A Time Dependent Density Functional Theory Study of α-84 Phycocyanobilin Chromophore in C-Phycocyanin

The optical characteristics of absorption and circular dichroism (CD) spectroscopy of an α-subunit of C-phycocyanin (C-PC) were investigated by using time dependent density functional theory (TDDFT) combined with the polarizable continuum model (PCM). When the protonation of α-84 phycocyanobilin (PCB) and its interaction with the protein moiety in C-PC have been taken into account, satisfactory assignment of the absorption and CD spectra of α-84 PCB can be achieved. The TDDFT−PCM calculations conclude that in the visible absorption region the main peak arises from the π electron excitation of the pyrrole rings and the shoulder peak comes from the charge transfer from Asp87 (a nearby amino acid residue) to PCBH+

A Time-Dependent Density Functional Theory Investigation of the Spectroscopic Properties of the β-Subunit in C-Phycocyanin

By using time-dependent density functional theory combined with the polarizable continuum model, a satisfactory assignment of the absorption and circular dichroism spectra and energy transfer flow of the β-subunit in C-phycocyanin (C-PC) was achieved when the protonation of β-84 and β-155 phycocyanobilin (PCB) and their interaction with the protein moiety in C-PC have been taken into account. We attribute the main peak for both β-84 and β-155 as arising from the π electron excitation of the pyrrole rings and the shoulder peak as arising from the charge transfer from the asparate residue to PCBH+. The satisfactory agreement between theory and experiment suggests that Förster resonance theory prevails such that energy transfer occurs from βs (β-155) to βf (β-84)

Understanding the Spectroscopic Properties of the Photosynthetic Reaction Center of <i>Rhodobacter sphaeroides</i> by a Combined Theoretical Study of Absorption and Circular Dichroism Spectra

In the present study, we calculate eight low-lying (1.3−1.7 eV energy region) electronic excited states in well accordance with the absorption and CD spectroscopic properties of PSRC from Rb. shpaeroides by using time-dependent density functional theory (TDDFT). Our present calculations demonstrate that, only when the interactions among the prosthetic groups have been taken into account, a set of satisfactory assignments for both absorption and CD spectra of PSRC from Rb. sphaeroides can be achieved simultaneously

Amide- and Urea-Functionalized Dithienylethene: Synthesis, Photochromism, and Binding with Halide Anions

A versatile amide- and urea-functionalized dithienylethene has been successfully synthesized. Upon irradiation with UV or visible light, the compound showed excellent fatigue resistance. As a synthetic receptor, the dithienylethene displayed switchable affinities for Cl^– and Br^– anions when the UV/vis light was introduced. The switchable binding ability also had good reversibility

Cov_DOX: A Method for Structure Prediction of Covalent Protein–Ligand Bindings

A handful of molecular docking tools have been extended to enable a covalent docking. However, all of them face the challenge brought by the covalent bond between proteins and ligands. Many covalent drug design scenarios still heavily rely on demanding crystallographic experiments for accurate binding structures. Aiming at filling the gap between covalent dockings and crystallographic experiments, we develop and validate a hybrid method, dubbed as Cov_DOX, in this work. Cov_DOX achieves an overall success rate of 81% with RMSD < 2 Å for the Top 1 pose prediction in the validation against a test set including 405 crystal structures for covalent protein–ligand complexes, covering various types of the warhead chemistry and receptors. Such accuracy is not far from the much more demanding crystallographic experiments, in sharp contrast to the performance of the covalent docking front runners (success rate: 40–60%)

Cov_DOX: A Method for Structure Prediction of Covalent Protein–Ligand Bindings

A handful of molecular docking tools have been extended to enable a covalent docking. However, all of them face the challenge brought by the covalent bond between proteins and ligands. Many covalent drug design scenarios still heavily rely on demanding crystallographic experiments for accurate binding structures. Aiming at filling the gap between covalent dockings and crystallographic experiments, we develop and validate a hybrid method, dubbed as Cov_DOX, in this work. Cov_DOX achieves an overall success rate of 81% with RMSD < 2 Å for the Top 1 pose prediction in the validation against a test set including 405 crystal structures for covalent protein–ligand complexes, covering various types of the warhead chemistry and receptors. Such accuracy is not far from the much more demanding crystallographic experiments, in sharp contrast to the performance of the covalent docking front runners (success rate: 40–60%)

Cov_DOX: A Method for Structure Prediction of Covalent Protein–Ligand Bindings

A handful of molecular docking tools have been extended to enable a covalent docking. However, all of them face the challenge brought by the covalent bond between proteins and ligands. Many covalent drug design scenarios still heavily rely on demanding crystallographic experiments for accurate binding structures. Aiming at filling the gap between covalent dockings and crystallographic experiments, we develop and validate a hybrid method, dubbed as Cov_DOX, in this work. Cov_DOX achieves an overall success rate of 81% with RMSD < 2 Å for the Top 1 pose prediction in the validation against a test set including 405 crystal structures for covalent protein–ligand complexes, covering various types of the warhead chemistry and receptors. Such accuracy is not far from the much more demanding crystallographic experiments, in sharp contrast to the performance of the covalent docking front runners (success rate: 40–60%)

Structure-Based Design and Synthesis of Novel Dual-Target Inhibitors against Cyanobacterial Fructose-1,6-Bisphosphate Aldolase and Fructose-1,6-Bisphosphatase

Cyanobacteria class II fructose-1,6-bisphoshate aldolase (Cy-FBA-II) and cyanobacteria fructose-1,6-bisphosphatase (Cy-FBPase) are two neighboring key regulatory enzymes in the Calvin cycle of the cyanobacteria photosynthesis system. Each of them might be taken as a potential target for designing novel inhibitors to chemically control harmful algal blooms (HABs). In the present paper, a series of novel inhibitors were rationally designed, synthesized, and optimized based upon the structural and interactional information of both Cy-FBA-II and Cy-FBPase, and their inhibitory activities were examined in vitro and in vivo. The experimental results showed that compounds L19e–L19g exhibited moderate inhibitory activities (IC50 = 28.1–103.2 μM) against both Cy-FBA-II and Cy-FBPase; compounds L19a–L19d, L19h, L20a–L20d exhibited high Cy-FBA-II inhibitory activities (IC50 = 2.3–16.9 μM) and moderate Cy-FBPase inhibitory activities (IC50 = 31.5–141.2 μM); however, compounds L20e–L20h could potently inhibit both Cy-FBA-II and Cy-FBPase with IC50 values less than 30 μM, which demonstrated more or less dual-target inhibitor’s feature. Moreover, most of them exhibited potent algicide activity (EC50 = 0.8–22.3 ppm) against cyanobacteria Synechocystis sp. PCC 6803

Cov_FB3D: A De Novo Covalent Drug Design Protocol Integrating the BA-SAMP Strategy and Machine-Learning-Based Synthetic Tractability Evaluation

De novo drug design actively seeks to use sets of chemical rules for the fast and efficient identification of structurally new chemotypes with the desired set of biological properties. Fragment-based de novo design tools have been successfully applied in the discovery of noncovalent inhibitors. Nevertheless, these tools are rarely applied in the field of covalent inhibitor design. Herein, we present a new protocol, called Cov_FB3D, which involves the in silico assembly of potential novel covalent inhibitors by identifying the active fragments in the covalently binding site of the target protein. In this protocol, we propose a BA-SAMP strategy, which combines the noncovalent moiety score with the X-Score as the molecular mechanism (MM) level, and the covalent candidate score with the PM7 as the QM level. The synthetic accessibility of each suggested compound could be further evaluated with machine-learning-based synthetic complexity evaluation (SCScore). An in-depth test of this protocol against the crystal structures of 15 covalent complexes consisting of BTK inhibitors, KRAS inhibitors, EGFR inhibitors, EphB1 inhibitors, MAGL inhibitors, and MAPK inhibitors revealed that most of these inhibitors could be de novo reproduced from the fragments by Cov_FB3D. The binding modes of most generated reference poses could accurately reproduce the known binding mode of most of the reference covalent adduct in the binding site (RMSD ≤ 2 Å). In particular, most of these inhibitors were ranked in the top 2%, using the BA-SAMP strategy. Notably, the novel human ALDOA inhibitor (T1) with potent inhibitory activity (0.34 ± 0.03 μM) and greater synthetic accessibility was successfully de novo designed by this protocol. The positive results confirm the abilities of Cov_FB3D protocol