Systems and methods for producing reaction products

Abstract

The present invention generally relates to systems and methods for generating reaction products. In certain aspects, the present invention provides a reaction system including a first substrate, a desorption electrospray ionization (DESI) device, a second substrate, and a controller operatively associated with each of the first and second substrates and the DESI device, such that the first and second substrates remain aligned in correspondence with one another such that reagents at a first location on the first substrate are desorbed and ionized via the DESI device to form microdroplets, and the reagents in the microdroplets react with one another to form reaction products that are deposited at first locations on the second substrate corresponding to the first locations on the first substrate.

Description

[Technical Field]

[0001] Related Applications This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 428,531, filed November 29, 2022, the entire contents of which are incorporated herein by reference.

[0002] FIELD OF THE INVENTION The present invention generally relates to systems and methods for producing reaction products. [Background technology]

[0003] background The drug discovery process underpins the entire pharmaceutical industry, encompassing the early stages of research from target discovery and validation to the identification of drug candidates or lead compounds. Initial identification of small therapeutic candidates occurs through various streams. Research can yield new insights into disease processes that highlight novel pathways that drugs can be developed to intervene. Alternatively, companies conduct large-scale trial-and-error programs to identify potential molecular compounds. This is most frequently the process performed during early lead discovery, with the goal of advancing novel compounds through preclinical and clinical trials. A thorough, calculated risk analysis at this point can increase the likelihood of success when investment in a lead is made.

[0004] The drug discovery process, from target identification and validation, hit identification and validation, hit-to-lead transition, lead optimization, and late-stage lead optimization, is a manual process that is fragmented and segmented into different manual processes and procedures. Therefore, drug discovery is a time-consuming, inefficient, and asynchronous process that ultimately requires years to develop a marketable drug. Summary of the Invention [Means for solving the problem]

[0005] overview The present invention provides a technology that is a key component of a multi-component system, allowing for the screening of reactions for optimal production of chemical products, such as potential drug candidates, as well as the collection of these products and assaying their activity against biological targets, such as enzymes. A key feature of this technology is a system and method for transporting the reaction products of a set of reagents located at specific points in an array of such chemical reagents to corresponding points on a receiving array, where the reaction occurs during this transport. Specific approaches for implementation are described herein and, in certain embodiments, can include any one or more (or combination) of the following: (i) The reaction may be performed using desorption electrospray ionization (DESI) / mass spectrometry (MS) to generate microdroplets from each spot on the precursor array, while a chemical reaction occurs at an accelerated rate in the microdroplets to give the product. (ii) The product-containing droplets may be deposited on a product (secondary) array at a location related by known parameters to the location of the original reaction mixture on the precursor array. (iii) The nature of the product may be inferred by ionizing the deposited product using DESI and identifying the material using MS. (iv) The bioactivity of the product may be determined by depositing a droplet of the product on a surface prepared by the addition of a bioactive substrate, or by adding such a bioactive substrate to specific or all locations on the as-prepared product array and then measuring the bioactivity, again using DESI-MS.

[0006] The present invention addresses the above-mentioned problems in drug discovery. It provides an approach for determining how to rapidly generate several drug candidates, determine their chemical identity, estimate their purity, and determine their biological activity without the use of any chromatographic separation or purification methods, covering a wide range of chemical structures, including sets of closely related chemicals, while maximizing speed and minimizing sample size. The provided system and method solve these problems by providing a single, interconnected, automated system in which an array of samples (reaction mixtures) is prepared using standard sample-handling automated pipetting methods, followed by rapid reactions by extraction of the reaction mixture into a DESI spray solvent, while the extract is deposited in the form of secondary microdroplets and transferred to a mass spectrometer for chemical analysis, or to a surface for subsequent analysis or reaction with reagents, including biological substrates, already deposited on or later added to the receiving surface. The same or a second DESI sprayer is used to characterize the products of the biological reactions and determine the reactivity of the synthesized drug candidates.

[0007] In certain aspects, the present invention provides a reaction system comprising a first substrate, a desorption electrospray ionization (DESI) device, a second substrate, and a controller operatively associated with each of the first and second substrates and the DESI device, such that the first and second substrates remain aligned in correspondence with one another such that reagents at a first location on the first substrate are desorbed and ionized via the DESI device to form microdroplets, and the reagents in the microdroplets react with each other to form reaction products that deposit at first locations on the second substrate corresponding to the first locations on the first substrate.

[0008] In certain embodiments, the system further includes one or more mass spectrometers, each including an inlet, where (i) the mass spectrometer inlet is positioned to be operatively associated with a first substrate to perform an initial screening of reagents at a first location on the first substrate and evaluate the reagents to determine the production of suitable reaction products of suitable purity, and / or (ii) the inlet is positioned to be operatively associated with a second substrate to allow attached reaction products to be desorbed and ionized from the second substrate, with the desorbed molecules of the reaction products entering the mass spectrometer inlet for analysis. In certain embodiments, the DESI device desorbs the attached reaction products. In other embodiments, the system further includes a second desorption electrospray ionization (DESI) device, where the second DESI device desorbs the attached reaction products.

[0009] The control device can include one or more motors for controlling the movement, alignment, and correspondence of the first substrate, the second substrate, and the DESI device. In certain embodiments, the second substrate is oriented substantially perpendicular to the first substrate. In certain embodiments, a first location on the second substrate contains a biomolecule that reacts with a reaction product attached to the first location on the second substrate. In certain embodiments, the reaction product and the biomolecule are desorbed and ionized from the second substrate, and the desorbed molecules of the reaction product and the biomolecule enter the inlet of a mass spectrometer, where their biological activity is measured. In certain embodiments, the system does not include a chromatographic separation device. In certain embodiments, the system does not include a purification device.

[0010] In another aspect, the present invention provides a method of producing a reaction product, comprising desorbing reagents from first locations on a first substrate via a desorption electrospray ionization (DESI) device to form microdroplets, wherein the first substrate and a second substrate are aligned in conformity with one another such that the reagents in the microdroplets react with one another to form a reaction product that is deposited at first locations on the second substrate corresponding to the first locations on the first substrate.

[0011] In certain embodiments, the methods of the present invention may additionally and / or optionally include (i) performing an initial screening of the reagents at the first location on the first substrate to evaluate the reagents to determine the production of suitable reaction products of suitable purity, and / or (ii) desorbing and ionizing the attached reaction products from the second substrate, with the desorbed molecules of the reaction products entering the inlet of a mass spectrometer and analyzing the desorbed molecules of the reaction products with the mass spectrometer. In certain embodiments, a DESI device desorbs the attached reaction products. In other embodiments, a second desorption electrospray ionization (DESI) device desorbs the attached reaction products.

[0012] In certain embodiments, the first and second substrates and the DESI apparatus are controlled by a controller including one or more motors for controlling the movement, alignment, and correspondence of the first and second substrates and the DESI apparatus. In certain embodiments, the second substrate is oriented substantially perpendicular to the first substrate. In certain embodiments, a first location on the second substrate contains a biomolecule that reacts with a reaction product attached to the first location on the second substrate. In certain embodiments, the reaction product and the biomolecule are desorbed and ionized from the second substrate, and the desorbed molecules of the reaction product and the biomolecule enter the inlet of a mass spectrometer, where their biological activity is measured. In certain embodiments, the method is performed without any chromatographic separation. In certain embodiments, the method is performed without any purification steps other than the DESI process. [Brief explanation of the drawings]

[0013] [Figure 1] 1-2 provide an overview of the systems and methods of the present invention. [Figure 2-1] 1-2 provide an overview of the systems and methods of the present invention. [Figure 2-2] Same as above. [Figure 2-3] Same as above. [Figure 2-4] Same as above. [Figure 2-5] Same as above. [Figure 2-6] Same as above.

[0014] [Figure 3] FIG. 3 illustrates an exemplary data analysis module for implementing the systems and methods of the present invention in one particular embodiment. DETAILED DESCRIPTION OF THE INVENTION

[0015] Detailed Description The present invention generally relates to systems and methods for generating reaction products, various embodiments of which are illustrated in Figures 1 and 2. To accelerate the drug discovery process, a system utilizing a technique called high-throughput (HT) desorption electrospray ionization mass spectrometry (DESI-MS) has been developed. DESI is described, for example, in Takats et al. (U.S. Patent No. 7,335,897), the entire contents of which are incorporated herein by reference. DESI is unique in that it functions not only as an analytical method but also as a synthetic tool. The contactless nature of DESI provides the ability to directly analyze complex, salt-containing reaction / biological mixtures without any sample post-treatment, and the phenomenon of reaction acceleration in microdroplets provides access to extremely fast reactions. In one specific embodiment, there are three components of the system, as summarized in Figure 1: (I) HT screening, (II) HT synthesis, and (III) HT analysis. Two biological systems were investigated: (i) an enzymatic assay for acetylcholinesterase (AChE) and (ii) an opioid receptor binding assay.

[0016] Using HT screening (Figures 1 and 2, Section I), we investigated the synthesis of AChE inhibitor mimics from small molecules (1, 2, and 3) and late-stage functionalization for diversification of known analgesics (4 and 5) (Figures 1 and 2, Section I(b)). By targeting moieties containing secondary amino, phenolic, carbonyl, and thiophene groups, we investigated nine reaction types: fluorosulfurylations, SO2F-mediated couplings, sulfur-fluoride exchange click reactions, alkenylations, Mannich-type reactions, acylation reactions, ene-type reactions, Schiff base formation, and N-alkylations (Figures 1 and 2, Sections I(a) and I(c)). HT-DESI-MS was utilized for screening with a throughput of 1 Hz and a consumption of 50 nL of each sample pinned onto a DESI slide. DESI as an analytical tool allows for direct determination of successful reactions without laborious purification, even with complex reaction mixtures (alkenylation) or salt-containing reaction mixtures (ene-type reactions). Furthermore, DESI droplets can act as synthesis microreactors, accelerating reactions and forming products without incubation. Over 200 different substrates and 2,000 reaction conditions were screened. Over 50 different products were generated for the synthesis of inhibitor mimetics (i), and many functionalized drug molecules were identified for the late-stage diversification of naloxone (>100) and PZM21 (15), respectively (ii). Furthermore, the ability to reanalyze the same sample on a DESI slide provides more detailed structural information about the reaction products (e.g., by MS / MS).

[0017] HT synthesis (Figures 1 and 2, Section II) was used to collect products generated in microdroplets as a complement to using MS for analysis. To achieve high-density, spatially resolved synthesis and analysis, we constructed an array-to-array system using a "typewriter"-like collection system (the roller system, labeled in red) and incorporated it into a two-dimensional DESI stage (labeled in blue) (Figures 1 and 2, Section II(a)). The DESI system included a DESI slide with various reaction mixtures in an array format, a 2D stage for X and Y movement to inspect the spots of interest and acquire information from the screening step, and stepper motors 1 and 2 for automation (Figures 1 and 2, Section II(b) blue). The roller system consisted of an old-fashioned typewriter roller and counter-roller controlled by motor 3 for rotational movement, a rail controlled by motor 4 for linear movement, and several adjustable parts to maximize system stability (Figures 1 and 2, Section II(b) red). The linear motion allows for the collection of droplets at different positions in a single row, while the rotational motion provides the capability for 2D collection of products in different rows. DESI acts as a "bridge" connecting these two systems by desorbing reaction mixtures from the high-density DESI array, accelerating the reaction in the droplets, and then collecting them to generate another array ("inter-array" synthesis). The system can be fully automated with high precision and high resolution of movement (0.625 μm for all linear motions and 0.35 μm for rotational motions). The system has been constructed, but further evaluation is ongoing.

[0018] The third HT operation, analysis (Figures 1 and 2, Section III), involves a surface bioassay procedure for evaluating the bioactivity of the compounds synthesized in the previous two steps. We utilized an AChE enzyme assay and evaluated the inhibition of this enzyme using two different inhibitors, neostigmine and pyridostigmine (Figures 1 and 2, Section III(a)). Inhibitors were deposited on the surface either by direct pipetting or by collecting them in DESI droplets to which the substrate (acetylcholine) and AChE were sequentially added. Enzyme activity and inhibition efficiency were determined by measuring the ratio of ion abundances at m / z 146 and 104 (the substrate and AChE product), allowing for label-free determination of bioactivity (Figures 1 and 2, Section III(b)). This procedure allowed us to distinguish the activity of various inhibitors at the same concentration (red and blue in Figures 1 and 2, Section III(c)) or at different concentrations of the same inhibitor (same color in Figures 1 and 2, Section III(c)). Furthermore, the spatially resolved results (Figures 1 and 2, section III(d)) demonstrate the feasibility of evaluating various products deposited on surfaces in a "make-to-measure" manner. The procedure is simple and amenable to automation.

[0019] The present invention illustrates herein that the iterative application of these three operations can be used to accelerate the process of drug discovery. DESI-MS is a versatile method that can be essential in both analysis and synthesis.

[0020] Certain aspects of fluid handling and mass spectrometry are described, for example, in PCT / US21 / 22923, the entire contents of which are incorporated herein by reference.

[0021] Fluid Handling Any fluid handling device known in the art can be used in the systems of the present invention. In certain embodiments, the liquid handling device is a Biomek liquid handler (e.g., I-series) manufactured and sold by Beckman Coulter. Descriptions of such liquid handlers can be found, for example, in U.S. Patent Nos. 10,274,505, 10,048,284, 9,910,054, 9,519,000, 9,506,943, 9,482,684, 9,446,418, 9,285,382, 9,274,132, 9,140,715, 9,046, 506, 9,046,455, 8,996,320, 8,973,736, 8,962,308, 8,956,570, 8,932,541, 8,840,848, 6,841,379, and 5,737,498, the entire contents of each of which are incorporated herein by reference.

[0022] Desorption electrospray ionization Desorption electrospray ionization (DESI) is described, for example, in Takats et al. (U.S. Patent No. 7,335,897), the entire contents of which are incorporated herein by reference. DESI allows for the ionization and desorption of materials (analytes) at atmospheric or reduced pressure under ambient conditions. DESI systems generally include a device for generating a DESI-active spray by delivering liquid droplets into a nebulizing gas. The system also includes a means for directing the DESI-active spray toward a surface. It is understood that the DESI-active spray may contain, at the point of contact with the surface, both charged and / or uncharged droplets, gaseous ions, nebulizing gas, and nearby atmospheric molecules. The air-pressure-assisted spray is directed toward the surface of the sample material, where it interacts with one or more analytes (if present in the sample) and generates desorbed ions of the one or more analytes. The desorbed ions can be directed to a mass analyzer for mass analysis, an IMS device for size separation and measurement of the resulting voltage fluctuations, a flame spectrometer, or the like for spectral analysis.

[0023] In this system, the spray is generated by a conventional electrospray device. This device includes a spray capillary into which a liquid solvent is supplied. A surrounding nebulizer capillary forms an annular space into which an nebulizer gas, such as nitrogen (N), is supplied at high velocity. In one example, the liquid was a water / methanol mixture and the gas was nitrogen. A high voltage is applied to the liquid solvent by a power supply through a metal connecting element. The fast-flowing nebulizer gas interacts with the liquid exiting the capillary, resulting in the formation of a DESI-activated spray containing droplets. The DESI-activated spray may include neutral atmospheric molecules, nebulizer gas, and gaseous ions. While an electrospray device is described, any device capable of generating a stream of droplets carried by an nebulizer gas jet can be used to form the DESI-activated spray.

[0024] The spray is directed onto the sample material, which in this example is supported on a surface. Desorbed ions leaving the sample are collected and introduced into the atmospheric inlet or interface of the mass spectrometer for analysis by an ion transfer line positioned sufficiently close to the sample to collect the desorbed ions. The surface may be a movable platform or may be attached to a movable platform that can be moved in the x, y, or z directions by known actuation means to desorb and ionize the sample in different regions, sometimes producing a map or image of the distribution of the sample's components. The potential and temperature of the platform may also be controlled by known means. Any atmospheric pressure interface typically found in mass spectrometers is suitable for use in the present invention. Good results have been obtained using a typical heated capillary atmospheric pressure interface. Good results have also been obtained using an atmospheric pressure interface that samples via an extended, flexible ion transfer line made of either metal or insulator.

[0025] Ion Trap and Mass Spectrometer Any ion trap known in the art can be used in the system of the present invention. Exemplary ion traps include hyperbolic ion traps (e.g., U.S. Pat. No. 5,644,131, the entire contents of which are incorporated herein by reference), cylindrical ion traps (e.g., Bonner et al., International Journal of Mass Spectrometry and Ion Physics, 24(3):255-269, 1977, the entire contents of which are incorporated herein by reference), linear ion traps (Hagar, Rapid Communications in Mass Spectrometry, 16(6):512-526, 2002, the entire contents of which are incorporated herein by reference), and rectilinear ion traps (U.S. Pat. No. 6,838,666, the entire contents of which are incorporated herein by reference).

[0026] Any mass spectrometer (e.g., a benchtop mass spectrometer of a miniature mass spectrometer) can be used in the system of the present invention, and in certain embodiments, the mass spectrometer is a miniature mass spectrometer. Exemplary miniature mass spectrometers are described, for example, in Gao et al. (Anal. Chem. 2008, 80, 7198-7205), the entire contents of which are incorporated herein by reference. Compared with the pumping systems used in laboratory-scale instruments with thousands of watts of power, miniature mass spectrometers generally have smaller pumping systems, such as the 18W pumping system described in Gao et al., which has only a 5 L / min (0.3 m / hr) diaphragm pump and an 11 L / s turbo pump. Other exemplary miniature mass spectrometers are described, for example, in Gao et al. (Anal. Chem., 2008, 80, 7198-7205), Hou et al. (Anal. Chem., 2011, 83, 1857-1861), and Sokol et al. (Int. J. Mass Spectrom., 2011, 306, 187-195), the entire contents of each of which are incorporated herein by reference.

[0027] Mini12 control system (Linfan Li, Tsung-Chi Chen, Yue Ren, Paul I. Hendricks, R. Graham Cooks and Zheng Ouyang “Miniature Ambient Mass Analysis System” Anal. Chem. 2014, 86 2909-2916, DOI: 10.102l / ac403766c; and 860. Paul I. Hendricks, Jon K. Dalgleish, Jacob T. Shelley, Matthew A. Kirleis, Matthew T. McNicholas, Linfan Li, Tsung-Chi Chen, Chien-Hsun Chen, Jason S. Duncan, Frank Boudreau, Robert J. Noll, John P. Denton, Timothy A. Roach, Zheng Ouyang, and R. Graham Cooks “Autonomous in-situ analysis and real-time chemical detection using a backpack miniature mass spectrometer: concept, instrumentation development, and performance” Anal. Chem., 2014, 86 2900-2908 DOI:10.1021 / ac403765x, the entire contents of which are incorporated herein by reference), and the vacuum system of the Mini10 (Liang Gao, Qingyu Song, Garth E. Patterson, R. Graham Cooks and Zheng Ouyang, “Handheld Rectilinear Ion Trap Mass Spectrometer”, Anal. Chem., 78 (2006) 5994-6002 DOI: 10.1021 / ac061144k, the entire contents of which are incorporated herein by reference) can be combined to produce the miniature mass spectrometer shown in FIG. 9.The miniature mass spectrometer can have a size similar to that of a shoebox (20 cm H x 25 cm W x 35 cm D). In certain embodiments, the miniature mass spectrometer uses a dual LIT configuration, as described, for example, in Owen et al. (U.S. Patent Application No. 14 / 345,672) and Ouyang et al. (U.S. Patent Application No. 61 / 865,377), the contents of each of which are incorporated herein by reference in their entirety.

[0028] System Architecture In certain embodiments, the systems and methods of the present invention can be implemented using automated systems and computing devices. Specifically, the aspects of the present invention described herein can be implemented using any type of computing device, such as a computer including a processor, e.g., a central processing unit, or any combination of computing devices, each performing at least a portion of a process or method. In some embodiments, the systems and methods described herein can be controlled using a handheld device, e.g., a smart tablet, or a smartphone, or a specialized device manufactured for the system.

[0029] The systems and methods of the present invention can be implemented using software, hardware, firmware, hardwiring, or any combination thereof. Features implementing functionality may be physically located in various locations, including being distributed such that portions of functionality are implemented in different physical locations (e.g., an imaging device in one room and a host workstation in another room or in a remote building, e.g., by wireless or wired connection).

[0030] Processors suitable for executing computer programs include, by way of example, both general-purpose and special-purpose microprocessors, as well as any one or more processors of any kind of digital computer. Generally, a processor receives instructions and data from a read-only memory or a random-access memory, or both. The essential elements of a computer are a processor for executing instructions and one or more memory devices for storing instructions and data. Generally, a computer also includes one or more mass storage devices, such as magnetic, magneto-optical, or optical disks, for storing data, or is operatively coupled to receive and / or transfer data therefrom. Suitable information carriers for embodying computer program instructions and data include, by way of example, all forms of non-volatile memory, including semiconductor memory devices (e.g., EPROMs, EEPROMs, solid-state drives (SSDs), and flash memory devices), magnetic disks (e.g., internal hard disks or removable disks), magneto-optical disks, and optical disks (e.g., CD and DVD disks). The processor and memory may be supplemented by, or incorporated in, dedicated logic circuitry.

[0031] To provide for user interaction, the subject matter described herein may be implemented in a computer having an I / O device, e.g., a CRT, LCD, LED, or projection device, for displaying information to the user, and input or output devices, such as a keyboard and pointing device (e.g., a mouse or trackball), through which the user can provide input to the computer. Other types of devices may also be used to provide for user interaction. For example, feedback provided to the user may be any form of sensory feedback (e.g., visual feedback, auditory feedback, or tactile feedback), and input from the user may be received in any form, including acoustic, speech, or tactile input.

[0032] The subject matter described herein may be implemented in a computing system including a back-end component (e.g., a data server), a middleware component (e.g., an application server), or a front-end component (e.g., a client computer having a graphical user interface or web browser through which a user can interact with an implementation of the subject matter described herein), or any combination of such back-end, middleware, and front-end components. The components of the system may be interconnected via a network by any form or medium of digital data communication, e.g., a communication network. For example, a reference set of data may be stored at a remote location, and a computer communicates across the network to access the reference set and compare data obtained from a female subject with the reference set. However, in other embodiments, the reference set is stored locally within the computer, and the computer accesses the reference set within the CPU and compares the subject data with the reference set. Examples of communication networks include a cellular network (e.g., 3G or 4G), a local area network (LAN), and a wide area network (WAN), e.g., the Internet.

[0033] The subject matter described herein may be implemented as one or more computer program products, such as one or more computer programs tangibly embodied in an information carrier (e.g., a non-transitory computer-readable medium) for execution by or to control the operation of a data processing device (e.g., a programmable processor, a computer, or multiple computers). The computer programs (also known as programs, software, software applications, apps, macros, or code) may be written in any form of programming language, including compiled or interpreted languages ​​(e.g., C, C++, Perl), and may be deployed in any form, including as a standalone program or as a module, component, subroutine, or other unit suitable for use in a computing environment. The systems and methods of the present invention may include instructions written in any suitable programming language known in the art, including, but not limited to, C, C++, Perl, Java, ActiveX, HTML5, Visual Basic, or JavaScript.

[0034] A computer program does not necessarily correspond to a file. A program may be stored in a file or portion of a file that holds other programs or data, in a single file dedicated to that program, or in multiple coordinated files (e.g., a file that stores one or more modules, subprograms, or portions of code). A computer program may be deployed to be executed on one computer, on multiple computers at one location, or on multiple computers distributed across multiple locations and interconnected by a communications network.

[0035] The file may be, for example, a digital file stored on a hard drive, SSD, CD, or other tangible, non-transitory medium. The file may be transmitted from one device to another over a network (e.g., as packets transmitted from a server to a client via a network interface card, modem, wireless card, or the like).

[0036] Writing a file in accordance with the present invention involves transforming a tangible, non-transitory computer-readable medium (e.g., using net charge or dipole moment to create a pattern of magnetization with a read / write head), for example, by adding, removing, or rearranging particles, so that the pattern then represents a new collocation of information about an objective physical phenomenon that is desired and useful to the user. In some embodiments, writing involves a physical transformation of material within the tangible, non-transitory computer-readable medium (e.g., burning a CD-ROM to include certain optical properties so that an optical read / write device can subsequently read the new, useful collocation of information). In some embodiments, writing a file involves transforming a physical flash memory device, such as a NAND flash memory device, and storing information by transforming physical elements within an array of memory cells made from floating-gate transistors. Methods for writing files are well known in the art and can be invoked manually or automatically, for example, by a program or by a save command from software or a write command from a programming language.

[0037] Suitable computing devices typically include mass memory, at least one graphical user interface, at least one display device, and typically include communication between devices. Mass memory exemplifies a type of computer-readable medium, namely, computer storage media. Computer storage media can include volatile, nonvolatile, removable, and non-removable media implemented in any method or technology for storage of information such as computer-readable instructions, data structures, program modules, or other data. Examples of computer storage media include RAM, ROM, EEPROM, flash memory, or other memory technology, CD-ROM, digital versatile disks (DVDs), or other optical storage devices, magnetic cassettes, magnetic tape, magnetic disk storage, or other magnetic storage devices, radio frequency identification tags or chips, or any other medium usable to store desired information and accessible by a computing device.

[0038] As those skilled in the art will recognize as necessary or optimal for practicing the methods of the present invention, a computer system or machine of the present invention includes one or more processors (e.g., a central processing unit (CPU), a graphics processing unit (GPU), or both), a main memory, and a static memory that communicate with each other via a bus.

[0039] In the exemplary embodiment shown in FIG. 3 , system 200 may include a computer 249 (e.g., a laptop, desktop, or tablet). Computer 249 may be configured to communicate over network 209. Computer 249 includes one or more processors 259 and memory 263, as well as input / output mechanisms 254. When the method of the present invention uses a client / server architecture, the steps of the method of the present invention may be performed using a server 213 including one or more processors 221 and memory 229, which may retrieve data, instructions, etc., or provide results via interface module 225 or as file 217. Server 213 may be engaged over network 209 via computer 249 or terminal 267, or server 213 may be directly connected to terminal 267, which may include one or more processors 275 and memory 279, as well as input / output mechanisms 271.

[0040] A system 200 or machine according to the invention may further include a video display unit (e.g., a liquid crystal display (LCD) or a cathode ray tube (CRT)) for any of I / O 249, 237, or 271. A computer system or machine according to the invention may also include an alphanumeric input device (e.g., a keyboard), a cursor control device (e.g., a mouse), a disk drive unit, a signal generating device (e.g., a speaker), a touch screen, an accelerometer, a microphone, a cellular radio frequency antenna, and a network interface device, which may be, for example, a network interface card (NIC), a Wi-Fi card, or a cellular modem.

[0041] Memory 263, 279, or 229 according to the present invention may include a machine-readable medium on which one or more sets of instructions (e.g., software) that embody any one or more of the methods or functions described herein are stored. The software may reside completely or at least partially within main memory and / or within the processor during execution by the computer system, with the main memory and processor also constituting machine-readable media. The software may also be transmitted or received over a network via a network interface device.

[0042] Incorporation by Reference References and citations to other documents, such as patents, patent applications, patent publications, journals, books, articles, web content, etc. are made throughout this disclosure, and all such documents are incorporated herein by reference in their entirety for all purposes.

[0043] equivalent The present invention may be embodied in other specific forms without departing from its spirit or essential characteristics. The foregoing embodiments, therefore, are to be considered in all respects as illustrative and not limiting of the invention described herein.

Claims

1. 1. A reaction system comprising: a first substrate; a desorption electrospray ionization (DESI) device; a second substrate; and a controller operatively associated with each of the first and second substrates and the DESI device, the controller causing the first and second substrates to remain aligned in correspondence with one another such that reagents at a first location on the first substrate are desorbed and ionized via the DESI device to form microdroplets, and the reagents in the microdroplets react with one another to form reaction products that are deposited at first locations on the second substrate corresponding to the first locations on the first substrate; and A reactive system, including:

2. further comprising one or more mass spectrometers, each of said mass spectrometers comprising an inlet; (i) the inlet of the mass spectrometer is positioned in operative association with the first substrate to perform an initial screening of the reagent at the first location on the first substrate and evaluate the reagent to determine production of a suitable reaction product of suitable purity; and / or 2. The system of claim 1, wherein (ii) an inlet is positioned in operative association with the second substrate such that the attached reaction products can be desorbed and ionized from the second substrate, and desorbed molecules of the reaction products enter the inlet of the mass spectrometer and are analyzed.

3. The system of claim 2 , wherein the DESI device desorbs the attached reaction products.

4. The system of claim 2 , further comprising a second desorption electrospray ionization (DESI) device, the second DESI device desorbing the attached reaction products.

5. The system of claim 1 , wherein the control device includes one or more motors for controlling the movement, alignment, and registration of the first and second substrates and the DESI device.

6. The system of claim 1 , wherein the second substrate is oriented substantially perpendicular to the first substrate.

7. The system of claim 1 , wherein the first locations on the second substrate include biomolecules that react with the reaction product attached to the first locations on the second substrate.

8. 8. The system of claim 7, wherein the reaction products and the biomolecules are desorbed and ionized from the second substrate, and the desorbed molecules of the reaction products and the biomolecules enter the inlet of the mass spectrometer and biological activity is measured.

9. The system of claim 1 , wherein the system does not include a chromatographic separation device.

10. The system of claim 1 , wherein the system does not include a purification device.

11. 1. A method for producing a reaction product, the method comprising desorbing reagents from first locations on a first substrate via a desorption electrospray ionization (DESI) device to form microdroplets, wherein the first substrate and the second substrate are aligned in coincidence with one another such that the reagents in the microdroplets react with one another to form a reaction product that is deposited at first locations on a second substrate corresponding to the first locations on the first substrate.

12. (i) performing an initial screening of the reagent at the first location of the first substrate to evaluate the reagent to determine production of a suitable reaction product of suitable purity; and / or (ii) desorbing and ionizing the attached reaction products from the second substrate, such that the desorbed molecules of the reaction products enter an inlet of a mass spectrometer, and analyzing the desorbed molecules of the reaction products in the mass spectrometer. The method of claim 11 further comprising:

13. The method of claim 12 , wherein the DESI device desorbs the attached reaction products.

14. 13. The method of claim 12, wherein a second desorption electrospray ionization (DESI) device desorbs the attached reaction products.

15. The method of claim 11, wherein the first and second substrates and the DESI device are controlled by a control device including one or more motors for controlling the movement, alignment, and registration of the first and second substrates and the DESI device.

16. The method of claim 11 , wherein the second substrate is oriented substantially perpendicular to the first substrate.

17. The method of claim 11 , wherein the first locations on the second substrate comprise biomolecules that react with the reaction product attached to the first locations on the second substrate.

18. 18. The method of claim 17, wherein the reaction products and the biomolecules are desorbed and ionized from the second substrate, and the desorbed molecules of the reaction products and the biomolecules enter the inlet of the mass spectrometer and biological activity is measured.

19. 12. The method of claim 11, wherein the method is carried out without any chromatographic separation.

20. 12. The method of claim 11, wherein the method is carried out without any purification steps other than the DESI process.

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