[Structural Analysis Using Cryo-electron Microscopy for Protein-based Drug Design].

Quantum Methods in Drug Discovery: An Introduction to the Theoceptor (Theoretical Receptor) Approach.

Theoceptor method can be applied to X-ray crystallography- or cryo-electron microscopy-derived structures, can be applied equally to covalent and noncovalent binders, and can provide excellent predictions for the changes in activity between matched molecular pairs.

HDX-MS reveals structurally dynamic mechanisms of drug action: Insights from deubiquitinase inhibitors

Abstract Protein conformational heterogeneity presents a major challenge for structure determination and structure-based inhibitor design, particularly for enzymes containing flexible or intrinsically disordered regions. X-ray crystallography and cryo-EM often capture only static conformations and frequently rely on truncated constructs that omit dynamic regions. Here, we integrate hydrogen-deuterium exchange mass spectrometry (HDX-MS) with molecular docking and available crystal structures to investigate the solution-state conformational dynamics of the mitochondrial deubiquitinase USP30. HDX-MS reveals dynamic features not resolved in crystal structures and shows that both covalent and non-covalent inhibitors bind the thumb-palm cleft of the catalytic domain through distinct binding modes. These interactions stabilize different conformational states of the regions surrounding switching (SL1) and blocking (BL1 and BL2) loops, providing mechanistic insight into inhibitor recognition and highlighting the value of HDX-MS for guiding DUB-targeted drug discovery.

Integrating AI-Based Protein Modeling and Fragment Molecular Orbital Analysis for Structure-Based Drug Design.

Open-Sourced In Silico Drug Screening.

This chapter describes a structure-based computational approach to perform high-throughput ligand screens of chemical libraries using open-source software programs and illustrates this workflow with the enzymatic molecular target NAD(P)H:quinone oxidoreductase1 (NQO1), which is overexpressed in a number of human solid tumors.

MOLECULAR DOCKING AS A TOOL FOR STRUCTURAL ELUCIDATION OF BIOACTIVE COMPOUNDS: A REVIEW

Structural elucidation is an important step in chemical, pharmaceutical, biochemical, and natural product research because it helps researchers identify a compound and understand how its atoms are arranged. Traditional techniques such as nuclear magnetic resonance spectroscopy, mass spectrometry, infrared spectroscopy, ultraviolet spectroscopy, and X-ray crystallography remain the main methods used for structure determination. However, these methods may sometimes face difficulties, especially when compounds have closely related structures, are unstable, or are obtained in very small quantities. Molecular docking has become a useful computational tool that can support structural elucidation by providing information on how an identified or proposed compound may interact with a biological target. It does not replace experimental methods, but it can help explain the possible relationship between chemical structure and biological activity. In docking studies, a ligand is placed into the binding site of a protein to predict its binding pose, interaction pattern, and possible binding strength. This is useful in natural product research, drug discovery, and studies involving bioactive compounds, where researchers often need to understand how a compound may produce its observed activity. Molecular docking can also support the comparison of related compounds, interpretation of structure–activity relationships, and selection of promising molecules for further testing. Despite its usefulness, docking has limitations, including issues with protein flexibility, scoring accuracy, ligand preparation, and binding site selection. Therefore, docking results should be interpreted carefully and supported with experimental data, validation methods, molecular dynamics simulation, and biological assays where possible. This review discusses the principles, workflow, applications, limitations, and future relevance of molecular docking as a complementary tool in structural elucidation.

Computational insights into the anti-Alzheimer potential of alkynyl-3-carboxamide derivatives.

Alzheimer's disease (AD) remains a major global health challenge due to its complex pathological mechanisms and the limited availability of effective disease-modifying therapies. In this study, a dataset of fifty novel alkynyl-3-carboxamide derivatives (1-50) was systematically evaluated as potential inhibitors of asparagine endopeptidase (legumain), a key enzyme implicated in AD-associated neurodegeneration. An integrated computational approach involving molecular docking, molecular dynamics (MD) simulations, molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) binding free energy analysis, density functional theory (DFT) calculations, and ADMET profiling was employed to investigate ligand-protein interactions, structural stability, electronic properties, and drug-likeness. Molecular docking analysis across ten disease-relevant protein targets identified ligand 4 as the most promising candidate, showing the highest binding affinity toward legumain (PDB ID: 5LUA) with a docking score of -8.1 kcal mol-1. Temperature-dependent MD simulations performed at 300, 305, 310, and 320 K confirmed the stability of the 5LUA-ligand 4 complex, as indicated by consistently low root-mean-square deviation (RMSD) fluctuations and stable binding interactions. MM/PBSA calculations further demonstrated favorable binding thermodynamics for ligand 4, with a total Gibbs free energy of binding (ΔG_bind) of -37.05 kcal mol-1. Furthermore, physicochemical and pharmacokinetic assessments revealed favorable drug-like characteristics, including compliance with Lipinski's and Veber's criteria, suitable lipophilicity (c log P = 2.03), topological polar surface area (TPSA = 131.4 Å2), and an acceptable predicted hERG inhibition profile (pIC50 = 0.9881) with no significant toxicity alerts. Overall, these computational findings, supported by previously reported in vitro evidence, suggest that ligand 4 represents a promising alkynyl-3-carboxamide-based lead scaffold for further development as a potential legumain-targeted therapeutic candidate for AD. Additional experimental validation through advanced biological assays and in vivo studies is required to confirm its efficacy and safety profile.