Dimorphite-DL: an open-source program for enumerating the ionization states of drug-like small molecules

Ropp, Patrick J.; Kaminsky, Jesse C.; Yablonski, Sara; Durrant, Jacob D.

doi:10.1186/s13321-019-0336-9

Cited by 57 publications

(51 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Both Gypsum-DL and Open Babel 2.3.2 were separately used to prepare 3D models of the 3151 ligands from the corresponding SMILES strings. In the case of Open Babel, we intentionally generated electrically neutral models (i.e., we omitted the Open-Babel - p flag) so as to better judge the impact of Gypsum-DL’s ionization feature on pose accuracy [11]. We docked both the Gypsum-DL-prepared and Open-Babel-prepared molecules into their corresponding protein receptors using AutoDock Vina 1.1.2 [12].…”

Section: Resultsmentioning

confidence: 99%

“…For example, Frog2 uses the Open Babel cheminformatics toolkit [10] to add hydrogen atoms to input molecules, but it does not consider alternate ionization states per a user-specified pH range. In contrast, Gypsum-DL uses the Dimorphite-DL algorithm [11] to predict ionization states. To illustrate the usefulness of this feature, we submitted oseltamivir carboxylate, an influenza neuraminidase inhibitor, to the Frog2 (v2.14) server (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Gypsum-DL uses RDKit (http://www.rdkit.org), MolVS 0.1.1 (https://molvs.readthedocs.io), and Dimorphite-DL 1.0 [11] to convert small-molecule representations (SMILES strings or flat SDF files) into 3D models (Fig. 1) [19].…”

Section: Methodsmentioning

confidence: 99%

“…Gypsum-DL uses the Dimorphite-DL 1.0 algorithm [11] to generate models with different ionization states. It considers a user-defined range of pH values (6.4–8.4 by default) rather than a single (e.g., physiological) pH.…”

Section: Methodsmentioning

confidence: 99%

See 3 more Smart Citations

Gypsum-DL: an open-source program for preparing small-molecule libraries for structure-based virtual screening

et al. 2019

Self Cite

View full text Add to dashboard Cite

Computational techniques such as structure-based virtual screening require carefully prepared 3D models of potential small-molecule ligands. Though powerful, existing commercial programs for virtual-library preparation have restrictive and/or expensive licenses. Freely available alternatives, though often effective, do not fully account for all possible ionization, tautomeric, and ring-conformational variants. We here present Gypsum-DL, a free, robust open-source program that addresses these challenges. As input, Gypsum-DL accepts virtual compound libraries in SMILES or flat SDF formats. For each molecule in the virtual library, it enumerates appropriate ionization, tautomeric, chiral, cis/trans isomeric, and ring-conformational forms. As output, Gypsum-DL produces an SDF file containing each molecular form, with 3D coordinates assigned. To demonstrate its utility, we processed 1558 molecules taken from the NCI Diversity Set VI and 56,608 molecules taken from a Distributed Drug Discovery (D3) combinatorial virtual library. We also used 4463 high-quality protein–ligand complexes from the PDBBind database to show that Gypsum-DL processing can improve virtual-screening pose prediction. Gypsum-DL is available free of charge under the terms of the Apache License, Version 2.0.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Gypsum-DL: an open-source program for preparing small-molecule libraries for structure-based virtual screening

et al. 2019

Self Cite

View full text Add to dashboard Cite

show abstract

“…AutoGrow4 uses the open-source program Gypsum-DL [11] to convert the SMILES representations of all new molecules into 3D models for docking. For each input SMILES, Gypsum-DL generates one or more 3D models with alternate ionization, tautomeric, chiral, cis/trans isomeric, and ring-conformational forms [11,27]. The user can specify the pH range to use for protonation as well as the maximum number of molecular forms (variants) that Gypsum-DL should produce per input SMILES.…”

Section: Conversion Of Smiles To 3d Pdbmentioning

confidence: 99%

AutoGrow4: an open-source genetic algorithm for de novo drug design and lead optimization

2020

Self Cite

View full text Add to dashboard Cite

We here present AutoGrow4, an open-source program for semi-automated computer-aided drug discovery. Auto-Grow4 uses a genetic algorithm to evolve predicted ligands on demand and so is not limited to a virtual library of pre-enumerated compounds. It is a useful tool for generating entirely novel drug-like molecules and for optimizing preexisting ligands. By leveraging recent computational and cheminformatics advancements, AutoGrow4 is faster, more stable, and more modular than previous versions. It implements new docking-program compatibility, chemical filters, multithreading options, and selection methods to support a wide range of user needs. To illustrate both de novo design and lead optimization, we here apply AutoGrow4 to the catalytic domain of poly(ADP-ribose) polymerase 1 (PARP-1), a well characterized DNA-damage-recognition protein. AutoGrow4 produces drug-like compounds with better predicted binding affinities than FDA-approved PARP-1 inhibitors (positive controls). The predicted binding modes of the AutoGrow4 compounds mimic those of the known inhibitors, even when AutoGrow4 is seeded with random small molecules. AutoGrow4 is available under the terms of the Apache License, Version 2.0. A copy can be downloaded free of charge from http://durra ntlab .com/autog row4.

show abstract

Toward α‐1,3/4 fucosyltransferases targeted drug discovery: In silico uncovering of promising natural inhibitors of fucosyltransferase 6

Magdaleno¹,

Grewal²,

Medina‐Franco

et al. 2023

J of Cellular Biochemistry

View full text Add to dashboard Cite

Sialyl Lewis X (sLex) antigen is a fucosylated cell‐surface glycan that is normally involved in cell‐cell interactions. The enhanced expression of sLex on cell surface glycans, which is attributed to the upregulation of fucosyltransferase 6 (FUT6), has been implicated in facilitating metastasis in human colorectal, lung, prostate, and oral cancers. The role that the upregulated FUT6 plays in the progression of tumor to malignancy, with reduced survival rates, makes it a potential target for anticancer drugs. Unfortunately, the lack of experimental structures for FUT6 has hampered the design and development of its inhibitors. In this study, we used in silico techniques to identify potential FUT6 inhibitors. We first modeled the three‐dimensional structure of human FUT6 using AlphaFold. Then, we screened the natural compound libraries from the COCONUT database to sort out potential natural products (NPs) with best affinity toward the FUT6 model. As a result of these simulations, we identified three NPs for which we predicted binding affinities and interaction patterns quite similar to those we calculated for two experimentally tested FUT6 inhibitors, that is, fucose mimetic‐1 and a GDP‐triazole derived compound. We also performed molecular dynamics (MD) simulations for the FUT6 complexes with identified NPs, to investigate their stability. Analysis of the MD simulations showed that the identified NPs establish stable contacts with FUT6 under dynamics conditions. On these grounds, the three screened compounds appear as promising natural alternatives to experimentally tested FUT6 synthetic inhibitors, with expected comparable binding affinity. This envisages good prospects for future experimental validation toward FUT6 inhibition.

show abstract

Dimorphite-DL: an open-source program for enumerating the ionization states of drug-like small molecules

Cited by 57 publications

References 29 publications

Gypsum-DL: an open-source program for preparing small-molecule libraries for structure-based virtual screening

Gypsum-DL: an open-source program for preparing small-molecule libraries for structure-based virtual screening

AutoGrow4: an open-source genetic algorithm for de novo drug design and lead optimization

Toward α‐1,3/4 fucosyltransferases targeted drug discovery: In silico uncovering of promising natural inhibitors of fucosyltransferase 6

Contact Info

Product

Resources

About