Wang-hee Shin

Accurate prediction of the binding affinity of a protein-ligand complex is essential for efficient and successful rational drug design. Therefore, many binding affinity prediction methods have been developed. In recent years, since deep learning technology has become powerful, it is also implemented to predict affinity. In this work, a new neural network model that predicts the binding affinity of a protein-ligand complex structure is developed. Our model predicts the binding affinity of a compl

In this article, an enhanced version of GalaxyDock protein-ligand docking program is introduced. GalaxyDock performs conformational space annealing (CSA) global optimization to find the optimal binding pose of a ligand both in the rigid-receptor mode and the flexible-receptor mode. Binding pose prediction has been improved compared to the earlier version by the efficient generation of high-quality initial conformations for CSA using a predocking method based on a beta-complex derived from the Vo

An important issue in developing protein-ligand docking methods is how to incorporate receptor flexibility. Consideration of receptor flexibility using an ensemble of precompiled receptor conformations or by employing an effectively enlarged binding pocket has been reported to be useful. However, direct consideration of receptor flexibility during energy optimization of the docked conformation has been less popular because of the large increase in computational complexity. In this paper, we pres

Virtual screening has been widely used in the drug discovery process. Ligand-based virtual screening (LBVS) methods compare a library of compounds with a known active ligand. Two notable advantages of LBVS methods are that they do not require structural information of a target receptor and that they are faster than structure-based methods. LBVS methods can be classified based on the complexity of ligand structure information utilized: one-dimensional (1D), two-dimensional (2D), and three-dimensi

It has been noticed that the efficiency of drug development has been decreasing in the past few decades. To overcome the situation, protein-protein interactions (PPIs) have been identified as new drug targets as early as 2000. PPIs are more abundant in human cells than single proteins and play numerous important roles in cellular processes including diseases. However, PPIs have very different physicochemical features from the conventional drug targets, which make targeting PPIs challenging. Ther

Protein-ligand docking techniques are one of the essential tools for structure-based drug design. Two major components of a successful docking program are an efficient search method and an accurate scoring function. In this work, a new docking method called LigDockCSA is developed by using a powerful global optimization technique, conformational space annealing (CSA), and a scoring function that combines the AutoDock energy and the piecewise linear potential (PLP) torsion energy. It is shown tha

Protein-protein interactions are the cornerstone of numerous biological processes. Although an increasing number of protein complex structures have been determined using experimental methods, relatively fewer studies have been performed to determine the assembly order of complexes. In addition to the insights into the molecular mechanisms of biological function provided by the structure of a complex, knowing the assembly order is important for understanding the process of complex formation. Asse

Virtual screening has become an indispensable procedure in drug discovery. Virtual screening methods can be classified into two categories: ligand-based and structure-based. While the former have advantages, including being quick to compute, in general they are relatively weak at discovering novel active compounds because they use known actives as references. On the other hand, structure-based methods have higher potential to find novel compounds because they directly predict the binding affinit

We introduce an advanced model for predicting protein-ligand interactions. Our approach combines the strengths of graph neural networks with physics-based scoring methods. Existing structure-based machine-learning models for protein-ligand binding prediction often fall short in practical virtual screening scenarios, hindered by the intricacies of binding poses, the chemical diversity of drug-like molecules, and the scarcity of crystallographic data for protein-ligand complexes. To overcome the l

Protein tertiary structure prediction methods have matured in recent years. However, some proteins defy accurate prediction due to factors such as inadequate template structures. While existing model quality assessment methods predict global model quality relatively well, there is substantial room for improvement in local quality assessment, i.e. assessment of the error at each residue position in a model. Local quality is a very important information for practical applications of structure mode

Rearranged during transfection (RET) is a tyrosine kinase oncogenic receptor, activated in several cancers including non-small-cell lung cancer (NSCLC). Multiple kinase inhibitors vandetanib and cabozantinib are commonly used in the treatment of RET-positive NSCLC. However, specificity, toxicity, and reduced efficacy limit the usage of multiple kinase inhibitors in targeting RET protein. Thus, in the present investigation, we aimed to figure out novel and potent candidates for the inhibition of

Fragment-based drug discovery is a technique that finds potent binding fragments to the binding hotspots and makes them a hit compound. The combination of fragments allows us to explore the large chemical space. Thus, it becomes an effective methodology for identifying lead compounds. Three concepts have been introduced to make the fragments into the compound: growing, merging, and linking. Recently, growing and merging techniques using AI have significantly improved the accuracy and efficiency