easily achieved by other materials) must be explored. Thus, through strong demands for research and consideration of ILs unique properties, we will be able to identify indispensable applications for ILs.

Li-ion hopping conduction in highly concentrated lithium bis(fluorosulfonyl)amide/dinitrile liquid electrolytes.

Li+ ion hopping conduction in highly concentrated solutions of lithium bis(fluorosulfonyl)amide (LiFSA) dissolved in dinitrile solvents, namely succinonitrile, glutaronitrile, and adiponitrile, was investigated. Phase behaviors of the LiFSA/dinitrile binary mixtures assessed by differential scanning calorimetry suggested that LiFSA and the dinitriles form stable solvates in a molar ratio of 1 : 2. For succinonitrile, a glass forming room temperature liquid is formed when [LiFSA]/[succinonitrile] > 1. The corresponding glutaronitrile and adiponitrile mixtures have melting points below 60 °C. The self-diffusion coefficients of Li+, FSA-, and dinitrile measured with pulsed field gradient NMR suggested that Li+ ion diffuses faster than anion and dinitrile in the liquids of composition [LiFSA]/[dinitrile] = 1/0.8, indicating emergence of Li+ ion hopping conduction. X-ray crystallography for the LiFSA-(dinitrile)2 solvates and Raman spectroscopy for the liquids with composition [LiFSA]/[dinitrile] > 1 revealed that the two cyano groups of the dinitrile coordinate to two different Li+ ions and form solvent-bridged structures of (Li+-dinitrile-Li+). In addition, the Raman spectra suggested that ionic aggregates (Li+-FSA--Li+) are formed in the liquids with composition [LiFSA]/[dinitrile] > 1. Although there is frequent ligand (dinitrile and/or anion) exchange for each Li+ ion in the liquid state, the polymeric network structures (solvent-bridged structure and ionic aggregates) restrict the facile motion of ligands because each ligand is interacting with multiple Li+ ions in the highly concentrated electrolytes. This induces the faster diffusion of the Li+ ion than that of the ligands, i.e., hopping conduction of Li+ through ligand exchange. Electrochemical measurements clarified that the [LiFSA]/[succinonitrile] = 1/0.8 electrolyte possesses a relatively high Li+ transport ability (limiting current density > 7 mA cm-2) thanks to the Li+ hopping conduction, regardless of its extremely high viscosity (3142 mPa s) and relatively low conductivity (0.26 mS cm-1) at room temperature. Furthermore, this electrolyte was shown to have a high Li+ transference number (>0.6), exhibited reversible Li metal deposition/dissolution i.e. suppression of reductive decomposition of the solvent, and could be successfully applied to graphite and LiNi1/3Mn1/3Co1/3O2 half-cells.

Ionic transport in highly concentrated lithium bis(fluorosulfonyl)amide electrolytes with keto ester solvents: structural implications for ion hopping conduction in liquid electrolytes.

Recent studies have suggested that a Li ion hopping or ligand- or anion-exchange mechanism is largely involved in Li ion conduction of highly concentrated liquid electrolytes. To understand the determining factors for the Li ion hopping/exchange dominant conduction in such liquid systems, ionic diffusion behavior and Li ion coordination structures of concentrated liquid electrolytes composed of lithium bis(fluorosulfonyl)amide (Li[FSA]) and keto ester solvents with two carbonyl coordinating sites of increasing intramolecular distance (methyl pyruvate (MP), methyl acetoacetate (MA), and methyl levulinate (ML)) were studied. Diffusivity measurements of MP- and MA-based concentrated electrolytes showed faster Li ion diffusion than the solvent and FSA anion, demonstrating that Li ion diffusion was dominated by the Li ion hopping/exchange mechanism. A solvent-bridged, chain-like Li ion coordination structure and highly aggregated ion pairs (AGGs) or ionic clusters e.g. Lix[FSA]y(y-x)- forming in the electrolytes were shown to contribute to Li ion hopping conduction. By contrast, ML, with greater intramolecular distance between the carbonyl moieties, is more prone to form a bidentate complex with a Li cation, which increased the contribution of the vehicle mechanism to Li ion diffusion even though similar AGGs and ionic clusters were also observed. The clear correlation between the unusual Li ion diffusion and the solvent-bridged, chain-like structure provides an important insight into the design principles for fast Li ion conducting liquid electrolytes that would enable Li ion transport decoupled from viscosity-controlled mass transfer processes.

Magnesium bis(trifluoromethanesulfonyl)amide complexes with triglyme and asymmetric homologues: phase behavior, coordination structures and melting point reduction.

The phase behavior of binary mixtures of triglyme (G3) and Mg[TFSA]2 (TFSA: bis(trifluoromethanesulfonyl)amide) was investigated, towards the development of a Mg2+-based room-temperature solvate ionic liquid (SIL) electrolyte. In a 1 : 1 molar ratio, G3 and Mg[TFSA]2 form a thermally stable complex (decomposition temperature, Td: 240 °C) with a melting point (Tm) of 70 °C, which is considerably lower than that of the analogous tetraglyme (G4) system (137 °C). X-ray crystallography of a single crystal of [Mg(G3)][TFSA]2 revealed that a single Mg2+ cation is coordinated by a single, distorted, tetradentate G3 molecule from one side, and two monodentate [TFSA]- anions, with transoid conformation, from the reverse side to form an ion pair. Raman spectra of [Mg(G3)][TFSA]2 in the molten state revealed the presence of different coordination structures, as the liquid exhibits changes in the vibrational modes corresponding to G3 and the [TFSA]- anion compared to those observed for the solid. Investigation of the ion pair stabilization energies by DFT calculations suggests that higher stability cation complexes and ion pairs co-exist in the molten state than those observed in the crystalline state. These results imply that the coordination structures of the ion pairs play a key role in providing SILs with low Tm. To decrease the Tm further, several asymmetric homologues of G3, which have higher conformational flexibility than G3, were investigated. Notably, a 1 : 1 mixture of Mg[TFSA]2 with G3Bu (where one of the terminal methyl groups of G3 is substituted for a butyl group) formed a thermally stable complex (Td: 251 °C) without any distinct Tm and showed reasonable ionic conductivity at room-temperature, indicating partial dissociation of ions. In this electrolyte, which showed high oxidative stability, quasi-reversible Mg deposition/dissolution was achieved, indicating that Mg2+-based room-temperature SILs can be utilized as a new class of Mg electrolyte.

PromptSMILES: prompting for scaffold decoration and fragment linking in chemical language models.

SMILES-based generative models are amongst the most robust and successful recent methods used to augment drug design. They are typically used for complete de novo generation, however, scaffold decoration and fragment linking applications are sometimes desirable which requires a different grammar, architecture, training dataset and therefore, re-training of a new model. In this work, we describe a simple procedure to conduct constrained molecule generation with a SMILES-based generative model to extend applicability to scaffold decoration and fragment linking by providing SMILES prompts, without the need for re-training. In combination with reinforcement learning, we show that pre-trained, decoder-only models adapt to these applications quickly and can further optimize molecule generation towards a specified objective. We compare the performance of this approach to a variety of orthogonal approaches and show that performance is comparable or better. For convenience, we provide an easy-to-use python package to facilitate model sampling which can be found on GitHub and the Python Package Index.Scientific contributionThis novel method extends an autoregressive chemical language model to scaffold decoration and fragment linking scenarios. This doesn't require re-training, the use of a bespoke grammar, or curation of a custom dataset, as commonly required by other approaches.