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Quantum chemical methods are used to investigate 1,2-carboxylate shift and the monodentate to bidentate rearrangement of terminal carboxylate ligands in the reduced forms of methane monooxygenase (MMOH) and the R2 subunit of ribonucleotide reductase (R2). Results lead to the conclusions that the carboxylate ligands of dinuclear complexes, such as MMOH(sub red) and R2(sub red) are flexible and in good agreement with the available experimental data.

Examples are used to indicate how quantum chemistry has been applied to address real problems found in coordination chemistry for which experimental chemistry alone could not produce an answer. It is suggested that theoretical studies have greatly improved understanding of a wide range of transition-metal-mediated reactions.

Protein guidance of reactivity in the vitamin B12 coenzyme-dependent enzymes is characterized by the acceleration of the effective cobalt-carbon bond cleavage rate by approximately 10(to the 12th power)-fold relative to the rate for the free coenzyme in solution. This feature is attributed to substrate-derived radical formation and the specific interactions of the cobalamin moeity of the protein. Techniques of X-band electron spin-echo envelope modulation spectroscopy confirmed these protein-specific effects on cob(II)alamin structure and reactivity.

Research was conducted to examine the (2+2) addition of ethylene to a Cr=O bond, eq 1, as well as the (2+3) addition, eq 2, of ethylene to the two terminal oxygen atoms. The aim is to test whether the unique product distribution from the reaction between CrO2Cl2 and C2H4 could be explained in terms of the preference for a (2+2) addition. A second objective is to analyze the factors determining the relative feasibility of the (2+2) and (2+3) additions of ethylene to CrO2Cl2, eqs 1 and 2, as well as OsO4, eqs 3 and 4.

The structure and stabilities of various intermediates of the water-assisted O-O bond activation reaction on the MMOH(sub red) and R2(sub red) are studied using the B3LYP hybrid density functional method.

The theoretical calculations of (Super 17) O and (Super 14) N Nuclear Quadrupole Coupling (NQC) constants (x) and assymetry parameters (n) for small alpha helix and beta-sheet protein fragments were carried out. The separate signals that resulted from alpha helix and beta-sheet models were experimentally distinguished for (Super 17) O but not for (Super 14) N.

The first applications of ONIOM to the models of metalloenzymes in which a large number of protein residues are added are detailed. The model active sites contain 39-46 atoms, consisting of two Fe centers and the first shell ligands of four formates, two imidazoles, and a few oxo, hydroxo, aquo groups.

It is possible to use density functional theory to analyze the 14N nuclear quadrupole coupling constants and asymmetry parameters for a series of small nitrogen-containing imidazole derivatives. It is difficult to reproduce asymmetry parameters accurately.

A study was conducted which aimed to theoretically investigate two assumed routes for the formation of phenols to furnish a better understanding of the mechanisms involved. The study also investigated a novel third route proposed in previous experiments in terms of its operativeness in relation to the two already assumed paths. It will be demonstrated that this third route emerges as the best alternative of the three discussed.

Examines the characterization of cobalt(II)alamin moiety in the biradical state of enzymes. Determination of dimethylbenzimidazole axial coordination; Integration of axial ligand nitrogen with free cobalt(II)alamin; Implication for Vitamin B12 coenzyme function in ethanolamine deaminase.

Affinity capture (AC) combined with mass spectrometry (MS)-based proteomics is highly utilized throughout the drug discovery pipeline to determine small-molecule target selectivity and engagement. However, the tedious sample preparation steps and time-consuming MS acquisition process have limited its use in a high-throughput format. Here, we report an automated workflow employing biotinylated probes and streptavidin magnetic beads for small-molecule target enrichment in the 96-well plate format, ending with direct sampling from EvoSep Solid Phase Extraction tips for liquid chromatography (LC)-tandem mass spectrometry (MS/MS) analysis. The streamlined process significantly reduced both the overall and hands-on time needed for sample preparation. Additionally, we developed a data-independent acquisition-mass spectrometry (DIA-MS) method to establish an efficient label-free quantitative chemical proteomic kinome profiling workflow. DIA-MS yielded a coverage of ∼380 kinases, a > 60% increase compared to using a data-dependent acquisition (DDA)-MS method, and provided reproducible target profiling of the kinase inhibitor dasatinib. We further showcased the applicability of this AC-MS workflow for assessing the selectivity of two clinical-stage CDK9 inhibitors against ∼250 probe-enriched kinases. Our study here provides a roadmap for efficient target engagement and selectivity profiling in native cell or tissue lysates using AC-MS.

TAM receptor tyrosine kinases have emerged as promising therapeutic targets for cancer treatment due to their roles in both tumor intrinsic survival mechanisms and suppression of antitumor immunity within the tumor microenvironment. Inhibiting MerTK and Axl selectively is believed to hinder cancer cell survival, reverse the protumor myeloid phenotype, and suppress efferocytosis, thereby eliciting an antitumor immune response. In this study, we present the discovery of A-910 , a highly potent and selective dual MerTK/Axl inhibitor, achieved through a structure-based medicinal chemistry campaign. The lead compound exhibits favorable oral bioavailability, exceptional kinome selectivity, and significantly improved in vivo target engagement. These findings support the use of A-910 as an orally bioavailable in vivo tool compound for investigating the immunotherapy potential of dual MerTK/Axl inhibition.

The BET family of proteins consists of BRD2, BRD3, BRD4, and BRDt. Each protein contains two distinct bromodomains (BD1 and BD2). BET family bromodomain inhibitors under clinical development for oncology bind to each of the eight bromodomains with similar affinities. We hypothesized that it may be possible to achieve an improved therapeutic index by selectively targeting subsets of the BET bromodomains. Both BD1 and BD2 are highly conserved across family members (>70% identity), whereas BD1 and BD2 from the same protein exhibit a larger degree of divergence (∼40% identity), suggesting selectivity between BD1 and BD2 of all family members would be more straightforward to achieve. Exploiting the Asp144/His437 and Ile146/Val439 sequence differences (BRD4 BD1/BD2 numbering) allowed the identification of compound 27 demonstrating greater than 100-fold selectivity for BRD4 BD2 over BRD4 BD1. Further optimization to improve BD2 selectivity and oral bioavailability resulted in the clinical development compound 46 (ABBV-744).

SETD8 is a histone H4-K20 methyltransferase that plays an essential role in the maintenance of genomic integrity during mitosis and in DNA damage repair, making it an intriguing target for cancer research. While some small molecule inhibitors for SETD8 have been reported, the structural binding modes for these inhibitors have not been revealed. Using the complex structure of the substrate peptide bound to SETD8 as a starting point, different natural and unnatural amino acid substitutions were tested, and a potent ( K i 50 nM, IC 50 0.33 μM) and selective norleucine containing peptide inhibitor has been obtained.

Aided by molecular modeling, compounds with a pyrimidine-based tricyclic scaffold were designed and confirmed to inhibit Wee1 kinase. Structure-activity studies identified key pharmacophores at the aminoaryl and halo-benzene regions responsible for binding affinity with sub-nM K i values. The potent inhibitors demonstrated sub-μM activities in both functional and mechanism-based cellular assays and also possessed desirable pharmacokinetic profiles. The lead molecule, 31, showed oral efficacy in potentiating the antiproliferative activity of irinotecan, a cytotoxic agent, in a NCI-H1299 mouse xenograft model.

Highly active antiretroviral therapy (HAART) significantly reduces human immunodeficiency virus (HIV) viral load and has led to a dramatic decrease in acquired immunodeficiency syndrome (AIDS) related mortality. Despite this success, there remains a critical need for new HIV therapies to address the emergence of drug resistant viral strains. Next generation NNRTIs are sought that are effective against these mutant forms of the HIV virus. The bound conformations of our lead inhibitors, MK-1107 (1) and MK-4965 (2), were divergent about the oxymethylene linker, and each of these conformations was rigidified using two isomeric cyclic constraints. The constraint derived from the bioactive conformation of 2provided novel, highly potent NNRTIs that possess broad spectrum antiviral activity and good pharmacokinetic profiles. Systematic SAR led to the identification of indazole as the optimal conformational constraint to provide MK-6186 (3) and MK-7445 (6). Despite their reduced flexibility, these compounds had potency comparable to that of the corresponding acyclic ethers in both recombinant enzyme and cell based assays against both the wild-type and the clinically relevant mutant strains.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have been shown to be a key component of highly active antiretroviral therapy (HAART). The use of NNRTIs has become part of standard combination antiviral therapies producing clinical outcomes with efficacy comparable to other antiviral regimens. There is, however, a critical issue with the emergence of clinical resistance, and a need has arisen for novel NNRTIs with a broad spectrum of activity against key HIV-1 RT mutations. Using a combination of traditional medicinal chemistry/SAR analyses, crystallography, and molecular modeling, we have designed and synthesized a series of novel, highly potent NNRTIs that possess broad spectrum antiviral activity and good pharmacokinetic profiles. Further refinement of key compounds in this series to optimize physical properties and pharmacokinetics has resulted in the identification of 8e (MK-4965), which has high levels of potency against wild-type and key mutant viruses, excellent oral bioavailability and overall pharmacokinetics, and a clean ancillary profile.

Inhibition of kinesin spindle protein (KSP) is a novel mechanism for treatment of cancer with the potential to overcome limitations associated with currently employed cytotoxic agents. Herein, we describe a C2-hydroxymethyl dihydropyrrole KSP inhibitor ( 11) that circumvents hERG channel binding and poor in vivo potency, issues that limited earlier compounds from our program. However, introduction of the C2-hydroxymethyl group caused 11 to be a substrate for cellular efflux by P-glycoprotein (Pgp). Utilizing knowledge garnered from previous KSP inhibitors, we found that beta-fluorination modulated the p K a of the piperidine nitrogen and reduced Pgp efflux, but the resulting compound ( 14) generated a toxic metabolite in vivo. Incorporation of fluorine in a strategic, metabolically benign position by synthesis of an N-methyl-3-fluoro-4-(aminomethyl)piperidine urea led to compound 30 that has an optimal in vitro and metabolic profile. Compound 30 (MK-0731) was recently studied in a phase I clinical trial in patients with taxane-refractory solid tumors.