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Previously, we examined the application of a molecular dynamics-based simulated annealing cycling protocol to docking peptides to proteins using two implicit-solvent models: a distance-dependent dielectric model (ε(r) = 4r) and a version of the Generalized Born model termed GBMV. We ...

The critical issues in docking include the prediction of the correct binding pose and the accurate estimation of the corresponding binding affinity. Different docking methodologies have all been successful in reproducing the crystallographic binding modes, but struggle when pr ...

Identifying hotspots responsible for protein interactions with other macromolecules or drugs provides insight into functional aspects of the protein network, and is a pivotal task in systems biology and drug discovery. Here, we present the protocol for the application of a machine-le ...

The prediction of the structure of protein-protein complexes based on structures or structural models of isolated partners is of increasing importance for structural biology and bioinformatics. The ATTRACT program can be used to perform systematic docking searches based on docki ...

Protein aggregation underlies the development of an increasing number of conformational human diseases of growing incidence, such as Alzheimer’s and Parkinson’s diseases. Furthermore, the accumulation of recombinant proteins as intracellular aggregates represents a cr ...

Recent advances in computational sciences enabled extensive use of in silico methods in projects at the interface between chemistry and biology. Among them virtual ligand screening, a modern set of approaches, facilitates hit identification and lead optimization in drug discovery ...

Virtual ligand screening uses computation to discover new ligands of a protein by screening one or more of its structural models against a database of potential ligands. Comparative protein structure modeling extends the applicability of virtual screening beyond the atomic struct ...

Receptors are inherently dynamic and this flexibility is important to consider when constructing a model of molecular association. Conformations from molecular dynamics simulations, a well-established method for examining protein dynamics, can be used in virtual screening to ...

Flexibility characteristics of biomacromolecules can be efficiently determined down to the atomic level by a graph-theoretical technique as implemented in the FIRST (Floppy Inclusion and Rigid Substructure Topology) and ProFlex software packages. The method has been succes ...

Conformational selection emerges as a theme in macromolecular interactions. Data validate it as a prevailing mechanism in protein–protein, protein–DNA, protein–RNA, and protein–small molecule drug recognition. This raises the question of whether this fundamental biomole ...

Structure-based virtual screening is a useful computational technique for ligand discovery. To systematically evaluate different docking approaches, it is important to have a consistent benchmarking protocol that is both relevant and unbiased. Here, we describe the designing ...

Protein–Ligand docking is a powerful technique routinely employed in structure-based drug design. Despite many reported success stories, docking is not always able to provide an accurate and easily interpretable prediction of the structure of the bound complex formed by a small organ ...

Explicitly accounting for target flexibility in docking still constitutes a difficult challenge due to the high dimensionality of the conformational space to be sampled. This especially applies to the high-throughput scenario, where the screening of hundreds of thousands compo ...

RosettaLigand is premiere software for predicting how a protein and a small molecule interact. Benchmark studies demonstrate that 70% of the top scoring RosettaLigand predicted interfaces are within 2� RMSD from the crystal structure . The latest release of Rosetta ligand software inc ...

The identification of molecular descriptors that are able to distinguish between different compound classes is of paramount importance in chemoinformatics. To aid in the identification of such discriminatory descriptors, concepts from information theory have been adapted. ...

The evolutionary trace (ET) is the single most validated approach to identify protein functional determinants and to target mutational analysis, protein engineering and drug design to the most relevant sites of a protein. It applies to the entire proteome; its predictions come with a relia ...

Computational solvent mapping globally samples the surface of target proteins using molecular probes—small molecules or functional groups—to identify potentially favorable binding positions. The method is based on X-ray and NMR screening studies showing that the binding sit ...

An expanding repertoire of “allosteric” drugs is revealing that structure-based drug design (SBDD) is not restricted to the “active site” of the target protein. Such compounds have been shown to bind distant regions of the protein topography, potentially providing higher levels of target ...

Many cancers have been associated with the deregulation of kinases, and thus, kinases have become a prime target for the development of cancer treatments. This focus on kinases has resulted in the approval of several small-molecule kinase inhibitors for cancer treatments. Further, the use of ...

Kinase inhibitors represent a relatively new class of drugs that offer novel therapies targeting specific �malfunctioning kinase-mediated signaling pathways in oncology and potentially inflammation. As the ATP binding sites of the ∼500 human kinases are structurally conser ...