Computer-Aided Drug Design Using the Fragment Molecular Orbital Method: Current Status and Future Applications for SBDD.

Owing to the increasing use of computers, computer-aided drug design (CADD) has become an essential component of drug discovery research. In structure-based drug design (SBDD), including inhibitor design and in silico screening of drug target molecules, concordance with wet experimental data is important to provide insights on unique perspectives derived from calculations. Fragment molecular orbital (FMO) method is a quantum chemical method that facilitates precise energy calculations.

Docosahexaenoic acid enhances the treatment efficacy for castration-resistant prostate cancer by inhibiting autophagy through Atg4B inhibition.

Autophagy induction in cancer is involved in cancer progression and the acquisition of resistance to anticancer agents. Therefore, autophagy is considered a potential therapeutic target in cancer therapy. In this study, we found that long-chain fatty acids (LCFAs) have inhibitory effects on Atg4B, which is essential for autophagosome formation, through screening based on the pharmacophore of 21f, a recently developed Atg4B inhibitor.

Quantum Chemical Interaction Analysis between SARS-CoV-2 Main Protease and Ensitrelvir Compared with Its Initial Screening Hit.

A non-covalent oral drug targeting SARS-CoV-2 main protease (M), ensitrelvir (Xocova), has been developed using structure-based drug design (SBDD). To elucidate the factors responsible for enhanced inhibitory activities from an screening hit compound to ensitrelvir, we analyzed the interaction energies of the inhibitors with each residue of M using fragment molecular orbital (FMO) calculations. This analysis reveals that functional group conversion for P1' and P1 parts in the inhibitors increases the strength of existing interactions with M and also provides novel interactions for ensitrelvir; the associated changes in the conformation of M induce further interactions for ensitrelvir in other parts, including hydrogen bonds, a halogen bond, and π-orbital interactions.

New antimalarials identified by a cell-based phenotypic approach: Structure-activity relationships of 2,3,4,9-tetrahydro-1H-β-carboline derivatives possessing a 2-((coumarin-5-yl)oxy)alkanoyl moiety.

The identification, structure-activity relationships (SARs), and biological effects of new antimalarials consisting of a 2,3,4,9-tetrahydro-1H-β-carboline core, a coumarin ring, and an oxyalkanoyl linker are described. A cell-based phenotypic approach was employed in this search for novel antimalarial drugs with unique modes of action. Our screening campaign of the RIKEN compound library succeeded in the identification of the known tetrahydro-β-carboline derivative (4e) as a hit compound showing significant in vitro activity.

Pharmacological intervention of cholesterol sulfate-mediated T cell exclusion promotes antitumor immunity.

Effective cancer immunotherapy requires physical contact of T cells with cancer cells. However, tumors often constitute special microenvironments that exclude T cells and resist immunotherapy. Cholesterol sulfate (CS) is a product of sulfotransferase SULT2B1b and acts as an endogenous inhibitor of DOCK2, a Rac activator essential for migration and activation of lymphocytes.

Molecular action of larvicidal flavonoids on ecdysteroidogenic glutathione S-transferase Noppera-bo in Aedes aegypti.

Background: Mosquito control is a crucial global issue for protecting the human community from mosquito-borne diseases. There is an urgent need for the development of selective and safe reagents for mosquito control. Flavonoids, a group of chemical substances with variable phenolic structures, such as daidzein, have been suggested as potential mosquito larvicides with less risk to the environment.

Special Features of COVID-19 in the FMODB: Fragment Molecular Orbital Calculations and Interaction Energy Analysis of SARS-CoV-2-Related Proteins.

SARS-CoV-2 is the causative agent of coronavirus (known as COVID-19), the virus causing the current pandemic. There are ongoing research studies to develop effective therapeutics and vaccines against COVID-19 using various methods and many results have been published. The structure-based drug design of SARS-CoV-2-related proteins is promising, however, reliable information regarding the structural and intra- and intermolecular interactions is required.

FMODB: The World's First Database of Quantum Mechanical Calculations for Biomacromolecules Based on the Fragment Molecular Orbital Method.

We developed the world's first web-based public database for the storage, management, and sharing of fragment molecular orbital (FMO) calculation data sets describing the complex interactions between biomacromolecules, named FMO Database (https://drugdesign.riken.jp/FMODB/).

Protein ligand interaction analysis against new CaMKK2 inhibitors by use of X-ray crystallography and the fragment molecular orbital (FMO) method.

CaMKK2 (calcium/calmodulin dependent protein kinase kinase 2) is a serine/threonine protein kinase that regulates phosphorylation of CaM kinases (CaMKs) such as CaMKI, CaMKIV, and AMP-activated protein kinase (AMPK). From a pathological perspective, CaMKK2 plays a role in obesity, diabetes, and prostate cancer. Therefore, CaMKK2 is an attractive target protein for drug design.

Interruption of Vif/Elongin C interaction: In silico and experimental elucidation of the underlying molecular mechanism of benzimidazole-based APOBEC3G stabilizers.

In 2014, two novel and promising benzimidazole-based APOBEC3G stabilizers MM-1 and MM-2 (MMs) were uncovered with an elusive mechanism of action. Vif-APOBEC3G axis has been recognized as a novel therapeutic target for anti HIV-1 drug development. The unexplored mechanism of MMs hindered their further development into lead compounds.

Characterization of crystal water molecules in a high-affinity inhibitor and hematopoietic prostaglandin D synthase complex by interaction energy studies.

Hematopoietic prostaglandin D synthase (H-PGDS) is one of the two enzymes that catalyze prostaglandin D synthesis and a potential therapeutic target of allergic and inflammatory responses. To reveal key molecular interactions between a high-affinity ligand and H-PGDS, we designed and synthesized a potent new inhibitor (K: 0.14 nM), determined the crystal structure in complex with human H-PGDS, and quantitatively analyzed the ligand-protein interactions by the fragment molecular orbital calculation method.

Targeting Ras-Driven Cancer Cell Survival and Invasion through Selective Inhibition of DOCK1.

Oncogenic Ras plays a key role in cancer initiation but also contributes to malignant phenotypes by stimulating nutrient uptake and promoting invasive migration. Because these latter cellular responses require Rac-mediated remodeling of the actin cytoskeleton, we hypothesized that molecules involved in Rac activation may be valuable targets for cancer therapy. We report that genetic inactivation of the Rac-specific guanine nucleotide exchange factor DOCK1 ablates both macropinocytosis-dependent nutrient uptake and cellular invasion in Ras-transformed cells.

HCV NS3 protease enhances liver fibrosis via binding to and activating TGF-β type I receptor.

Viruses sometimes mimic host proteins and hijack the host cell machinery. Hepatitis C virus (HCV) causes liver fibrosis, a process largely mediated by the overexpression of transforming growth factor (TGF)-β and collagen, although the precise underlying mechanism is unknown. Here, we report that HCV non-structural protein 3 (NS3) protease affects the antigenicity and bioactivity of TGF-β2 in (CAGA)9-Luc CCL64 cells and in human hepatic cell lines via binding to TGF-β type I receptor (TβRI).

Prediction of ligand-induced structural polymorphism of receptor interaction sites using machine learning.

Protein functions are closely related to their three-dimensional structures. Various degrees of conformational changes in the main and side chains occur when binding with other molecules, such as small ligands or proteins. The ligand-induced structural polymorphism of proteins is also referred to as "induced-fit", and it plays an important role in the recognition of a particular class of ligands as well as in signal transduction.

Application of support vector machine to three-dimensional shape-based virtual screening using comprehensive three-dimensional molecular shape overlay with known inhibitors.

In this study, machine learning using support vector machine was combined with three-dimensional (3D) molecular shape overlay, to improve the screening efficiency. Since the 3D molecular shape overlay does not use fingerprints or descriptors to compare two compounds, unlike 2D similarity methods, the application of machine learning to a 3D shape-based method has not been extensively investigated. The 3D similarity profile of a compound is defined as the array of 3D shape similarities with multiple known active compounds of the target protein and is used as the explanatory variable of support vector machine.

A new method for induced fit docking (GENIUS) and its application to virtual screening of novel HCV NS3-4A protease inhibitors.

Hepatitis C virus (HCV) is an etiologic agent of chronic liver disease, and approximately 170 million people worldwide are infected with the virus. HCV NS3-4A serine protease is essential for the replication of this virus, and thus has been investigated as an attractive target for anti-HCV drugs. In this study, we developed our new induced-fit docking program (genius), and applied it to the discovery of a new class of NS3-4A protease inhibitors (IC(50)=1-10 μM including high selectivity index).

Structural basis for compound C inhibition of the human AMP-activated protein kinase α2 subunit kinase domain.

AMP-activated protein kinase (AMPK) is a serine/threonine kinase that functions as a sensor to maintain energy balance at both the cellular and the whole-body levels and is therefore a potential target for drug design against metabolic syndrome, obesity and type 2 diabetes. Here, the crystal structure of the phosphorylated-state mimic T172D mutant kinase domain from the human AMPK α2 subunit is reported in the apo form and in complex with a selective inhibitor, compound C. The AMPK α2 kinase domain exhibits a typical bilobal kinase fold and exists as a monomer in the crystal.

Bioinformatics based Ligand-Docking and in-silico screening.

We report a novel method, ChooseLD (CHOOse biological information Semi-Empirically on the Ligand Docking), which uses simulated annealing (SA) based on bioinformatics for protein-ligand flexible docking. The fingerprint alignment score (FPAScore) value is used to determine the docking conformation of the ligand. This method includes the matching of chemical descriptors such as fingerprints (FPs) and the root mean square deviation (rmsd) calculation of the coordinates of atoms of the chemical descriptors.

The SKE-DOCK server and human teams based on a combined method of shape complementarity and free energy estimation.

We participated in rounds 6-12 of the critical assessment of predicted interaction (CAPRI) contest as the SKE-DOCK server and human teams. The SKE-DOCK server is based on simple geometry docking and a knowledge base scoring function. The procedure is summarized in the following three steps: (1) protein docking according to shape complementarity, (2) evaluating complex models, and (3) repacking side-chain of models.

FAMS complex: a fully automated homology modeling system for protein complex structures.

The formation of a protein-protein complex is responsible for many biological functions; therefore, three-dimensional structures of protein complexes are essential for deeper understandings of protein functions and the mechanisms of diseases at the atomic level. However, compared with individual proteins, complex structures are difficult to solve experimentally because of technical limitations. Thus a method that can predict protein complex structures would be invaluable.

Protein structure prediction in CASP6 using CHIMERA and FAMS.

In CASP6, the CHIMERA-group predicted full-atom models of all targets using SKE-CHIMERA, a Web-user interface system for protein structure prediction that allows human intervention at necessary stages; we used a lot of information from our own data and from publicly available data. Using SKE-CHIMERA, we iterated manual step (template selection and alignment by the in-house program CHIMERA) and automatic step (three-dimensional model building by the in-house program FAMS). The official CASP6 assessment showed that CHIMERA-group was one of the most successful predictors in homology modeling, especially for FR/H (Fold Recognition/Homologous).

Searching for protein-protein interaction sites and docking by the methods of molecular dynamics, grid scoring, and the pairwise interaction potential of amino acid residues.

In CAPRI Rounds 1 and 2, we assumed that because there are many ionic charges that weaken electrostatic interaction forces in living cells, the hydrophobic interaction force might be important entropically. As a result of Rounds 1 and 2, the predictions for binding sites and geometric centers were acceptable, but those of the binding axes were poor, because only the largest benzene cluster was used for generating the initial docking structures. These were generated by fitting of benzene clusters formed on the surface of receptor and ligand.

Remarkably different structures and reaction mechanisms of ketoreductases for the opposite stereochemical control in the biosynthesis of BIQ antibiotics.

Two ketoreductases, RED1 and RED2, are involved in the biosynthesis of actinorhodin in Streptomyces coelicolor A3(2) and dihydrogranaticin in S. violaceoruber Tu22, respectively. They are responsible for the stereospecific reductions of the bicyclic intermediate to give (S)- or (R)-DNPA, although there is no similarity between their amino acid sequences.