SuCOS is Better than RMSD for Evaluating Fragment Elaboration and Docking Poses

One of the fundamental assumptions of fragment-based drug discovery is that the fragment’s binding mode will be conserved upon elaboration into larger compounds. The most common way of quantifying binding mode similarity is Root Mean Square Deviation (RMSD), but Protein Ligand Interaction Fingerprint (PLIF) similarity and shape-based metrics are sometimes used. We introduce SuCOS, an open-source shape and chemical feature overlap metric. We explore the strengths and weaknesses of RMSD, PLIF similarity, and SuCOS on a dataset of X-ray crystal structures of paired elaborated larger and smaller molecules bound to the same protein. Our redocking and cross-docking studies show that SuCOS is superior to RMSD and PLIF similarity. When redocking, SuCOS produces fewer false positives and false negatives than RMSD and PLIF similarity; and in cross-docking, SuCOS is better at differentiating experimentally-observed binding modes of an elaborated molecule given the pose of its non-elaborated counterpart. Finally we show that SuCOS performs better than AutoDock Vina at differentiating actives from decoy ligands using the DUD-E dataset. SuCOS is available at https://github.com/susanhleung/SuCOS . <br>

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Flavonoids as Putative Epi-Modulators: Insight into Their Binding Mode with BRD4 Bromodomains Using Molecular Docking and Dynamics

Biomolecules ◽

10.3390/biom8030061 ◽

2018 ◽

Vol 8 (3) ◽

pp. 61 ◽

Cited By ~ 9

Author(s):

Fernando Prieto-Martínez ◽

José Medina-Franco

Keyword(s):

Kinase Inhibitors ◽

Binding Mode ◽

Binding Modes ◽

Ligand Interaction ◽

Bet Inhibitors ◽

Protein Ligand Interaction ◽

Brd4 Inhibition ◽

Dynamics Simulations ◽

Insight Into

Flavonoids are widely recognized as natural polydrugs, given their anti-inflammatory, antioxidant, sedative, and antineoplastic activities. Recently, different studies showed that flavonoids have the potential to inhibit bromodomain and extraterminal (BET) bromodomains. Previous reports suggested that flavonoids bind between the Z and A loops of the bromodomain (ZA channel) due to their orientation and interactions with P86, V87, L92, L94, and N140. Herein, a comprehensive characterization of the binding modes of fisetin and the biflavonoid, amentoflavone, is discussed. To this end, both compounds were docked with BET bromodomain 4 (BRD4) using four docking programs. The results were post-processed with protein–ligand interaction fingerprints. To gain further insight into the binding mode of the two natural products, the docking results were further analyzed with molecular dynamics simulations. The results showed that amentoflavone makes numerous contacts in the ZA channel, as previously described for flavonoids and kinase inhibitors. It was also found that amentoflavone can potentially make contacts with non-canonical residues for BET inhibition. Most of these contacts were not observed with fisetin. Based on these results, amentoflavone was experimentally tested for BRD4 inhibition, showing activity in the micromolar range. This work may serve as the basis for scaffold optimization and the further characterization of flavonoids as BET inhibitors.

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Spiro-acridine inhibiting tyrosinase enzyme: Kinetic, protein-ligand interaction and molecular docking studies

International Journal of Biological Macromolecules ◽

10.1016/j.ijbiomac.2018.10.175 ◽

2019 ◽

Vol 122 ◽

pp. 289-297 ◽

Cited By ~ 6

Author(s):

Thaís Meira Menezes ◽

Sinara Mônica Vitalino de Almeida ◽

Ricardo Olímpio de Moura ◽

Gustavo Seabra ◽

Maria do Carmo Alves de Lima ◽

...

Keyword(s):

Molecular Docking ◽

Docking Studies ◽

Enzyme Kinetic ◽

Ligand Interaction ◽

Molecular Docking Studies ◽

Protein Ligand Interaction ◽

Tyrosinase Enzyme

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Docking, Binding Free Energy Estimation, and MD Simulation of Newly Designed CQ and HCQ Analogues Against the Spike-ACE2 Complex of SARS-CoV-2

International Journal of Quantitative Structure-Property Relationships ◽

10.4018/ijqspr.2021100105 ◽

2021 ◽

Vol 6 (4) ◽

pp. 77-89

Author(s):

Anjoomaara H. Patel ◽

Riya B. Patel ◽

MahammadHussain J. Memon ◽

Samiya S. Patel ◽

Sharav A. Desai ◽

...

Keyword(s):

Free Energy ◽

Md Simulation ◽

Binding Free Energy ◽

Docking Studies ◽

Radius Of Gyration ◽

Ligand Interaction ◽

Energy Estimation ◽

Efficacious Treatment ◽

Protein Ligand Interaction ◽

Derivatives Of

The coronavirus disease 2019 (COVID-19) virus has been spreading rapidly, and scientists are endeavouring to discover drugs for its efficacious treatment. Chloroquine phosphate, an old drug for treatment of malaria, has shown to have apparent efficacy and acceptable safety against COVID-19. As a part of Drug Discovery Hackathon-2020, in this study, the authors have tried making the derivatives of CQ and HCQ using MarvinSketch by ChemAxon. Molecular docking studies of these ligands were performed using Glide by Schrodinger, and ADME profiles were obtained by using QikProp. The obtained results after data analysis demonstrated that ligands HCQ_imidazoll, choloroquine_3c, HCQ_pyrrolC had good binding affinity and complied with all the ADME parameters. The molecular dynamic simulation of these ligands in complex with the 2019-nCoV RBD/ACE-2-B0AT1 complex PDB ID: 6M17 were carried out, and the parameters like RMSD, RMSF, and radius of gyration were observed to understand the fluctuations and protein-ligand interaction.

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Predicting Ligand Binding Modes from Neural Networks Trained on Protein–Ligand Interaction Fingerprints

Journal of Chemical Information and Modeling ◽

10.1021/ci300200r ◽

2013 ◽

Vol 53 (4) ◽

pp. 763-772 ◽

Cited By ~ 31

Author(s):

Vladimir Chupakhin ◽

Gilles Marcou ◽

Igor Baskin ◽

Alexandre Varnek ◽

Didier Rognan

Keyword(s):

Neural Networks ◽

Ligand Binding ◽

Binding Modes ◽

Ligand Interaction ◽

Protein Ligand Interaction ◽

Interaction Fingerprints

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An Investigation of Small GTPases in relation to Liver Tumorigenesis Using Traditional Chinese Medicine

BioMed Research International ◽

10.1155/2014/428210 ◽

2014 ◽

Vol 2014 ◽

pp. 1-11 ◽

Cited By ~ 1

Author(s):

Tzu-Chieh Hung ◽

Wen-Yuan Lee ◽

Kuen-Bao Chen ◽

Yueh-Chiu Chan ◽

Calvin Yu-Chian Chen

Keyword(s):

Molecular Dynamics ◽

Chinese Medicine ◽

Traditional Chinese Medicine ◽

Hydrophobic Interactions ◽

Small Gtpases ◽

Ligand Interaction ◽

Protein Ligand Interactions ◽

Ligand Interactions ◽

Protein Ligand Interaction ◽

Better Than

Recently, an important topic of liver tumorigenesis had been published in 2013. In this report, Ras and Rho had defined the relation of liver tumorigenesis. The traditional Chinese medicine (TCM) database has been screened for molecular compounds by simulating molecular docking and molecular dynamics to regulate Ras and liver tumorigenesis. Saussureamine C, S-allylmercaptocysteine, and Tryptophan are selected based on the highest docking score than other TCM compounds. The molecular dynamics are helpful in the analysis and detection of protein-ligand interactions. Based on the docking poses, hydrophobic interactions, and hydrogen bond variations, this research surmises are the main regions of important amino acids in Ras. In addition to the detection of TCM compound efficacy, we suggest Saussureamine C is better than the others for protein-ligand interaction.

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Computational design of novel cyclic urea as HIV-1 protease inhibitor

Open Chemistry ◽

10.2478/s11532-007-0040-x ◽

2007 ◽

Vol 5 (4) ◽

pp. 1064-1072 ◽

Cited By ~ 3

Author(s):

Manga Vijjulatha ◽

S. Kanth

Keyword(s):

Biological Activity ◽

Interaction Energy ◽

Model Equation ◽

Computational Design ◽

Docking Studies ◽

Computational Techniques ◽

Ligand Interaction ◽

Protein Ligand Interaction ◽

Adme Properties ◽

Hiv 1

AbstractA series of novel cyclic urea molecules 5,6-dihydroxy-1,3-diazepane-2,4,7-trione as HIV-1 protease inhibitors were designed using computational techniques. The designed molecules were compared with the known cyclic urea molecules by performing docking studies, calculating their ADME (Absorption, Distribution, Metabolism, and Excretion) properties and protein ligand interaction energy. These novel molecules were designed by substituting the P 1/P′ 1 positions (4th and 7th position of 1, 3-diazepan-2-one) with double bonded oxygens. This reduces the molecular weight and increases the bioavailability, indicating better ADME properties. The docking studies showed good binding affinity towards HIV-1 protease. The biological activity of these inhibitors were predicted by a model equation generated by the regression analysis between biological activity (log 1/K i ) of known inhibitors and their protein ligand interaction energy. The synthetic studies are in progress.

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In Silico Screening of Semi-Synthesized Compounds as Potential Inhibitors for SARS-CoV-2 Papain-Like Protease: Pharmacophoric Features, Molecular Docking, ADMET, Toxicity and DFT Studies

Molecules ◽

10.3390/molecules26216593 ◽

2021 ◽

Vol 26 (21) ◽

pp. 6593

Author(s):

Mohamed S. Alesawy ◽

Eslam B. Elkaeed ◽

Aisha A. Alsfouk ◽

Ahmed M. Metwaly ◽

Ibrahim. H. Eissa

Keyword(s):

Structural Features ◽

Docking Studies ◽

Proteolytic Processing ◽

Binding Modes ◽

Free Energies ◽

Essential Enzyme ◽

Potential Inhibitors ◽

Molecular Electrostatic Potential Maps ◽

Better Than ◽

Binding Free Energies

Papain-like protease is an essential enzyme in the proteolytic processing required for the replication of SARS-CoV-2. Accordingly, such an enzyme is an important target for the development of anti-SARS-CoV-2 agents which may reduce the mortality associated with outbreaks of SARS-CoV-2. A set of 69 semi-synthesized molecules that exhibited the structural features of SARS-CoV-2 papain-like protease inhibitors (PLPI) were docked against the coronavirus papain-like protease (PLpro) enzyme (PDB ID: (4OW0). Docking studies showed that derivatives 34 and 58 were better than the co-crystallized ligand while derivatives 17, 28, 31, 40, 41, 43, 47, 54, and 65 exhibited good binding modes and binding free energies. The pharmacokinetic profiling study was conducted according to the four principles of the Lipinski rules and excluded derivative 31. Furthermore, ADMET and toxicity studies showed that derivatives 28, 34, and 47 have the potential to be drugs and have been demonstrated as safe when assessed via seven toxicity models. Finally, comparing the molecular orbital energies and the molecular electrostatic potential maps of 28, 34, and 47 against the co-crystallized ligand in a DFT study indicated that 28 is the most promising candidate to interact with the target receptor (PLpro).

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Protein Ligand Interaction Fingerprints

Pharmaceutical Sciences ◽

10.4018/978-1-5225-1762-7.ch041 ◽

2017 ◽

pp. 1072-1091

Author(s):

Ali HajiEbrahimi ◽

Hamidreza Ghafouri ◽

Mohsen Ranjbar ◽

Amirhossein Sakhteman

Keyword(s):

Virtual Screening ◽

Docking Studies ◽

Scoring Functions ◽

Ligand Interaction ◽

Advantages And Disadvantages ◽

Protein Affinity ◽

Binding Cavity ◽

Protein Ligand Interaction ◽

Interaction Fingerprints ◽

Activity Information

A most challenging part in docking-based virtual screening is the scoring functions implemented in various docking programs in order to evaluate different poses of the ligands inside the binding cavity of the receptor. Precise and trustable measurement of ligand-protein affinity for Structure-Based Virtual Screening (SB-VS) is therefore, an outstanding problem in docking studies. Empirical post-docking filters can be helpful as a way to provide various types of structure-activity information. Different types of interaction have been presented between the ligands and the receptor so far. Based on the diversity and importance of PLIF methods, this chapter will focus on the comparison of different protocols. The advantages and disadvantages of all methods will be discussed explicitly in this chapter as well as future sights for further progress in this field. Different classifications approaches for the protein-ligand interaction fingerprints were also discussed in this chapter.

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