Docking Ligands into Flexible and Solvated Macromolecules. 8. Forming New Bonds─Challenges and Opportunities.

Over the years, structure-based design programs and specifically docking small molecules to proteins have become prominent in drug discovery. However, many of these computational tools have been developed to primarily dock enzyme inhibitors (and ligands to other protein classes) relying heavily on hydrogen bonds and electrostatic and hydrophobic interactions. In reality, many drug targets either feature metal ions, can be targeted covalently, or are simply not even proteins (e.g., nucleic acids). Herein, we describe several new features that we have implemented into Fitted to broaden its applicability to a wide range of covalent enzyme inhibitors and to metalloenzymes, where metal coordination is essential for drug binding. This updated version of our docking program was tested for its ability to predict the correct binding mode of drug-sized molecules in a large variety of proteins. We also report new datasets that were essential to demonstrate areas of success and those where additional efforts are required. This resource could be used by other program developers to assess their own software.

14 examples of how LLMs can transform materials science and chemistry: a reflection on a large language model hackathon.

Large-language models (LLMs) such as GPT-4 caught the interest of many scientists. Recent studies suggested that these models could be useful in chemistry and materials science. To explore these possibilities, we organized a hackathon. This article chronicles the projects built as part of this hackathon. Participants employed LLMs for various applications, including predicting properties of molecules and materials, designing novel interfaces for tools, extracting knowledge from unstructured data, and developing new educational applications. The diverse topics and the fact that working prototypes could be generated in less than two days highlight that LLMs will profoundly impact the future of our fields. The rich collection of ideas and projects also indicates that the applications of LLMs are not limited to materials science and chemistry but offer potential benefits to a wide range of scientific disciplines.

Modulating the selectivity of inhibitors for prolyl oligopeptidase inhibitors and fibroblast activation protein-α for different indications.

We have previously described several different chemical series of bicyclic prolyl oligopeptidase (POP) inhibitors as probes for neurodegenerative diseases that demonstrated nanomolar activity in vitro and submicromolar activity in cellulo. The more recent implication of POP in cancer, together with homologous fibroblast activation protein α (FAP), implicated in tumor growth, led us to consider developing POP/FAP dual inhibitors as a promising strategy for the development of cancer therapeutics. At this stage, we thought to evaluate the requirements for selectivity of inhibitors for POP over FAP and to evaluate molecular platforms that would enable the development of selective POP and dual POP/FAP inhibitors. We report herein docking-guided design of a new bicyclic scaffold and synthesis of both covalent and non-covalent bicyclic inhibitors. Biological evaluation of first-of-their-kind [4.3.0] bicyclic compounds confirmed that reactive groups, or covalent warheads, are required for inhibitor activity. This work ultimately led to one scaffold yielding new POP-selective inhibitors and a dual inhibitor equipotent to the only drug targeting FAP and POP that ever reached clinical trials.

Design, synthesis and in vitro evaluation of novel SARS-CoV-2 3CLpro covalent inhibitors.

Severe diseases such as the ongoing COVID-19 pandemic, as well as the previous SARS and MERS outbreaks, are the result of coronavirus infections and have demonstrated the urgent need for antiviral drugs to combat these deadly viruses. Due to its essential role in viral replication and function, 3CLpro (main coronaviruses cysteine-protease) has been identified as a promising target for the development of antiviral drugs. Previously reported SARS-CoV 3CLpro non-covalent inhibitors were used as a starting point for the development of covalent inhibitors of SARS-CoV-2 3CLpro. We report herein our efforts in the design and synthesis of submicromolar covalent inhibitors when the enzymatic activity of the viral protease was used as a screening platform.

Inhibition of vascular calcification by inositol phosphates derivatized with ethylene glycol oligomers.

Myo-inositol hexakisphosphate (IP6) is a natural product known to inhibit vascular calcification (VC), but with limited potency and low plasma exposure following bolus administration. Here we report the design of a series of inositol phosphate analogs as crystallization inhibitors, among which 4,6-di-O-(methoxy-diethyleneglycol)-myo-inositol-1,2,3,5-tetrakis(phosphate), (OEG2)2-IP4, displays increased in vitro activity, as well as more favorable pharmacokinetic and safety profiles than IP6 after subcutaneous injection. (OEG2)2-IP4 potently stabilizes calciprotein particle (CPP) growth, consistently demonstrates low micromolar activity in different in vitro models of VC (i.e., human serum, primary cell cultures, and tissue explants), and largely abolishes the development of VC in rodent models, while not causing toxicity related to serum calcium chelation. The data suggest a mechanism of action independent of the etiology of VC, whereby (OEG2)2-IP4 disrupts the nucleation and growth of pathological calcification.

Characterization of Calcium Phosphate Nanoparticles Based on a PEGylated Chelator for Gene Delivery.

Calcium phosphate (CaP) nanoparticles are promising gene delivery carriers due to their bioresorbability, ease of preparation, high gene loading efficacy, and endosomal escape properties. However, the rapid aggregation of the particles needs to be addressed in order to have potential in vivo. In addition, there is a need to better understand the relationship between CaP nanoparticle properties and their interactions with cells. Here, a new synthesis route involving click chemistry was developed to prepare the PEGylated chelator PEG-inositol 1,3,4,5,6-pentakisphosphate (PEG-IP5) that can coat and stabilize CaP nanoparticles. Two methods (1 and 2) differing on the time of addition of the PEGylated chelator were employed to produce stabilized particles. Method 1 yielded amorphous aggregated spheres with a particle size of about 200 nm, whereas method 2 yielded 40 nm amorphous loose aggregates of clusters, which were quickly turned into needle bundle-like crystals of about 80 nm in a few hours. Nanoparticles prepared by method 1 were internalized with significantly higher efficiency in HepG2 cells than those prepared by method 2, and the uptake was dramatically influenced by the reaction time of Ca2+ and PO43- and sedimentation of the particles. Interestingly, morphological transformations were observed for both types of particles after different storage times, but this barely influenced their in vitro cellular uptake. The transfection efficiency of the particles prepared by method 1 was significantly higher, and none of the formulations tested showed signs of cytotoxicity. This study provides a better understanding of the properties (e.g., size, morphology, and crystallinity) of PEGylated CaP nanoparticles and how these influence the particles' in vitro uptake and transfection efficiency.