PRO_LIGAND: An approach to de novo molecular design. 1. Application to the design of organic molecules

Clark, David E.; Frenkel, David A.; Levy, Stephen A.; Li, Jin; Murray, Christopher W.; Robson, Barry; Waszkowycz, Bohdan; Westhead, David R.

doi:10.1007/bf00117275

Cited by 121 publications

(99 citation statements)

References 64 publications

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“…LUDI is the first program developed for such a purpose [5]. Programs with similar functions include HOOK [46], PRO_ligand [47], Skelgen [48], CCLD [49], BREED [50], Lea3D [51], and GANDI [52]. These programs mainly differ in the design strategy (ligand-or receptorbased), the building blocks used to construct the ligands (atoms or fragments), the strategy used to sample the chemical and structural space, and the scoring function used to rank the putative ligands [53].…”

Section: In Silico Fragment-based Approachesmentioning

confidence: 99%

Fragment‐Based Approaches in Virtual Screening

Huang

Caflisch

2011

Methods and Principles in Medicinal Chemistry

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IntroductionFragment-based screening (FBS) as a method to identify starting points for smallmolecule drug discovery has become increasingly popular in recent years [1]. As a complementary and alternative approach to the traditional high-throughput screening (HTS), FBS starts from molecules whose molecular weights typically range from 150 to 250 Da. This approach is more routinely undertaken in therapeutic areas such as infectious disease, for which conventional screening has usually resulted in low hit rates [2]. The theoretical basis regarding the benefits of the fragment linking approach has already been reported about 30 years ago [3]. Interestingly, the importance of molecular fragments has been first recognized and exploited by computational approaches [4][5][6], which share similar aspects with experimental techniques that have been developed afterward, such as structure-activity relationship by nuclear magnetic resonance (NMR) [7]. More recently, fragment-based drug discovery strategies have been developed using X-ray crystallography [8], NMR spectroscopy [9], surface plasmon resonance [10], mass spectrometry [11,12], substrate activity screening (where the fragments are substrates later converted into inhibitors [13-15]), and tethering [16,17]. Experimental techniques for fragmentbased drug discovery have been discussed in previous reviews that contain a large number of applications [1,[18][19][20][21][22]. Successful in vitro screening campaigns have been reported for several targets, and a nonexhaustive list includes b-secretase [10,18,23,24], several protein kinases [25][26][27][28][29], DNA gyrase [30], caspase [31, 32], anthrax lethal factor [33], and phosphodiesterase [34]. The advantages of FBS over HTS have been reported [1], the main benefit being that a larger degree of chemical space can be explored using fragment libraries. HTS handles compounds up to millions but this amount only covers a tiny amount of the chemical space accessible to the small druglike molecules, which is estimated in the range of 10 60 -10 100 [35,36]. Fragment-based approaches, however, allow sampling of a much larger amount of chemical diversity using a much smaller number of starting molecules. It has been estimated that the number of stable and synthetically Virtual Screening. Edited by C. Sotriffer

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Section: In Silico Fragment-based Approachesmentioning

confidence: 99%

Fragment‐Based Approaches in Virtual Screening

Huang

Caflisch

2011

Methods and Principles in Medicinal Chemistry

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“…The other of the two SBDD methods is the de novo design which builds chemical structures that fit into the ligand binding site of a target protein either atom-by-atom or fragment-by-fragment [39,40,41,42]. Although many successful application results were reported for the 3D search as shown above, few examples of de novo designed and synthesized nonpeptide compounds, which Met303 Leu300…”

Section: Structure-based Approachesmentioning

confidence: 99%

Molecular Modeling and Structure-based Drug Discovery Studies of Aldose Reductase Inhibitors

Miyamoto

2002

CBIJ

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Aldose reductase has been implicated in the etiology of diabetic complications. A variety of compounds have been observed to inhibit aldose reductase and effective, orally active inhibitors of the enzyme have been investigated for many years. Although several of these compounds have progressed to the clinical level, only one such drug is currently on the market. Due to the limited number of available drugs for the treatment of diabetic complications, a number of rational approaches for the discovery of aldose reductase inhibitors have been taken since the determination of the 3-dimensional structure of the enzyme. In this review, rational approaches such as the molecular modeling of aldose reductase and its complex structure and structure-based drug discovery are presented, following a short summary of known inhibitors.

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“…These preferred geometries (in terms of distances and angles) have been incorporated into the LUDI program, which can join up the favourable sites for different functional groups using a library of bridging fragments. A very similar approach has also been incorporated into the PRO LIGAND program of Clark et al (1995).…”

Section: Introductionmentioning

confidence: 99%