The computer program LUDI: A new method for the de novo design of enzyme inhibitors

Böhm, Hans‐Joachim

doi:10.1007/bf00124387

Cited by 791 publications

(300 citation statements)

References 30 publications

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“…Of course nothing prevented this, and indeed such an idea is implicit in the fragment approach and anticipated by computational design methods like LUDI, HOOK, GrowMol, and MCSS (36)(37)(38)(39). Still, late-stage optimization with fragments seems underdeveloped; it can reveal derivatization strategies, both in geometry and in chemotype, that may otherwise remain unknown without an industrial-scale hit-to-lead campaign.…”

Section: Discussionmentioning

confidence: 99%

Fragment-guided design of subnanomolar β-lactamase inhibitors active in vivo

Eidam¹,

Romagnoli

Dalmasso

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Fragment-based design was used to guide derivatization of a lead series of β-lactamase inhibitors that had heretofore resisted optimization for in vivo activity. X-ray structures of fragments overlaid with the lead suggested new, unanticipated functionality and points of attachment. Synthesis of three derivatives improved affinity over 20-fold and improved efficacy in cell culture. Crystal structures were consistent with the fragment-based design, enabling further optimization to a K i of 50 pM, a 500-fold improvement that required the synthesis of only six derivatives. One of these, compound 5, was tested in mice. Whereas cefotaxime alone failed to cure mice infected with β-lactamase-expressing Escherichia coli, 65% were cleared of infection when treated with a cefotaxime:5 combination. Fragment complexes offer a path around design hurdles, even for advanced molecules; the series described here may provide leads to overcome β-lactamase-based resistance, a key clinical challenge.antibiotic resistance | antimicrobial | drug discovery | structure-based | boronic acid

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Section: Discussionmentioning

confidence: 99%

Fragment-guided design of subnanomolar β-lactamase inhibitors active in vivo

Eidam¹,

Romagnoli

Dalmasso

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…One class of docking programs including GOLD [3], DARWIN [4], implementations of AUTODOCK [5] and several others [6][7][8] use genetic algorithms to optimize ligand conformations in the context of the binding site. Other approaches to flexible ligand docking include optimizing the ligands in the context of the binding site, [9][10][11] enumeration of multiple low energy ligand minima followed by energy refinement [12,13] or placing fragments into the binding site for later connection [14][15][16][17]. A common technique for flexible docking is that of anchor-and-grow or incremental construction.…”

Section: Introductionmentioning

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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“…The ranking or "scoring" of the numerous molecules with a reasonable fit is a nontrivial exercise but, with the application of more elaborate evaluation schemes, improvements are being made (Meng et al, 1992). Another database screening program is LUDI (Bohm, 1992), which describes the active site of a target protein in terms of hydrogen bond donors, hydrogen bond acceptors, and hydrophobic surfaces. This description is then checked for a reasonable match with a similar description of the molecules in the small molecule database.…”

Section: Structure-based Drug Designmentioning

confidence: 99%

Protein crystallography and infectious diseases

et al. 1994

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The current rapid growth in the number of known 3-dimensional protein structures is producing a database of structures that is increasingly useful as a starting point for the development of new medically relevant molecules such as drugs, therapeutic proteins, and vaccines. This development is beautifully illustrated in the recent book, Protein structure: New approaches to disease and therapy (Perutz, 1992). There is a great and growing promise for the design of molecules for the treatment or prevention of a wide variety of diseases, an endeavor made possible by the insights derived from the structure and function of crucial proteins from pathogenic organisms and from man.We present here 2 illustrations of structure-based drug design. The first is the prospect of developing antitrypanosoma1 drugs based on crystallographic, ligand-binding, and molecular modeling studies of glycolytic glycosomal enzymes from Trypanosomatidae. These unicellular organisms are responsible for several tropical diseases, including African and American trypanosomiases, as well as various forms of leishmaniasis. Because the target enzymes are also present in the human host, this project is a pioneering study in selective design. The second illustrative case is the prospect of designing anti-cholera drugs based on detailed analysis of the structure of cholera toxin and the closely related Escherichia coli heat-labile enterotoxin. Such potential drugs can be targeted either at inhibiting the toxin's receptor binding site or at blocking the toxin's intracellular catalytic activity.Study of the Vibrio cholerae and E. coli toxins serves at the same time as an example of a general approach to structure-based vaccine design. These toxins exhibit a remarkable ability to stimulate the mucosal immune system, and early results have suggested that this property can be maintained by engineered fusion proteins based on the native toxin structure. The challenge is thus to incorporate selected epitopes from foreign pathogens into the native framework of the toxin such that crucial features of both the epitope and the toxin are maintained.That is, the modified toxin must continue to evoke a strong mucosal immune response, and this response must be directed against an epitope conformation characteristic of the original pathogen.

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The computer program LUDI: A new method for the de novo design of enzyme inhibitors

Cited by 791 publications

References 30 publications

Fragment-guided design of subnanomolar β-lactamase inhibitors active in vivo

Fragment-guided design of subnanomolar β-lactamase inhibitors active in vivo

Hierarchical Docking of Databases of Multiple Ligand Conformations

Protein crystallography and infectious diseases

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