Docking and Scoring in Drug Discovery

Spyrakis, Francesca; Cozzini, Pietro; Kellogg, Glen E.

doi:10.1002/0471266949.bmc140

Cited by 9 publications

(6 citation statements)

References 586 publications

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“…This contrasts to the better-defined and easier problem of small molecule docking in pockets of proteins. Even there, however, no universal scoring function has emerged that can confidently predict either the docked conformation or the free energy of binding [66] - [68] . Despite these major issues, computational algorithms and protocols are being developed for macromolecular docking [69] - [73] .…”

Section: Resultsmentioning

confidence: 99%

Bound Water at Protein-Protein Interfaces: Partners, Roles and Hydrophobic Bubbles as a Conserved Motif

et al. 2011

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BackgroundThere is a great interest in understanding and exploiting protein-protein associations as new routes for treating human disease. However, these associations are difficult to structurally characterize or model although the number of X-ray structures for protein-protein complexes is expanding. One feature of these complexes that has received little attention is the role of water molecules in the interfacial region.MethodologyA data set of 4741 water molecules abstracted from 179 high-resolution (≤ 2.30 Å) X-ray crystal structures of protein-protein complexes was analyzed with a suite of modeling tools based on the HINT forcefield and hydrogen-bonding geometry. A metric termed Relevance was used to classify the general roles of the water molecules.ResultsThe water molecules were found to be involved in: a) (bridging) interactions with both proteins (21%), b) favorable interactions with only one protein (53%), and c) no interactions with either protein (26%). This trend is shown to be independent of the crystallographic resolution. Interactions with residue backbones are consistent for all classes and account for 21.5% of all interactions. Interactions with polar residues are significantly more common for the first group and interactions with non-polar residues dominate the last group. Waters interacting with both proteins stabilize on average the proteins' interaction (−0.46 kcal mol−1), but the overall average contribution of a single water to the protein-protein interaction energy is unfavorable (+0.03 kcal mol−1). Analysis of the waters without favorable interactions with either protein suggests that this is a conserved phenomenon: 42% of these waters have SASA ≤ 10 Å2 and are thus largely buried, and 69% of these are within predominantly hydrophobic environments or “hydrophobic bubbles”. Such water molecules may have an important biological purpose in mediating protein-protein interactions.

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Section: Resultsmentioning

confidence: 99%

Bound Water at Protein-Protein Interfaces: Partners, Roles and Hydrophobic Bubbles as a Conserved Motif

et al. 2011

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“…Docking, used as a virtual screening tool to assess the affinity of ligands, uses fast, yet approximate methods, i.e., scoring functions (SFs). Commonly used SFs belong to four groups: force field-based, empirical, knowledge-based, and relatively new, machine-learning-based [114][115][116][117]. Better at distinguishing active from inactive molecules are scoring functions based on quantum mechanics, which give a much lower number of false positives, although at the cost of increased computation time by one to two orders of magnitude [118][119][120][121][122].…”

Section: Characteristics Of In Silico Methodsmentioning

confidence: 99%

“…The binding of a ligand to a protein usually changes the conformation of both the ligand and the protein. Thus, it is also important for flexible ligands to properly sample their conformational space during docking [116]. The more significant challenge is to account for the conformational changes in the protein during ligand binding [123][124][125][126][127][128].…”

Section: Characteristics Of In Silico Methodsmentioning

confidence: 99%

New Perspectives of CYP1B1 Inhibitors in the Light of Molecular Studies

Mikstacka

Dutkiewicz

2021

Processes

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Human cytochrome P450 1B1 (CYP1B1) is an extrahepatic heme-containing monooxygenase. CYP1B1 contributes to the oxidative metabolism of xenobiotics, drugs, and endogenous substrates like melatonin, fatty acids, steroid hormones, and retinoids, which are involved in diverse critical cellular functions. CYP1B1 plays an important role in the pathogenesis of cardiovascular diseases, hormone-related cancers and is responsible for anti-cancer drug resistance. Inhibition of CYP1B1 activity is considered as an approach in cancer chemoprevention and cancer chemotherapy. CYP1B1 can activate anti-cancer prodrugs in tumor cells which display overexpression of CYP1B1 in comparison to normal cells. CYP1B1 involvement in carcinogenesis and cancer progression encourages investigation of CYP1B1 interactions with its ligands: substrates and inhibitors. Computational methods, with a simulation of molecular dynamics (MD), allow the observation of molecular interactions at the binding site of CYP1B1, which are essential in relation to the enzyme’s functions.

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“…In cases where a number of different ligands are being interrogated, the scoring function aims to generate a rank list that corresponds to the binding affinity. This is a challenging task as many scoring functions fail to accurately predict binding affinity and often simply report a score which may or may not be at all congruent with experimentally measured binding affinities [6]. …”

Section: Introductionmentioning

confidence: 99%

“…Where fi is a simple geometrical function of the ligand (rl) and receptor (rp) coordinates [6]. However, accuracy of these methods depends upon the quality of the experimental binding data and of the crystallographic structural data of the training set.…”

Section: Introductionmentioning

confidence: 99%

Molecular Docking: From Lock and Key to Combination Lock

Tripathi

Bankaitis

2018

J Mol Med Clin Appl

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Accurate modeling of protein ligand binding is an important step in structure-based drug design, is a useful starting point for finding new lead compounds or drug candidates. The ‘Lock and Key’ concept of protein-ligand binding has dominated descriptions of these interactions, and has been effectively translated to computational molecular docking approaches. In turn, molecular docking can reveal key elements in protein-ligand interactions-thereby enabling design of potent small molecule inhibitors directed against specific targets. However, accurate predictions of binding pose and energetic remain challenging problems. The last decade has witnessed more sophisticated molecular docking approaches to modeling protein-ligand binding and energetics. However, the complexities that confront accurate modeling of binding phenomena remain formidable. Subtle recognition and discrimination patterns governed by three-dimensional features and microenvironments of the active site play vital roles in consolidating the key intermolecular interactions that mediates ligand binding. Herein, we briefly review contemporary approaches and suggest that future approaches treat protein-ligand docking problems in the context of a ‘combination lock’ system.

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Docking and Scoring in Drug Discovery

Cited by 9 publications

References 586 publications

Bound Water at Protein-Protein Interfaces: Partners, Roles and Hydrophobic Bubbles as a Conserved Motif

Bound Water at Protein-Protein Interfaces: Partners, Roles and Hydrophobic Bubbles as a Conserved Motif

New Perspectives of CYP1B1 Inhibitors in the Light of Molecular Studies

Molecular Docking: From Lock and Key to Combination Lock

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