Novel Thiourea and Oxime Ether Isosteviol-Based Anticoagulants: MD Simulation and ADMET Prediction.

Activated blood coagulation factor X (FXa) plays a critical initiation step of the blood-coagulation pathway and is considered a desirable target for anticoagulant drug development. It is reversibly inhibited by nonvitamin K antagonist oral anticoagulants (NOACs) such as apixaban, betrixaban, edoxaban, and rivaroxaban. Thrombosis is extremely common and is one of the leading causes of death in developed countries.

Nucleolar Essential Protein 1 (Nep1): Elucidation of enzymatic catalysis mechanism by molecular dynamics simulation and quantum mechanics study.

The Nep1 protein is essential for the formation of eukaryotic and archaeal small ribosomal subunits, and it catalyzes the site-directed SAM-dependent methylation of pseudouridine (Ψ) during pre-rRNA processing. It possesses a non-trivial topology, namely, a 3 knot in the active site. Here, we address the issue of seemingly unfeasible deprotonation of Ψ in Nep1 active site by a distant aspartate residue (D101 in S.

The Reaction Mechanism of Loganic Acid Methyltransferase: A Molecular Dynamics Simulation and Quantum Mechanics Study.

In this work, the catalytic mechanism of loganic acid methyltransferase was characterized at the molecular level. This enzyme is responsible for the biosynthesis of loganin, which is a precursor for a wide range of biologically active compounds. Due to the lack of detailed knowledge about this process, the aim of this study was the analysis of the structure and activity of loganic acid methyltransferase.

The Connectivity Matrix: A Toolbox for Monitoring Bonded Atoms and Bonds.

The concept of a connectivity matrix, essential for the reaction fragility (RF) spectra technique for monitoring electron density evolution in a chemical reaction, has been supported with a novel formulation for the diagonal matrix elements; their direct link to the electron density function ρ() has been demonstrated. By combining the concept with the atomization energy of a system, the separation of the potential energy into atomic and/or bond contributions has been achieved. The energy derivative diagrams for atoms and bonds that are variable along a reaction path provide new insight into the reaction mechanism.

Bond Softening Indices Studied by the Fragility Spectra for Proton Migration in Formamide and Related Structures.

Computational scheme to obtain bond softening index λ, defined within the conceptual DFT, has been obtained with the use of the reaction fragility (RF) concept. Numerical results were obtained with the RF spectra for the proton transfer reaction in formamide molecule (HNCHO) and the water assisted proton migration in HNCHO·HO complex. Double proton transfer reaction in the formamide dimer, (HNCHO), and its analogues, (HNCHS) and (HNCHO)·(HNCHS), have also been studied.

Conceptual DFT analysis of the fragility spectra of atoms along the minimum energy reaction coordinate.

Theoretical justification has been provided to the method for monitoring the sequence of chemical bonds' rearrangement along a reaction path, by tracing the evolution of the diagonal elements of the Hessian matrix. Relations between the divergences of Hellman-Feynman forces and the energy and electron density derivatives have been demonstrated. By the proof presented on the grounds of the conceptual density functional theory formalism, the spectral amplitude observed on the atomic fragility spectra [L.

The reaction fragility spectrum.

We report an original method that provides a new insight into the reaction mechanism by direct observation of bond breaking and formation. Variations of the diagonal elements of the Hessian along the IRC are shown to reflect the anharmonic properties of the system that are induced by electron density modifications upon the reaction. This information is presented in the form of the reaction spectrum, demonstrating how particular atoms engage in the reorganization of bonds.

Atomic Resolution for the Energy Derivatives on the Reaction Path.

Definite algorithms for calculation of the atomic contributions to the reaction force Fξ and the reaction force constant kξ (the first and the second derivatives of the energy over the reaction path step) are presented. The electronic part in the atomic and group contributions has been separated, and this opened the way to identification of the reactive molecule fragments on the consecutive stages of the reaction path. Properties have been studied for the two canonical test reactions: CO + HF → HCOF and HONS → ONSH.

Variation of the electronic dipole polarizability on the reaction path.

The reaction force and the electronic flux, first proposed by Toro-Labbé et al. (J Phys Chem A 103:4398, 1999) have been expressed by the existing conceptual DFT apparatus. The critical points (extremes) of the chemical potential, global hardness and softness have been identified by means of the existing and computable energy derivatives: the Hellman-Feynman force, nuclear reactivity and nuclear stiffness.