Histone deacetylase (HDAC) 8 has been implicated as a potential therapeutic target in a variety of cancers, neurodegenerative disorders, metabolic dysregulation, and autoimmune and inflammatory diseases. Several nonselective HDAC inhibitors, including SAHA, TSA, M344, PTSB-hydroxamate, CRA19156, aroyl pyrrole hydroxy amide (APHA), Trapoxin A, and largazole thiol, have been co-crystallized with HDAC8. Molecular dynamics (MD) studies examining the stability of these inhibitors in the active site of HDAC8 may provide a better sampling of the binding poses over time. Here, using 11 X-ray crystal structures of human HDAC8 (complexes) structure-based pharmacophore models were built and clustered based on distance which is a function of the number of common pharmacophore features and the root-mean-squared displacement between the matching features. Based on this information, one complex from each pharmacophore cluster (total of 7 pharmacophore clusters) was selected for further studies. A total of 7 complexes (1T64, 1W22, 3RQD, 3SFF, 3F0R, 5VI6, and 5FCW) were processed by insertion of missing atoms in incomplete residues, modelling missing loop regions based on primary sequence of the respective proteins, deleting alternate conformations, and protonating titratable residues using predicted pKa values. These complexes were then submitted to 200 ns-MD simulations.

Intermolecular interactions in human HDAC8 crystal structures and the stability of binding modes of co-crystallized inhibitors

The number of women students enrolling in chemistry programs and the number of women faculty, publications from women chemists is increasing. Also, the number of patents issued by the USPTO and the WIPO are also increasing each year. However, the growth in number of women chemists taking their expertise and research work beyond teaching and  publishing,  to make their contributions more impactful to society by commercializing their work is not very prominent. The presentation will discuss how women chemists can leverage their subject matter expertise and problem solving skills to the next level. A road map on how to transition from being a researcher to an innovator and entrepreneur (if needed) to make their discoveries in the lab translate into products that have an impact/benefit to a larger section of the society around us, will be discussed.

Transitioning from a chemist to an innovator and an entrepreneur

The goal of the patent system is to encourage innovation by giving inventors the exclusive right to use their creations. But enforcing those rights requires engaging in the sometimes lengthy and complex process of patent litigation, which can be a daunting proposition. This presentation will cover the different stages of U.S. patent litigation—everything from initiating a lawsuit to challenging the outcome on appeal—and will discuss common issues that arise at each stage. It will also touch on additional considerations and procedures applicable to pharmaceutical patent litigation under the Hatch-Waxman Act.

Protecting inventions through litigation in the United States: What every chemist needs to know

Lanthanide oxide and boride clusters have complex electronic structures that arise due to the partial occupation of the lanthanide-centered 4f subshells. Density functional theory calculations were performed on a class of lanthanide-based clusters in order to explore the electronic and molecular structures of these clusters. Our results show intriguing structure and bonding trends, which are dependent on the nature of the ligands in addition to the oxidation state of the lanthanide center. Natural ionization orbital analysis was also used to determine the nature of electron detachment in photoelectron spectra of these species and probe resulting electron rearrangement upon ionization. As this presentation will show, such analysis allows us to differentiate between one-electron detachments and shake-up/shake-off transitions.

Modeling the photodetachment processes of lanthanide oxide and boride clusters

&lt;!--StartFragment --&gt;The most important challenges and opportunities in environmental science that impact society require effective forms of dissemination. Science and technology are major drivers of social change and this project will engage chemists to collaborate with humanists to disseminate unprecedented global challenges impacting the environment. Films will be showcased that are aligned with the meeting theme in the areas of ‘People and Water’, ‘Land and Water’, and ‘Water’s Effect on Chemistry’.&lt;!--EndFragment --&gt;

Environmental chemistry through the transformation power of film: An environmental film competition of CEI & ENVR

Not satisfied with nature’s vast catalyst repertoire, we want to create new protein catalysts and expand the space of genetically encoded enzyme functions. I will describe how we can use the most powerful biological design process, evolution, to optimize existing enzymes and invent new ones, thereby circumventing our profound ignorance of how sequence encodes function. Using mechanistic understanding and mimicking nature’s evolutionary processes, we can generate whole new enzyme families that catalyze synthetically important reactions not known in biology. Recent successes include selective carbene insertion to form C-Si and C-B bonds, and alkyne cyclopropanation to make highly strained carbocycles, all in living cells. Extending the capabilities and uncovering the mechanisms of these new enzymes derived from natural iron-heme proteins provides a basis for discovering new biocatalysts for increasingly challenging reactions. These new capabilities increase the scope of molecules and materials we can build using synthetic biology and move us closer to a sustainable world where chemical synthesis can be fully programmed in DNA.

Innovation by evolution: Bringing new chemistry to life

The hydrogen bond is one of the most versatile units of chemical, material and biological systems facilitating water’s many anomalous properties, promoting efficient proton transport in fuel cell membranes, and endowing catalytic functionality in enzymatic reactions. The hydrogen bond arises from the interplay of the quantum mechanical behavior of the light hydrogen nucleus and its electrons. In this talk I will show how our recent developments, which allow us to efficiently simulate the quantum mechanical nature of both the nuclei and electrons, provide insights into how hydrogen bonds are harnessed in chemical and biological processes ranging from the atmospheric separation of hydrogen isotopes, to the spectroscopy and transport of aqueous protons, and proton delocalization in enzyme active sites.

Harnessing the quantum mechanics of the hydrogen bond: From atmospheric science to enzyme catalysis

Grand canonical Monte Carlo (GCMC) simulations of H2 sorption were performed in different members of the M-MOF-74 series (M = Mg, Ni, Co, Zn, Cu), a family of isostructural metal–organic frameworks (MOFs) that consists of M2+ ions coordinated to 2,5-dioxido-1,4-benzenedicarboxylate (dobdc) ligands. The simulations were performed using four different H2 potentials of increasing complexity, with the most realistic potential including induced dipole parameters to account for explicit many-body polarization interactions. Explicit polarization effects were implemented in classical GCMC simulation using a Thole-Applequist type model. The experimental H2 adsorption isotherms and isosteric heat of adsorption (Qst) values for all five M-MOF-74 analogues were closely reproduced in simulation using only the polarizable H2 potential. Simulations using potentials that include only explicit repulsion and dispersion and/or permanent electrostatic interactions failed to reproduce such measurements. Utilizing the polarizable H2 model in classical GCMC simulation also resulted in M2+–H2 distances that are comparable to those obtained through neutron powder diffraction measurements for the individual variants. Consistent with experimental measurements, the simulations reproduced the following trend for the H2−metal interaction strength: Ni-MOF-74 &gt; Co-MOF-74 &gt; Mg-MOF-74 &gt; Zn-MOF-74 &gt; Cu-MOF-74. The simulations revealed that stronger H2−metal interactions within the M-MOF-74 series corresponds to shorter H2−metal distances and higher induced dipoles on the metal-adsorbed H2 molecules. The observed H2 adsorption trend within this series were potentially rationalized by analyzing the calculated partial charges of the MOF atoms, the polarizability of the metal ions, and steric interactions within the crystal structures.

Capturing the H2–metal interaction in the M-MOF-74 series using classical polarization

Structure based coarse-grained models typically overestimate the system’s pressure. We previously resolved this issue by employing a global density dependent term in the approximation to the potential of mean force that we parameterized via iterative pressure matching. We then demonstrated that changing this potential into a function of the local density around each particle provides a reasonable estimate of the equation of state which can be improved through slight adjustments to the local density potential. We have now parameterized local density potentials via the multi-scale coarse-graining method from atomistic simulations of liquid-vapor interfaces. We compare and contrast the advantages and drawbacks of the two different parameterization schemes. Additionally, we use the generalized Yvon-Born-Green framework to analyze the sources of structural features that frequently arise during coarse-grained simulations employing local density potentials that are absent from the atomistic simulation. We show that an imbalance of attractive and repulsive forces arising from the local density and pair potentials causes various levels of bunching at the interface. Furthermore, we implemented external basis functions in our force matching code to help our models reproduce the density distribution as well as the average mapped atomistic force, with the option to include the corresponding external potential. Finally, we demonstrate that the basis vectors for the standard pair potential and the local density potential are non-orthogonal, which results from the decomposition of the local density force into a sum of pairwise contributions. As a result, given an initial pair potential and local density potential, it is possible to construct an infinite number of other sets of pair potentials and local density potentials that produce the exact same forces, by making one more attractive and the other one correspondingly more repulsive.

Bottom-up coarse graining of inhomogeneous environments

Selecting the right compounds to create a screening set has always been a challenge. The main obstacle to overcome is to process and evaluate millions of molecules to generate a few thousand compound set. The solution to this challenge is to create compound sets from Chemspace library using biased ligand based, molecular docking or chemoinformatics approaches towards different uses. Our compound sets include CNS-permeable compounds, PPI modulators, kinase binders, RNA-binders, and other sets (26 in total). There are two separate approaches to focused set: (i) libraries prepared from stock available compounds and (ii) to make on-demand compounds. This allows a comprehensive coverage of chemical space and quick iterative follow up to generate new hits. We have created a robust platform to produce and deliver on-demand compounds almost as fast as the in-stock items: synthesis in 3 weeks with 80% success rate. Overall diversity and novelty of the compounds in the Chemspace libraries make them a useful tool to generate new starting points at an early phase of a drug discovery project.

Compound libraries on Chemspace: An approach to chart useful regions in available chemical space

High Energy Molecules (HEMs) are molecules or substances which when subjected to heat, pressure or detonation, undergo a very rapid decomposition accompanied by a large release of energy. In other words, HEMs is a generic term used for the class of materials known as explosives and are mainly used for military purposes. Toxicalogical tests have been performed on such molecules and have demonstrated their potential toxicity for health and environement [X]. The manufacturing, testing, using and destruction of HEMs, and more generally their extensive use during the past century, have lead to large contamination of soil and groundwaters [X Hawari, 2000]. Physicochemical treatments of contaminated sites exist but they are costly, damaging for the environment and in most cases, unfeasable [Hawari, 2000]. Bioremediation has emerged recently as an alternative way to detoxify soil from HEMs. By using bacteria or plants, it offers a more environmentally friendly approach to solve contamination issues. However some metabolic pathways remain unclear and the rate of detoxification is variable from one HEMs to another.[X] To address this, we propose a rational design strategy for the modelisation of a nitroreductase able to specifically reduce the nitro group of the HEM HMX. We based our study on E Cloacae nitroreductases NTR (PDB structure 1KQB). It has been show that NTR reduces a broad range of nitroaromatic substrates such as TNT)[X]. We used the Rosetta modelling Suite, and specifically hte algorithm Coupled Moves to redesign the active site of the nitroreductase around the substrate HMX.

Degradation of high energy molecules using biological reduction: Rational way to reach bioremediation

Patent owners are granted the right to prevent others from using their invention for a limited period of time. Although the patent term is measured starting from the filing date of the application, patent owners do not obtain the right to exclude others until the patent issues from the patent office, which can take years. Further, some patented products cannot be marketed without approval from a regulatory agency. Patent Term Adjustment (PTA) and Patent Term Extension (PTE) can restore potions of the patent term lost due to patent office or regulatory delays. This presentation will provide an overview of PTA and PTE, discuss recent developments in the law, and give best practices for preserving PTA and PTE.

Navigating patent term adjustment (PTA) and patent term extension (PTE)

Inventorship is a fundamental concept in patent law, yet the question of inventorship is often difficult to answer. This presentation will examine the legal framework for identifying and determining who is an inventor, the implications of the improper naming of inventors, and best practice for correcting errors. The presentation will also discuss best practices for documenting inventive contributions and rights associated with joint inventorship.

Inventor or contributor? A U.S. perspective

The recent Pfizer Inc. v. Chugai Pharmaceutical Co. Ltd. inter partes review case in front of the USPTO Patent Trials and Appeals Board highlights the significant differences in nuanced antibody purification methods which impact obviousness of the described methods. Moreover, the challenger’s burden is examined in the context of establishing a direct versus inherent property of cited art to support a theory of obviousness in antibody purification methods.

Antibody purification is sometimes not quite so obvious

In the past two decades there has been great progress going beyond the non-reactive approximation in classical molecular dynamics (MD) force fields (FF) to describe chemical reactions where charge flow is an essential process. At present reactive force fields are limited in their applicability to describe important phenomena such as redox reactions, electrocatalysis and ionic liquids, for which the reference charge state changes dynamically. Here we present a new model which accounts for both polarization and charge flow on an equal footing based on an explicit treatment of electrons which are free to migrate during the course of the simulation. This is achieved by splitting the atom into a positive charged core and a negative charged shell and then tuning the interaction energy between the core and shell to match the ionization potential of a specific atom type. The basic principle of this method is that when two atoms of different types approach one another the shell of the atom with the lower electron affinity will move towards the atom with the higher electron affinity and induce polarization. We show that our model can reproduce with high accuracy the dipole moments and charge distribution of various molecules calculated with all electron ab-initio methods. In addition we present for the first time a classical reactive model which can describe the dissociation of hydrogen chloride into ionic fragments in water.

Electron transfer model for reactive force fields

Earthquakes are not limited to the western states and, thus, there is some level of risk that an earthquake of sufficient magnitude and duration could cause significant chemical spillage in laboratories in other regions of the United States as well as elsewhere in the world. The post-earthquake challenge for campus health and safety professionals is how to safely and efficiently assess chemical spillage and prioritize mitigation / clean-up efforts in a manner that supports safe re-entry into laboratories. Researchers are highly motivated to re-enter to the extent that delays in clearing a building will compel some of them to prematurely re-enter, thus putting their safety at risk. Stanford University has developed a process for rapid post-earthquake lab spill assessment that coordinates the assessment process with building ventilation restart procedures. The primary objective is to ensure the safety of facilities staff, EH&S response personal, and the researchers anxious to reenter theses spaces. This presentation will cover the development and testing of the assessment process, PPE selection, sequencing of assessments, use of instrumentation, and management of situational status information. Design of response drills, efforts to build core competencies within the response team, and response priorities will also be covered

Post-earthquake lab spill assessment

The aftermath of the 2018 Camp Fire made clear how large-scale drinking water infrastructure contamination can jeopardize public health and safety. This was the deadliest and most destructive wildfire in California’s history. More than 35,000 people lived in the area before the fire, and roughly 90% of the structures burned to the ground. In the fire’s aftermath, the remaining standing home population a continued to receive and use contaminated receive water from their public water suppliers. In January 2019, Dr. Whelton’s multi-university team was contacted for assistance to help better respond to and recover from the drinking water contamination. Scientific assistance was provided to the utilities, local, state, and federal agencies. In May 2019, the team conducted a standing home community assessment survey and continued providing the community assistance. Results of their work will be presented along with experiences in providing scientific support following large-scale drinking water contamination and recovery caused by tank spills, oil spills, and backflow incidents. Experiences engaging with health officials, policy makers, and community groups will also be described

Importance of science in responding to large-scale drinking water contamination disasters: Wildfires, chemical spills, and more

Claim construction in patent litigation is the strongest determinant for non-infringement analysis. The recent United Technologies Corp. v. General Electric Co. Federal Circuit case highlights the significance of claim construction of a described chemical layer bonding technology on the outcome of a recent patent litigation matter.

Layers upon layers of layer complexity: simple chemistry made complex by patent laws

Recent case law impacting the definitions of prior sales will drive changes in vendor relationships and contracting. In particular, virtual or asset-light emerging growth companies that use vendors for synthesizing, analyzing, or conducting clinical trials may need to adjust their contracting behavior going forward to preserve necessary intellectual property rights.

What your competitors don’t know can hurt you: Strategies to avoid secret sales from invalidating your patent

State-specific changes in marijuana laws have impacted the intellectual property potential of this nascent field.  Patents in this field will be reviewed, including those in the processing, fermentation, and formulations areas.  Marijuana represents a growing opportunity for enterprising chemists to establish innovative technologies which can be patented using traditional patent prosecution methods.  Recent patent litigation in the marijuana area also highlights the risk of ignorance when operating in the field of marijuana cultivation and formulation development.

Blunt talk about cannabis patents

The Chemical Angel Network (CAN) is an organization of angel investors who came together to source, evaluate, and invest in early stage chemical companies. CAN encompasses several unique elements. It is a nationwide angel investing network and the only network with a chemical sector focus (i.e., businesses with a significant chemistry component.) CAN offers chemists, chemical engineers, and allied professionals a unique opportunity to participate in the growth of companies in the chemical and related industries by investing both intellectual and financial capital. The network is able to draw upon the members' unique experience and knowledge base to provide technical due diligence, mentoring, contacts, and general subject matter expertise. Finishing its fifth year of operations, this talk will highlight why the Chemical Angel Network has become the smart choice for early stage chemical companies and highlight some of the recent successes.

Updates and news from the Chemical Angel Network (CaN) and its sixth year of supporting chemists and chemistry-based company creation

A team of scientists and graduate students from Scripps Institution of Oceanography will offer a presentation and a panel discussion on ocean science. Related topics include natural products, acidification, calcification, ecology, conservation, and pollution/remediation.

Ocean science: Research reflections at the marina

Over 60,000 people died in the US last year from overdosing on illicit drugs.  In addition to opioid overdoses, clusters of deaths are caused by  "designer drugs" that have never undergone testing in humans, or less toxic drugs spiked with dangerous opioids. The idPAD is a paper analytical device that runs 12 chemical color tests simultaneously on a sample of a street drug in under 4 minutes. All of the reagents are stored in dry form on the idPAD; the user only needs to smear the drug across the paper and dip the bottom into water to activate the tests. Some of the color tests detect active ingredients such as meth or heroin, and others detect common cutting agents.  The test results form a “color bar code” that can be read by a cell phone app or by eye.  How could a device like this help to track the supply chain for illicit drugs and prevent overdose deaths?

What if you could identify street drugs with a paper test card?

When you hear the word chemist, you may think bench chemistry and researcher. But being a chemist prepares you for much more than just a laboratory career. Chemistry is an art where analytical thinking, problem solving, research methodology and many other skills are learned and crafted. Those skills are highly valuable in many places outside of the laboratory. In fact, many chemists go on to have careers in a wide variety of industries and types of positions. This symposium is focused on just that. We will have a variety of chemists who have pursued non-traditional careers, i.e., careers outside of typical academic or industry research. We will discuss what their backgrounds are, what their current jobs are, how they came to choose their current careers, and how their background in chemistry provides skills useful for their current careers. The panelists have careers in the areas of business, law and legal support, press, and other areas. The speakers will each provide a brief synopsis of what they do and how they got where they are followed by open question and answers with the audience. If have considered a career outside of the laboratory or are simply interested in what other chemists have gone on to do in non-traditional careers, you won’t want to miss this symposium.

Beyond the bench: Nontraditional careers in chemistry

2019 Fall National Meeting

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.