Investigation of Crystal Structures in Structure-Based Virtual Screening for Protein Kinase Inhibitors

Abstract

Protein kinases are important drug targets in several therapeutic areas ,and structure-based virtual screening (SBVS) is an important strategy in discovering lead compounds for kinase targets. However, there are multiple crystal structures available for each target, and determining which one is the most favorable is a key step in molecular docking for SBVS due to the ligand induce-fit effect. This work aimed to find the most desirable crystal structures for molecular docking by a comprehensive analysis of the protein kinase database which covers 190 different kinases from all eight main kinase families. Through an integrated self-docking and cross-docking evaluation, 86 targets were eventually evaluated on a total of 2608 crystal structures. Results showed that molecular docking has great capability in reproducing conformation of crystallized ligands and for each target, the most favorable crystal structure was selected, and the AGC family outperformed the other family targets based on RMSD comparison. In addition, RMSD values, GlideScore, and corresponding bioactivity data were compared and demonstrated certain relationships. This work provides great convenience for researchers to directly select the optimal crystal structure in SBVS-based kinase drug design and further validates the effectiveness of molecular docking in drug discovery.

Discovery of Dual FGFR4 and EGFR Inhibitors by Machine Learning and Biological Evaluation

“…The X-ray crystal structures of FGFR4 (PDB: 4UXQ) and EGFR (PDB: 4ZAU) were downloaded from the Protein Data Bank (PDB) and prepared using the Protein Preparation Wizard Workflow in Maestro of the Schrodinger 2009 package. , Proteins were protonated, and then, the added hydrogens were minimized using the OPLS2005 force field . The small molecules were minimized by the LigPrep module .…”

The Diverse Roles of TAO Kinases in Health and Diseases

“…The development of inhibitors that disrupt the TAOK2 C-terminal interaction may have potential use in the clinic if the interaction is involved in disease pathology. Recently, various kinase inhibitor candidates have been developed by structure-guided, kinase domain virtual screening [ 85 , 86 ]. This is usually achieved by searching a compound that binds to a target through the quantitative structure–activity relationship model derived from existing molecule datasets [ 85 ].…”

“…Recently, various kinase inhibitor candidates have been developed by structure-guided, kinase domain virtual screening [ 85 , 86 ]. This is usually achieved by searching a compound that binds to a target through the quantitative structure–activity relationship model derived from existing molecule datasets [ 85 ]. Via computer-aided molecular docking, optimal binding modes of ligands for a given binding pocket can be generated, thus facilitating the discovery of specific inhibitors.…”

Accelerated Organic Crystal Structure Prediction with Genetic Algorithms and Machine Learning

“…To calculate rmsd, we use our own matching technique, employing Pymatgen’s StructureMatcher to compare generated structures with the experimentally derived polymorph. StructureMatcher is designed to operate on similar crystal structures, and has been used for crystal comparison in a number of other works, ,− including both GAtor and Genarris . Using Pymatgen’s StructureMatcher, a generated structure is put into a similar basis to the reference structure without changing any of the interatomic distances.…”

“…These multiple stable forms are called polymorphs, each of which may exhibit different chemical and physical properties . The problem of organic (or molecular) crystal structure prediction (CSP) has important applications in a number of areas including drug discovery, where the crystallized form of a molecule may affect the efficacy, safety, and formulation of a drug, − and in the development of organic semiconductors in flexible electronic devices, where polymorphism has consequences for opto-electronic performance. − In a broader context, the ability to do accurate CSP in silico, as a complementary approach to experimental high-throughput screening in the laboratory, has shown proof of greatly reducing the time and money required to generate a candidate crystal with desired properties, , and has the potential to allow practitioners to explore a larger part of chemical space, facilitating the discovery of novel chemical entities …”