Pharmacophore Fingerprinting. 2. Application to Primary Library Design

McGregor, Malcolm J.; Muskal, Steven M.

doi:10.1021/ci990313h

Cited by 78 publications

(54 citation statements)

References 26 publications

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“…The MDDR contains drug-like small molecules annotated for biological activity and, like often, molecular target. It is commonly used to train and test cheminformatics methods for library design, [23,24] pharmacophore fingerprinting [25][26][27][28] and determining drug-likeness [29][30][31]. This annotated database provides a list of likeness ligands that we can track.…”

Section: Overview Of the Docking Methods And Its Evaluationmentioning

confidence: 99%

Hierarchical Docking of Databases of Multiple Ligand Conformations

Lorber¹,

Shoichet²

2005

CTMC

137

192

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Ligand flexibility is an important problem in molecular docking and virtual screening. To address this challenge, we investigate a hierarchical pre-organization of multiple conformations of small molecules. Such organization of pre-calculated conformations removes the exploration of ligand conformational space from the docking calculation and allows for concise representation of what can be thousands of conformations. The hierarchy also recognizes and prunes incompatible conformations early in the calculation, eliminating redundant calculations of fit. We investigate the method by docking the MDL Drug Data Report (MDDR), an annotated database of 100,000 molecules, into apo and holo forms of seven unrelated targets. This annotated database allows us to track the ranking of tens to hundreds of annotated ligands in each of the docking systems. The binding sites and database are prepared in an automated fashion in an attempt to remove some human bias from the calculations. Many thousands of explicit and implicit ligand conformations may be docked in calculations not much longer than required for single conformer docking. As long as internal energies are not considered, recombination with the hierarchy is additive as the number of degrees of freedom is increased. Molecules with even millions of conformations can be docked in a few minutes on a single desktop computer.

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Section: Overview Of the Docking Methods And Its Evaluationmentioning

confidence: 99%

Hierarchical Docking of Databases of Multiple Ligand Conformations

Lorber¹,

Shoichet²

2005

CTMC

137

192

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“…47,48 A pharmacophore fingerprint is an extension of this concept, and typically annotates a molecule as a unique data string. All possible three-point or four-point sets of pharmacophore features (points) are enumerated for each ligand.…”

Section: Pharmacophore Fingerprintmentioning

confidence: 99%

“…Indeed, considering the large number of available and potential compounds, the trend is to design libraries very carefully in order to cover chemical space efficiently in any search process. 47,48,58,59 No protein structure, but active ligand structures are known…”

mentioning

confidence: 99%

Pharmacophore modeling: advances, limitations, and current utility in drug discovery

Qing¹,

Lee²,

Raeymaecker³

et al. 2014

JRLCR

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Pharmacophore modeling is a successful yet very diverse subfield of computer-aided drug design. The concept of the pharmacophore has been widely applied to the rational design of novel drugs. In this paper, we review the computational implementation of this concept and its common usage in the drug discovery process. Pharmacophores can be used to represent and identify molecules on a 2D or 3D level by schematically depicting the key elements of molecular recognition. The most common application of pharmacophores is virtual screening, and different strategies are possible depending on the prior knowledge. However, the pharmacophore concept is also useful for ADME-tox modeling, side effect, and off-target prediction as well as target identification. Furthermore, pharmacophores are often combined with molecular docking simulations to improve virtual screening. We conclude this review by summarizing the new areas where significant progress may be expected through the application of pharmacophore modeling; these include protein-protein interaction inhibitors and protein design. Keywords: ADME-tox, computer-aided drug design, pharmacophore fingerprint, protein design, virtual screening What is computer-aided drug design?Drug design is an expensive and laborious process of developing new medicine. This process has its origin in herbal remedies dating back millennia.1 Only since the last century have drugs had a (semi)synthetic origin.2 The first hit compounds often lack both potency and safety, and must therefore be optimized. While historically this was a trial-and-error process, 3,4 soon rational strategies were developed to improve potency. 5,6 As with any data handling procedures, computers have become a more prominent and ubiquitous tool in drug discovery since the 1980s. The crossover between computational and pharmaceutical research is typically designated computer-aided drug design (CADD). 8,9 CADD covers a broad range of applications spanning the drug discovery pipeline, although these are highly clustered in the early phases. The main purpose of CADD is to speed up and rationalize the drug design process while reducing costs. 10 The aim of the earliest phase in drug discovery is to identify the first hit compounds, which is sometimes attempted by high-throughput screening (HTS), the testing of many thousands of compounds with a suitable activity assay. The in silico counterpart of in vitro HTS is referred to as virtual screening and aims at filtering libraries of molecules using computational methods to prioritize those most likely to be active for a given

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“…[1][2][3] Thereafter several groups investigated the use of pharmacophore distance tripletsstrios of feature types and the three corresponding pairwise distances separating them 4 s in library design and diversity analysis. [5][6][7][8][9][10][11][12] Most of these groups used tools available in the ChemX software 13 (or in modified versions thereof 12 ), in the PD Triplets module in SYBYL and UNITY, 14 or in analogous software suites developed internally by pharmaceutical or academic research organizations.…”

Section: Introductionmentioning

confidence: 99%

Efficient Generation, Storage, and Manipulation of Fully Flexible Pharmacophore Multiplets and Their Use in 3-D Similarity Searching

Abrahamian

Fox

Nærum

et al. 2003

J. Chem. Inf. Comput. Sci.

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Pharmacophore triplets and quartets have been used by many groups in recent years, primarily as a tool for molecular diversity analysis. In most cases, slow processing speeds and the very large size of the bitsets generated have forced researchers to compromise in terms of how such multiplets were stored, manipulated, and compared, e.g., by using simple unions to represent multiplets for sets of molecules. Here we report using bitmaps in place of bitsets to reduce storage demands and to improve processing speed. Here, a bitset is taken to mean a fully enumerated string of zeros and ones, from which a compressed bitmap is obtained by replacing uniform blocks ("runs") of digits in the bitset with a pair of values identifying the content and length of the block (run-length encoding compression). High-resolution multiplets involving four features are enabled by using 64 bit executables to create and manipulate bitmaps, which "connect" to the 32 bit executables used for database access and feature identification via an extensible mark-up language (XML) data stream. The encoding system used supports simple pairs, triplets, and quartets; multiplets in which a privileged substructure is used as an anchor point; and augmented multiplets in which an additional vertex is added to represent a contingent feature such as a hydrogen bond extension point linked to a complementary feature (e.g., a donor or an acceptor atom) in a base pair or triplet. It can readily be extended to larger, more complex multiplets as well. Database searching is one particular potential application for this technology. Consensus bitmaps built up from active ligands identified in preliminary screening can be used to generate hypothesis bitmaps, a process which includes allowance for differential weighting to allow greater emphasis to be placed on bits arising from multiplets expected to be particularly discriminating. Such hypothesis bitmaps are shown to be useful queries for database searching, successfully retrieving active compounds across a range of structural classes from a corporate database. The current implementation allows multiconformer bitmaps to be obtained from pregenerated conformations or by random perturbation onthe-fly. The latter application involves random sampling of the full range of conformations not precluded by steric clashes, which limits the usefulness of classical fingerprint similarity measures. A new measure of similarity, The Stochastic Cosine, is introduced here to address this need. This new similarity measure uses the average number of bits common to independently drawn conformer sets to normalize the cosine coefficient. Its use frees the user from having to ensure strict comparability of starting conformations and having to use fixed torsional increments, thereby allowing fully flexible characterization of pharmacophoric patterns.

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Pharmacophore Fingerprinting. 2. Application to Primary Library Design

Cited by 78 publications

References 26 publications

Hierarchical Docking of Databases of Multiple Ligand Conformations

Hierarchical Docking of Databases of Multiple Ligand Conformations

Pharmacophore modeling: advances, limitations, and current utility in drug discovery

Efficient Generation, Storage, and Manipulation of Fully Flexible Pharmacophore Multiplets and Their Use in 3-D Similarity Searching

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