DruGUI 2.0: mapping protein druggability with probe-based molecular dynamics

Open-Sourced In Silico Drug Screening.

Protein hydration and druggability

A priori assessment of target proteins’ druggability remains an unsolved problem in the field of drug development. The empirical approaches widely used to solve this problem demonstrate low efficiency. In this work, we investigated the factor of hydration of a representative set of 65 evolutionarily and structurally unrelated human enzymes in a water environment. This factor depends only on the structure of the proteins, and not on the physical and chemical properties of any potential ligands. The results show that, unlike the widely used approaches based on calculations of the accessible surface area (ASA), the content of low-entropy water molecules (LEW) in the active sites of human enzymes is systematically higher than that in other areas of their surface, including inactive cavities. Optimal criteria and a step-by-step procedure for identifying protein ligand binding sites are proposed. The proposed approach, based on the calculation of the LEW content in the first hydration layer of potentially interesting target proteins, makes it possible to evaluate their medicinal suitability even before the development of any ligands. The article also presents the results of a comparative analysis of experimental Raman spectroscopy data and the results of molecular dynamics simulations of water hydrogen bonds using three widely used water models (TIP3P, OPC3, and TIP5P) and standard algorithms for calculating hydrogen bond networks.

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

Pep2Mol: 3D Molecule Generation Targeting Protein-Protein Interfaces with Diffusion Models

P Pep2Mol is introduced, a diffusion-based generative model for 3D molecule design that targets orthosteric PPI sites by explicitly incorporating binding peptides or proteins as structural guidance, moving beyond conventional pocket-conditioned generation.

PFM: perturbed flow matching for structure-based drug design

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

Structure-based drug design (SBDD) plays a crucial role in modern drug discovery. SBDD is a methodology that utilizes the three-dimensional (3D) structural information of a target protein to computationally search for compounds that bind to it and/or to optimize the binding of known compounds. This article provides an overview of recent advances in SBDD. Furthermore, we introduce 2 case studies conducted by the authors using single-particle analysis via Cryo-electron microscopy (Cryo-EM), a powerful technique for obtaining protein structures. The first example is the sodium ion (Na+)-translocating NADH-quinone oxidoreductase derived from Vibrio cholerae. This enzyme is suggested to undergo large conformational changes during the reaction cycle. By performing classification in single-particle analysis, we successfully captured a partial view of these conformational dynamics. The second example involves the angiotensin-converting enzyme 2 (ACE2) decoy, which binds to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein and inhibits infection. Focusing on ACE2, which is critical for SARS-CoV-2 infection, an ACE2 decoy was developed to achieve higher binding affinity than the wild-type ACE2. We successfully elucidated how this ACE2 decoy binds to the spike protein.