Side chain virtual screening of matched molecular pairs: a PDB-wide and ChEMBL-wide analysis.

Abstract:

:Optimization in medicinal chemistry often involves designing replacements for a section of a molecule which aim to retain potency while improving other properties of the compound. In this study, we perform a retrospective analysis using a number of computational methods to identify active side chains amongst a pool of random decoy side chains, mimicking a similar procedure that might be undertaken in a real medicinal chemistry project. We constructed a dataset derived from public ChEMBL and PDB data by identifying all ChEMBL assays where at least one of the compounds tested has also been co-crystallized in the PDB. Additionally, we required that there be at least ten active compounds tested in the same ChEMBL assay that are matched molecular pairs to the crystallized ligand. Using the compiled dataset consisting of sets of compounds from 402 assays, we have tested a number of methods for scoring side chains including Spark, a bioisostere replacement tool from Cresset, molecular docking using Glide from Schrodinger, docking with Smina, as well as other methods. In this work, we present a comparison of the performance of these methods in discriminating active side chains from decoys as well as recommendations for circumstances when different methods should be used.

journal_name

J Comput Aided Mol Des

authors

Baumgartner MP,Evans DA

doi

10.1007/s10822-020-00313-1

subject

Has Abstract

pub_date

2020-09-01 00:00:00

pages

953-963

issue

9

eissn

0920-654X

issn

1573-4951

pii

10.1007/s10822-020-00313-1

journal_volume

34

pub_type

杂志文章
  • Property distribution of drug-related chemical databases.

    abstract::The process of compound selection and prioritization is crucial for both combinatorial chemistry (CBC) and high throughput screening (HTS). Compound libraries have to be screened for unwanted chemical structures, as well as for unwanted chemical properties. Property extrema can be eliminated by using property filters,...

    journal_title:Journal of computer-aided molecular design

    pub_type: 杂志文章

    doi:10.1023/a:1008130001697

    authors: Oprea TI

    更新日期:2000-03-01 00:00:00

  • Why relevant chemical information cannot be exchanged without disclosing structures.

    abstract::Both society and industry are interested in increasing the safety of pharmaceuticals. Potentially dangerous compounds could be filtered out at early stages of R&D by computer prediction of biological activity and ADMET characteristics. Accuracy of such predictions strongly depends on the quality & quantity of informat...

    journal_title:Journal of computer-aided molecular design

    pub_type: 杂志文章

    doi:10.1007/s10822-005-9014-2

    authors: Filimonov D,Poroikov V

    更新日期:2005-09-01 00:00:00

  • Structure-activity relationships of thiostrepton derivatives: implications for rational drug design.

    abstract::The bacterial ribosome is a major target of naturally occurring thiopeptides antibiotics. Studying thiopeptide (e.g. thiostrepton) binding to the GAR's 23S·L11 ribosomal subunit using docking methods is challenging. Regarding the target, the binding site is composed of a flexible protein-RNA nonbonded interface whose ...

    journal_title:Journal of computer-aided molecular design

    pub_type: 杂志文章

    doi:10.1007/s10822-014-9797-0

    authors: Wolf A,Schoof S,Baumann S,Arndt HD,Kirschner KN

    更新日期:2014-12-01 00:00:00

  • Comparison of commercially available genetic algorithms: gas as variable selection tool.

    abstract::Many commercially available software programs claim similar efficiency and accuracy as variable selection tools. Genetic algorithms are commonly used variable selection methods where most relevant variables can be differentiated from 'less important' variables using evolutionary computing techniques. However, differen...

    journal_title:Journal of computer-aided molecular design

    pub_type: 杂志文章

    doi:10.1007/s10822-004-5322-1

    authors: Schefzick S,Bradley M

    更新日期:2004-07-01 00:00:00

  • In silico models for the prediction of dose-dependent human hepatotoxicity.

    abstract::The liver is extremely vulnerable to the effects of xenobiotics due to its critical role in metabolism. Drug-induced hepatotoxicity may involve any number of different liver injuries, some of which lead to organ failure and, ultimately, patient death. Understandably, liver toxicity is one of the most important dose-li...

    journal_title:Journal of computer-aided molecular design

    pub_type: 杂志文章

    doi:10.1023/b:jcam.0000021834.50768.c6

    authors: Cheng A,Dixon SL

    更新日期:2003-12-01 00:00:00

  • Classification of auxin plant hormones by interaction property similarity indices.

    abstract::Although auxins were the first type of plant hormone to be identified, little is known about the molecular mechanism of this important class of plant hormones. We present a classification of a set of about 50 compounds with measured auxin activities, according to their interaction properties. Four classes of compounds...

    journal_title:Journal of computer-aided molecular design

    pub_type: 杂志文章

    doi:10.1023/a:1007973008558

    authors: Tomić S,Gabdoulline RR,Kojić-Prodić B,Wade RC

    更新日期:1998-01-01 00:00:00

  • Rational creation and systematic analysis of cervical cancer kinase-inhibitor binding profile.

    abstract::The kinase-regulatory cell signaling networks play a central role in the pathogenesis of human cervical cancer (hCC). However, only few kinase inhibitors have been successfully developed for treatment of this cancer to date. Considering that the active sites of protein kinases are highly conserved and small-molecule i...

    journal_title:Journal of computer-aided molecular design

    pub_type: 杂志文章

    doi:10.1007/s10822-019-00211-1

    authors: Han M,Sun D

    更新日期:2019-07-01 00:00:00

  • Mutation-mediated influences on binding of anaplastic lymphoma kinase to crizotinib decoded by multiple replica Gaussian accelerated molecular dynamics.

    abstract::Anaplastic lymphoma kinase (ALK) has been thought to be a prospective target of anti-drug resistance design in treatment of tumors and specific neuron diseases. It is highly useful for the seeking of possible strategy alleviating drug resistance to probe the mutation-mediated effect on binding of inhibitors to ALK. In...

    journal_title:Journal of computer-aided molecular design

    pub_type: 杂志文章

    doi:10.1007/s10822-020-00355-5

    authors: Chen J,Wang W,Sun H,Pang L,Yin B

    更新日期:2020-12-01 00:00:00

  • Functionality map analysis of the active site cleft of human thrombin.

    abstract::The Multiple Copy Simultaneous Search methodology has been used to construct functionality maps for an extended region of human thrombin, including the active site. This method allows the determination of energetically favorable positions and orientations for functional groups defined by the user on the three-dimensio...

    journal_title:Journal of computer-aided molecular design

    pub_type: 杂志文章

    doi:10.1007/BF00124460

    authors: Grootenhuis PD,Karplus M

    更新日期:1996-02-01 00:00:00

  • Covalent inhibitor reactivity prediction by the electrophilicity index-in and out of scope.

    abstract::Drug discovery is an expensive and time-consuming process. To make this process more efficient quantum chemistry methods can be employed. The electrophilicity index is one property that can be calculated by quantum chemistry methods, and if calculated correctly gives insight into the reactivity of covalent inhibitors....

    journal_title:Journal of computer-aided molecular design

    pub_type: 杂志文章

    doi:10.1007/s10822-020-00342-w

    authors: Hermann MR,Pautsch A,Grundl MA,Weber A,Tautermann CS

    更新日期:2020-10-05 00:00:00

  • CADD medicine: design is the potion that can cure my disease.

    abstract::The acronym "CADD" is often used interchangeably to refer to "Computer Aided Drug Discovery" and "Computer Aided Drug Design". While the former definition implies the use of a computer to impact one or more aspects of discovering a drug, in this paper we contend that computational chemists are most effective when they...

    journal_title:Journal of computer-aided molecular design

    pub_type: 杂志文章

    doi:10.1007/s10822-016-0004-3

    authors: Manas ES,Green DV

    更新日期:2017-03-01 00:00:00

  • Cavity search: an algorithm for the isolation and display of cavity-like binding regions.

    abstract::A set of algorithms designed to enhance the display of protein binding cavities is presented. These algorithms, collectively entitled CAVITY SEARCH, allow the user to isolate and fully define the extent of a particular cavity. Solid modeling techniques are employed to produce a detailed cast of the active site region,...

    journal_title:Journal of computer-aided molecular design

    pub_type: 杂志文章

    doi:10.1007/BF00117400

    authors: Ho CM,Marshall GR

    更新日期:1990-12-01 00:00:00

  • Virtual screening using a conformationally flexible target protein: models for ligand binding to p38α MAPK.

    abstract::We have used virtual screening to develop models for the binding of aryl substituted heterocycles to p38α MAPK. Virtual screening was conducted on a number of p38α MAPK crystal structures using a library of 46 known p38α MAPK inhibitors containing a heterocyclic core substituted by pyridine and fluorophenyl rings (str...

    journal_title:Journal of computer-aided molecular design

    pub_type: 杂志文章

    doi:10.1007/s10822-012-9569-7

    authors: Vinh NB,Simpson JS,Scammells PJ,Chalmers DK

    更新日期:2012-04-01 00:00:00

  • Addressing free fatty acid receptor 1 (FFAR1) activation using supervised molecular dynamics.

    abstract::The free fatty acid receptor 1 (FFAR1, formerly GPR40), is a potential G protein-coupled receptor (GPCR) target for the treatment of type 2 diabetes mellitus (T2DM), as it enhances glucose-dependent insulin secretion upon activation by endogenous long-chain free fatty acids. The presence of two allosterically communic...

    journal_title:Journal of computer-aided molecular design

    pub_type: 杂志文章

    doi:10.1007/s10822-020-00338-6

    authors: Atanasio S,Deganutti G,Reynolds CA

    更新日期:2020-11-01 00:00:00

  • The importance of molecular complexity in the design of screening libraries.

    abstract::The one-dimensional model of Hann et al. (JChem Inf Comput Sci 41(3):856–864) has been extended to include reverse binding and wrap-around interaction modes between the protein and ligand to explore the complete combinatorial matrix of molecular recognition. The cumulative distribution function of the Maxwell–Boltzman...

    journal_title:Journal of computer-aided molecular design

    pub_type: 杂志文章

    doi:10.1007/s10822-013-9683-1

    authors: Nilar SH,Ma NL,Keller TH

    更新日期:2013-09-01 00:00:00

  • Supervised molecular dynamics for exploring the druggability of the SARS-CoV-2 spike protein.

    abstract::The recent outbreak of the respiratory syndrome-related coronavirus (SARS-CoV-2) is stimulating an unprecedented scientific campaign to alleviate the burden of the coronavirus disease (COVID-19). One line of research has focused on targeting SARS-CoV-2 proteins fundamental for its replication by repurposing drugs appr...

    journal_title:Journal of computer-aided molecular design

    pub_type: 杂志文章

    doi:10.1007/s10822-020-00356-4

    authors: Deganutti G,Prischi F,Reynolds CA

    更新日期:2020-10-26 00:00:00

  • HINT: a new method of empirical hydrophobic field calculation for CoMFA.

    abstract::An empirical hydrophobic field-like 3D function has been calculated with the program HINT (hydrophobic interactions) and imported into the SYBYL implementation of CoMFA (Comparative Molecular Field Analysis). The addition of hydrophobicity appears to offer increased chemical interpretability of CoMFA models. An exampl...

    journal_title:Journal of computer-aided molecular design

    pub_type: 杂志文章

    doi:10.1007/BF00135313

    authors: Kellogg GE,Semus SF,Abraham DJ

    更新日期:1991-12-01 00:00:00

  • Predicting the relative binding affinity of mineralocorticoid receptor antagonists by density functional methods.

    abstract::In drug discovery, prediction of binding affinity ahead of synthesis to aid compound prioritization is still hampered by the low throughput of the more accurate methods and the lack of general pertinence of one method that fits all systems. Here we show the applicability of a method based on density functional theory ...

    journal_title:Journal of computer-aided molecular design

    pub_type: 杂志文章

    doi:10.1007/s10822-015-9880-1

    authors: Roos K,Hogner A,Ogg D,Packer MJ,Hansson E,Granberg KL,Evertsson E,Nordqvist A

    更新日期:2015-12-01 00:00:00

  • Protein-ligand docking using FFT based sampling: D3R case study.

    abstract::Fast Fourier transform (FFT) based approaches have been successful in application to modeling of relatively rigid protein-protein complexes. Recently, we have been able to adapt the FFT methodology to treatment of flexible protein-peptide interactions. Here, we report our latest attempt to expand the capabilities of t...

    journal_title:Journal of computer-aided molecular design

    pub_type: 杂志文章

    doi:10.1007/s10822-017-0069-7

    authors: Padhorny D,Hall DR,Mirzaei H,Mamonov AB,Moghadasi M,Alekseenko A,Beglov D,Kozakov D

    更新日期:2018-01-01 00:00:00

  • Improving binding mode and binding affinity predictions of docking by ligand-based search of protein conformations: evaluation in D3R grand challenge 2015.

    abstract::The growing number of protein-ligand complex structures, particularly the structures of proteins co-bound with different ligands, in the Protein Data Bank helps us tackle two major challenges in molecular docking studies: the protein flexibility and the scoring function. Here, we introduced a systematic strategy by us...

    journal_title:Journal of computer-aided molecular design

    pub_type: 杂志文章

    doi:10.1007/s10822-017-0038-1

    authors: Xu X,Yan C,Zou X

    更新日期:2017-08-01 00:00:00

  • Large-scale evaluation of cytochrome P450 2C9 mediated drug interaction potential with machine learning-based consensus modeling.

    abstract::Cytochrome P450 (CYP) enzymes play an important role in the metabolism of xenobiotics. Since they are connected to drug interactions, screening for potential inhibitors is of utmost importance in drug discovery settings. Our study provides an extensive classification model for P450-drug interactions with one of the mo...

    journal_title:Journal of computer-aided molecular design

    pub_type: 杂志文章

    doi:10.1007/s10822-020-00308-y

    authors: Rácz A,Keserű GM

    更新日期:2020-08-01 00:00:00

  • Computational studies of new potential antimalarial compounds--stereoelectronic complementarity with the receptor.

    abstract::One of the most important pharmacological mechanisms of antimalarial action is the inhibition of the aggregation of hematin into hemozoin. We present a group of new potential antimalarial molecules for which we have performed a DFT study of their stereoelectronic properties. Additionally, the same calculations were ca...

    journal_title:Journal of computer-aided molecular design

    pub_type: 杂志文章

    doi:10.1023/b:jcam.0000005754.24588.a0

    authors: Portela C,Afonso CM,Pinto MM,Ramos MJ

    更新日期:2003-09-01 00:00:00

  • In silico prediction of drug toxicity.

    abstract::It is essential, in order to minimise expensive drug failures due to toxicity being found in late development or even in clinical trials, to determine potential toxicity problems as early as possible. In view of the large libraries of compounds now being handled by combinatorial chemistry and high-throughput screening...

    journal_title:Journal of computer-aided molecular design

    pub_type: 杂志文章,评审

    doi:10.1023/a:1025361621494

    authors: Dearden JC

    更新日期:2003-02-01 00:00:00

  • Predicting the effects of amino acid replacements in peptide hormones on their binding affinities for class B GPCRs and application to the design of secretin receptor antagonists.

    abstract::Computational prediction of the effects of residue changes on peptide-protein binding affinities, followed by experimental testing of the top predicted binders, is an efficient strategy for the rational structure-based design of peptide inhibitors. In this study we apply this approach to the discovery of competitive a...

    journal_title:Journal of computer-aided molecular design

    pub_type: 杂志文章

    doi:10.1007/s10822-012-9574-x

    authors: Te JA,Dong M,Miller LJ,Bordner AJ

    更新日期:2012-07-01 00:00:00

  • QSAR without arbitrary descriptors: the electron-conformational method.

    abstract::The electron-conformational (EC) method in QSAR problems employs a unique (based on first principles) descriptor of molecular properties that incorporates the electronic structure and topology of the molecule and is presented in a digital-matrix form suitable for computer processing, the EC matrix of congruity (ECMC)....

    journal_title:Journal of computer-aided molecular design

    pub_type: 杂志文章

    doi:10.1007/s10822-008-9191-x

    authors: Bersuker IB

    更新日期:2008-06-01 00:00:00

  • Hydrophobic molecular similarity from MST fractional contributions to the octanol/water partition coefficient.

    abstract::The use of a recently proposed hydrophobic similarity index for the alignment of molecules and the prediction of their differences in biological activity is described. The hydrophobic similarity index exploits atomic contributions to the octanol/water transfer free energy, which are evaluated by means of the fractiona...

    journal_title:Journal of computer-aided molecular design

    pub_type: 杂志文章

    doi:10.1007/s10822-005-7928-3

    authors: Muñoz-Muriedas J,Perspicace S,Bech N,Guccione S,Orozco M,Luque FJ

    更新日期:2005-06-01 00:00:00

  • Computational insights into the interaction mechanism of triazolyl substituted tetrahydrobenzofuran derivatives with H(+),K(+)-ATPase at different pH.

    abstract::The interaction mechanism of triazolyl substituted tetrahydrobenzofuran derivatives (compound 1 (N, N-Dipropyl-1-(2-phenyl-4,5,6,7-tetrahydrobenzofuran-4-yl)-1H-1,2,3-triazole-4-methanamine) and 2 (1-(2-Phenyl-4,5,6,7-tetrahydrobenzofuran-4-yl)-4-(morpholin-4-ylmethyl)-1H-1,2,3-triazole)) with H(+),K(+)-ATPase at diff...

    journal_title:Journal of computer-aided molecular design

    pub_type: 杂志文章

    doi:10.1007/s10822-015-9886-8

    authors: Luo HJ,Wang JZ,Huang NY,Deng WQ,Zou K

    更新日期:2016-01-01 00:00:00

  • Conformational specificity of non-canonical base pairs and higher order structures in nucleic acids: crystal structure database analysis.

    abstract::Non-canonical base pairs contribute immensely to the structural and functional variability of RNA, which calls for a detailed characterization of their spatial conformation. Intra-base pair parameters, namely propeller, buckle, open-angle, stagger, shear and stretch describe structure of base pairs indicating planarit...

    journal_title:Journal of computer-aided molecular design

    pub_type: 杂志文章

    doi:10.1007/s10822-006-9083-x

    authors: Mukherjee S,Bansal M,Bhattacharyya D

    更新日期:2006-10-01 00:00:00

  • Molecular dynamics simulation of halogen bonding mimics experimental data for cathepsin L inhibition.

    abstract::A MD simulation protocol was developed to model halogen bonding in protein-ligand complexes by inclusion of a charged extra point to represent the anisotropic distribution of charge on the halogen atom. This protocol was then used to simulate the interactions of cathepsin L with a series of halogenated and non-halogen...

    journal_title:Journal of computer-aided molecular design

    pub_type: 杂志文章

    doi:10.1007/s10822-014-9802-7

    authors: Celis-Barros C,Saavedra-Rivas L,Salgado JC,Cassels BK,Zapata-Torres G

    更新日期:2015-01-01 00:00:00

  • Binding free energy calculations to rationalize the interactions of huprines with acetylcholinesterase.

    abstract::In the present study, the binding free energy of a family of huprines with acetylcholinesterase (AChE) is calculated by means of the free energy perturbation method, based on hybrid quantum mechanics and molecular mechanics potentials. Binding free energy calculations and the analysis of the geometrical parameters hig...

    journal_title:Journal of computer-aided molecular design

    pub_type: 杂志文章

    doi:10.1007/s10822-018-0114-1

    authors: Nascimento ÉCM,Oliva M,Andrés J

    更新日期:2018-05-01 00:00:00