LinChemIn: Route Arithmetic─Operations on Digital Synthetic Routes.

Computational tools are revolutionizing our understanding and prediction of chemical reactivity by combining traditional data analysis techniques with new predictive models. These tools extract additional value from the reaction data , but to effectively convert this value into actionable knowledge, domain specialists need to interact easily with the computer-generated output. In this application note, we demonstrate the capabilities of the open-source Python toolkit LinChemIn, which simplifies the manipulation of reaction networks and provides advanced functionality for working with synthetic routes.

Fast Customization of Chemical Language Models to Out-of-Distribution Data Sets.

The world is on the verge of a new industrial revolution, and language models are poised to play a pivotal role in this transformative era. Their ability to offer intelligent insights and forecasts has made them a valuable asset for businesses seeking a competitive advantage. The chemical industry, in particular, can benefit significantly from harnessing their power.

LinChemIn: SynGraph-a data model and a toolkit to analyze and compare synthetic routes.

Background: The increasing amount of chemical reaction data makes traditional ways to navigate its corpus less effective, while the demand for novel approaches and instruments is rising. Recent data science and machine learning techniques support the development of new ways to extract value from the available reaction data. On the one side, Computer-Aided Synthesis Planning tools can predict synthetic routes in a model-driven approach; on the other side, experimental routes can be extracted from the Network of Organic Chemistry, in which reaction data are linked in a network.

Target-site resistance to neonicotinoids.

Neonicotinoid insecticides selectively target the invertebrate nicotinic acetylcholine receptor and disrupt excitatory cholinergic neurotransmission. First launched over 20 years ago, their broad pest spectrum, variety of application methods and relatively low risk to nontarget organisms have resulted in this class dominating the insecticide market with global annual sales in excess of $3.5 bn.

Reaction Mechanism and Catalytic Fingerprint of Allantoin Racemase.

The stereospecific oxidative decomposition of urate into allantoin is the core of purine catabolism in many organisms. The spontaneous decomposition of upstream intermediates and the nonenzymatic racemization of allantoin lead to an accumulation of (R)-allantoin, because the enzymes converting allantoin into allantoate are specific for the (S) isomer. The enzyme allantoin racemase catalyzes the reversible conversion between the two allantoin enantiomers, thus ensuring the overall efficiency of the catabolic pathway and preventing allantoin accumulation.

Functional dissection of intersubunit interactions in the EspR virulence regulator of Mycobacterium tuberculosis.

The nucleoid-associated protein EspR, a chromosome organizer, has pleiotropic effects on expression of genes associated with cell wall function and pathogenesis in Mycobacterium tuberculosis. In particular, EspR binds to several sites upstream of the espACD locus to promote its expression, thereby ensuring full function of the ESX-1 secretion system, a major virulence determinant. The N terminus of EspR contains the helix-turn-helix DNA-binding domain, whereas the C-terminal dimerization domain harbors residues involved in intersubunit interactions.

TAL effectors specificity stems from negative discrimination.

Transcription Activator-Like (TAL) effectors are DNA-binding proteins secreted by phytopathogenic bacteria that interfere with native cellular functions by binding to plant DNA promoters. The key element of their architecture is a domain of tandem-repeats with almost identical sequences. Most of the polymorphism is located at two consecutive amino acids termed Repeat Variable Diresidue (RVD).

In situ structural analysis of the Yersinia enterocolitica injectisome.

Injectisomes are multi-protein transmembrane machines allowing pathogenic bacteria to inject effector proteins into eukaryotic host cells, a process called type III secretion. Here we present the first three-dimensional structure of Yersinia enterocolitica and Shigella flexneri injectisomes in situ and the first structural analysis of the Yersinia injectisome. Unexpectedly, basal bodies of injectisomes inside the bacterial cells showed length variations of 20%.

A rational approach towards a new ferrocenyl pyrrolidine for stereoselective enamine catalysis.

Ironing out the details: Proline and pyrrolidine derivatives (Hayashi- Jørgensen catalysts) are considered "work horses" in organocatalysis. This report describes a new effective ferrocenyl pyrrolidine catalyst that is able to perform well in benchmark organocatalytic reactions (see figure). The ferrocene moiety controls the conformational space and a simple alkyl group effectively covers a face of the derived enamine.

Molecular Simulations Highlight the Role of Metals in Catalysis and Inhibition of Type II Topoisomerase.

Type II topoisomerase (topoII) is a metalloenzyme targeted by clinical antibiotics and anticancer agents. Here, we integrate existing structural data with molecular simulation and propose a model for the yet uncharacterized structure of the reactant state of topoII. This model describes a canonical two-metal-ion mechanism and suggests how the metals could rearrange at the catalytic pocket during enzymatic turnover, explaining also experimental evidence for topoII inhibition.

The lipopolysaccharide from Capnocytophaga canimorsus reveals an unexpected role of the core-oligosaccharide in MD-2 binding.

Capnocytophaga canimorsus is a usual member of dog's mouths flora that causes rare but dramatic human infections after dog bites. We determined the structure of C. canimorsus lipid A.

Atypical DNA recognition mechanism used by the EspR virulence regulator of Mycobacterium tuberculosis.

The human pathogen Mycobacterium tuberculosis requires the ESX-1 secretion system for full virulence. EspR plays a key role in ESX-1 regulation via direct binding and transcriptional activation of the espACD operon. Here, we describe the crystal structures of EspR, a C-terminally truncated form, EspRΔ10, as well as an EspR-DNA complex.

An introduction to quantum chemical methods applied to drug design.

The advent of molecular medicine allowed identifying the malfunctioning of subcellular processes as the source of many diseases. Since then, drugs are not only discovered, but actually designed to fulfill a precise task. Modern computational techniques, based on molecular modeling, play a relevant role both in target identification and drug lead development.

Product formation in rhodopsin by fast hydrogen motions.

The photochemical cis-trans isomerization of retinal in rhodopsin is investigated by structure sampling and excited state QM/MM trajectories with surface hopping. The calculations uncover the motions responsible for photoproduct formation and elucidate the reasons behind the efficient photoisomerization in the primary event of visual transduction.

Asymmetric phase-transfer-catalyzed intramolecular N-alkylation of indoles and pyrroles: a combined experimental and theoretical investigation.

Asymmetric phase-transfer catalysis (PTC) has risen to prominence over the last decade as a straightforward synthetic methodology for the preparation of pharmacologically active compounds in enantiomerically pure form. However, the complex interplay of weak nonbonded interactions (between catalyst and substrate) that could account for the stereoselection in these processes is still unclear, with tentative pictorial mechanistic representations usually proposed. Here we present a full account dealing with the enantioselective phase-transfer-catalyzed intramolecular aza-Michael reaction (IMAMR) of indolyl esters, as a valuable synthetic tool to obtain added-value compounds, such as dihydro-pyrazinoindolinones.

Length control of the injectisome needle requires only one molecule of Yop secretion protein P (YscP).

The needle length of the Yersinia spp. injectisome is determined by Yop secretion protein P (YscP), an early substrate of the injectisome itself. There is a linear correlation between the length of YscP and the length of the needle, suggesting that YscP acts as a molecular ruler.

Adenine deactivation in DNA resolved at the CASPT2//CASSCF/ AMBER level.

We have employed hybrid CASPT2//CASSCF/AMBER calculations to map the (1)L(a)(1pipi*) deactivation path of a single quantum mechanical adenine in a d(A)(10).d(T)(10) double strand in water that is treated at the molecular mechanics level. We find that (a) the L(a) relaxation route is flatter in DNA than in vacuo and (b) the L(a) relaxation energy in DNA is much larger than the stabilization energy of the corresponding L(a) excimer.

Ring-opening/ring-closing protocols from nitrothiophenes: six-membered versus unusual eight-membered sulfur heterocycles through Michael-type addition on nitrobutadienes.

When Ar is a low-aromaticity homo- or heterosystem, the sulfonyl-stabilized anion of nitrobutadienes 4 (which derive from the initial ring opening of 3-nitrothiophene) undergoes a rather surprising addition onto the aromatic ring itself, thereby leading to the construction of an unusual eight-membered sulfur heterocycle condensed with the original Ar ring. The competitiveness of such a pathway with respect to the formation of the thiopyran ring (i.e.

ortho-Substituted (aryl)(3-nitrobenzo[b]thiophen-2-yl)amines: study of the electrochemical behavior.

The reduction potentials of the title compounds 4 have been measured by cyclic voltammetry. The effect of the substituents has been evaluated by using a linear free energy relationship treatment, thus evidencing that the present ortho-substituents affect the Epc values basically by electronic effects. A comparison with data previously collected on ortho-substituted (aryl)(2-nitrobenzo[b]thiophen-3-yl)amines 3 has provided some interesting information.

Catalytic Mechanism of Diaminopimelate Epimerase: A QM/MM Investigation.

A QM/MM investigation, based on a DFT(B3LYP)//Amber-ff99 potential, has been carried out to elucidate the mechanism of diaminopimelate epimerase. This enzyme catalyzes the reversible stereoconversion of one of the two stereocenters of diaminopimelate and represents a promising target for rational drug design aimed to develop new selective antibacterial therapeutic agents. The QM/MM computations show that the reaction proceeds through a highly asynchronous mechanism where the side-chain of a negatively charged Cys-73 (thiolate) deprotonates the α-carbon substrate.

Deciphering intrinsic deactivation/isomerization routes in a phytochrome chromophore model.

High level ab initio correlated (CASPT2) computations have been used to elucidate the details of the photoinduced molecular motion and decay mechanisms of a realistic phytochrome chromophore model in vacuo and to explore the reasons underneath its photophysical/photochemical properties. Competitive deactivation routes emerge that unveil the primary photochemical event and the intrinsic photoisomerization ability of this system. The emerged in vacuo based static (i.

Electrostatic control of the photoisomerization efficiency and optical properties in visual pigments: on the role of counterion quenching.

Hybrid QM(CASPT2//CASSCF/6-31G*)/MM(Amber) computations have been used to map the photoisomerization path of the retinal chromophore in Rhodopsin and explore the reasons behind the photoactivity efficiency and spectral control in the visual pigments. It is shown that while the electrostatic environment plays a central role in properly tuning the optical properties of the chromophore, it is also critical in biasing the ultrafast photochemical event: it controls the slope of the photoisomerization channel as well as the accessibility of the S(1)/S(0) crossing space triggering the ultrafast decay. The roles of the E113 counterion, the E181 residue, and the other amino acids of the protein pocket are explicitly analyzed: it appears that counterion quenching by the protein environment plays a key role in setting up the chromophore's optical properties and its photochemical efficiency.

The catalytic activity of proline racemase: a quantum mechanical/molecular mechanical study.

The enzyme proline racemase from the eukaryotic parasite Trypanosoma cruzi (responsible for endemic Chagas disease) catalyzes the reversible stereoinversion of chiral Calpha in proline. We employed a new combined quantum mechanical and molecular mechanical (QM/MM) potential to study the reaction mechanism of the enzyme. Three critical points were found: two almost isoenergetic minima (M1a and M2a), in which the enzyme is bound to L- and D-Pro, respectively, and a transition state (TSCa), unveiling a highly asynchronous concerted process.