In Silico Pharmacology: Computer-Aided Methods Could Transform Drug Development

Shekhar, Chandra

doi:10.1016/j.chembiol.2008.05.001

Cited by 46 publications

(23 citation statements)

References 6 publications

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“…Rapid developments in combinatorial chemistry and high-throughput screening technologies have provided an environment to expedite the drug discovery process by enabling huge libraries of compounds to be screened and synthesized in short time [3,4] . Although the investment in new drug development has grown significantly in the past decades, the output is not positively proportional to the investment because of the low efficiency and high failure rate in drug discovery [5] . Consequently, various approaches have been developed to shorten the research cycle and reduce the expense and risk of failure for drug discovery.…”

Section: Introductionmentioning

confidence: 99%

Computational drug discovery

et al. 2012

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Computational drug discovery is an effective strategy for accelerating and economizing drug discovery and development process. Because of the dramatic increase in the availability of biological macromolecule and small molecule information, the applicability of computational drug discovery has been extended and broadly applied to nearly every stage in the drug discovery and development workflow, including target identification and validation, lead discovery and optimization and preclinical tests. Over the past decades, computational drug discovery methods such as molecular docking, pharmacophore modeling and mapping, de novo design, molecular similarity calculation and sequence-based virtual screening have been greatly improved. In this review, we present an overview of these important computational methods, platforms and successful applications in this field.

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Section: Introductionmentioning

confidence: 99%

Computational drug discovery

et al. 2012

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“…The percentage of lead compounds identified from a library that is prescreened by in silico docking is estimated to increase some 10-fold compared with a high throughput only screen (14). In the case of this study, in silico docking was used as part of the process used to select a reasonable number of compounds for purchase and in vitro analysis from a library of 110,000 structures derived from nearly 70,000 commercially available compounds.…”

Section: Comparative Analyses Of Compounds and Docking Sites In Humanmentioning

confidence: 99%

Allosteric Inhibition of Human Porphobilinogen Synthase

Lawrence

Ramirez

Selwood

et al. 2009

Journal of Biological Chemistry

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Porphobilinogen synthase (PBGS) catalyzes the first common step in tetrapyrrole (e.g. heme, chlorophyll) biosynthesis. Human PBGS exists as an equilibrium of high activity octamers, low activity hexamers, and alternate dimer configurations that dictate the stoichiometry and architecture of further assembly. It is posited that small molecules can be found that inhibit human PBGS activity by stabilizing the hexamer. Such molecules, if present in the environment, could potentiate disease states associated with reduced PBGS activity, such as lead poisoning and ALAD porphyria, the latter of which is associated with human PBGS variants whose quaternary structure equilibrium is shifted toward the hexamer (Jaffe, E. K., and Stith, L. (2007) Am. J. Hum. Genet. 80, 329 -337). Hexamer-stabilizing inhibitors of human PBGS were identified using in silico prescreening (docking) of ϳ111,000 structures to a hexamer-specific surface cavity of a human PBGS crystal structure. Seventyseven compounds were evaluated in vitro; three provided 90 -100% conversion of octamer to hexamer in a native PAGE mobility shift assay. Based on chemical purity, two (ML-3A9 and ML-3H2) were subjected to further evaluation of their effect on the quaternary structure equilibrium and enzymatic activity. Naturally occurring ALAD porphyria-associated human PBGS variants are shown to have an increased susceptibility to inhibition by both ML-3A9 and ML-3H2. ML-3H2 is a structural analog of amebicidal drugs, which have porphyria-like side effects. Data support the hypothesis that human PBGS hexamer stabilization may explain these side effects. The current work identifies allosteric ligands of human PBGS and, thus, identifies human PBGS as a medically relevant allosteric enzyme.Human porphobilinogen synthase (PBGS, 2 EC 4.2.1.24, also known as 5-aminolevulinate dehydratase) exists as a quaternary structure equilibrium consisting of a high activity octamer, a low activity hexamer, and a dimer that can take on two distinct conformations, each of which dictates assembly to either the octamer or the hexamer (see Fig. 1a) (1). For the wild type protein at neutral pH, the octamer is the dominant assembly in the equilibrium (1). As PBGS catalyzes the first common step in the biosynthesis of the tetrapyrroles such as heme, low activity mutations in the human population are associated with the disease ALAD porphyria (2); all eight porphyria-associated PBGS mutations increase the propensity of the human protein to exist in the low activity hexameric assembly, thus establishing the physiologic relevance of the quaternary structure equilibrium to human health (3). In addition to ALAD porphyria, PBGS inhibition by divalent lead is a primary consequence of lead poisoning. Factors that stabilize the hexamer will further inhibit PBGS activity and, thus, potentiate the physiologic effects of lead poisoning.The arrangement of the subunits in the PBGS hexamer creates a surface cavity that is not present in the octamer or the dimers (see Fig. 1b) (4). Ligand binding to this cavi...

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“…One group at Eli Lilly used a traditional HTS to identify a lead compound that was subsequently improved by examination of structure-activity relationship using in vitro assays (Sawyer et al, 2003), whereas a group at Biogen Idec used a CADD approach involving virtual HTS based on the structural interactions between a weak inhibitor and transforming growth factorb1 receptor kinase (Singh et al, 2003a). Upon the virtual screening of compounds, the group at Biogen Idec identified 87 hits, the best hit being identical in structure to the lead compound discovered through the traditional HTS approach at Eli Lilly (Shekhar 2008). In this situation, CADD, a method involving reduced cost and workload, was capable of producing the same lead as a full-scale HTS ( Fig.…”

Section: Introductionmentioning

confidence: 99%