Multistep Reaction Based De Novo Drug Design: Generating Synthetically Feasible Design Ideas

We describe a “multistep reaction driven” evolutionary algorithm approach to de novo molecular design. Structures generated by the approach include a proposed synthesis path intended to aid the chemist in assessing the synthetic feasibility of the ideas that are generated. The methodology is independent of how the design ideas are scored, allowing multicriteria drug design […]

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Man vs. Machine

Drug discovery teams often face roadblocks in their projects due to gaps between computer-aided drug design (CADD) and the medicinal chemistry lab. Thus, CADD scientists frequently identify promising ideas only to find that the medicinal chemists are unable to synthesize them.

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A Time-Saving Discovery Workflow

Chemists at a large chemical company improved their discovery hit rate fivefold by combining Muse molecular discovery platform with custom database search. A large chemical company initially turned to Muse® as part of a proprietary compound purchasing workflow. Then the company found a new way to leverage Muse to dramatically accelerate the discovery of new […]

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Finding Novel Ideas Through Both Ligand- and Target-based Discovery

Certara’s Muse Invent and a custom scoring function helped chemists differing needs to achieve faster discovery of innovative, realistic leads Discovery chemists at a large life sciences company needed to improve both speed and novelty in their generation of fresh ideas. When Certara® scientific consultants demonstrated the Muse® Invent™ molecular design workflow, they saw an […]

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R-group template CoMFA combines benefits of “ad hoc” and topomer alignments using 3D-QSAR for lead optimization

Template CoMFA methodologies extend topomer CoMFA by allowing user-designated templates, for example the experimental receptor-bound conformation of a prototypical ligand, to help determine the alignment of training and test set structures for 3D-QSAR. The algorithms that generate its new structural modality, template-constrained topomers, are described.

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Rethinking 3D-QSAR

The average error of pIC50 prediction reported for 140 structures in make-and-test applications of topomer CoMFA by four discovery organizations is 0.5. This remarkable accuracy can be understood to result from a topomer pose’s goal of generating field differences only at lattice intersections adjacent to intended structural change.

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Virtual screening for R-groups, including predicted pIC50 contributions, within large structural databases, using Topomer CoMFA

Multiple R-groups (monovalent fragments) are implicitly accessible within most of the molecular structures that populate large structural databases. R-group searching would desirably consider pIC50 contribution forecasts as well as ligand similarities or docking scores. However, R-group searching, with or without pIC50 forecasts, is currently not practical. The most prevalent and reliable source of pIC50 predictions, […]

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Quantitative Series Enrichment Analysis (QSEA): a novel procedure for 3D-QSAR analysis

A novel procedure is proposed for 3D-QSAR analysis. The composition of 16 published QSAR datasets has been examined using Quantitative Series Enrichment Analysis (QSEA). The procedure is based on topomer technologies. A heatmap display in combination with topomer CoMFA and a novel series trajectory analysis revealed critical information for the assembly of structures into meaningful […]

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A structure-guided approach for protein pocket modeling and affinity prediction

Binding affinity prediction is frequently addressed using computational models constructed solely with molecular structure and activity data. We present a hybrid structure-guided strategy that combines molecular similarity, docking, and multiple-instance learning such that information from protein structures can be used to inform models of structure–activity relationships. The Surflex-QMOD approach has been shown to produce accurate […]

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Template CoMFA: The 3D-QSAR Grail?

Template CoMFA, a novel alignment methodology for training or test set structures in 3D-QSAR, is introduced. Its two most significant advantages are its complete automation and its ability to derive a single combined model from multiple structural series affecting a biological target. Its only two inputs are one or more “template” structures having 3D coordinates […]

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2D- and 3D-QSAR studies on 54 anti-tumor Rubiaceae-type cyclopeptides

RA-VII, a bicyclic hexapeptide isolated from the roots of Rubia cordifolia, Rubia akane belongs to Rubiaceae-type cyclopeptides (RAs) and has attracted much attention for its potent anti-tumor activity and its bicyclic structure incorporating the isodityrosine moiety. In this work, hologram quantitative structure-activity relationship (HQSAR), comparative molecular field analysis (CoMFA), and comparative molecular similarity indices analysis […]

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3D-QSAR and molecular docking studies on 3-Anilino-4-Arylmaleimide derivatives as glycogen synthase kinase-3β inhibitors

Glycogen synthase kinase-3 (GSK-3), a serine/threonine kinase, is a fascinating enzyme with diverse biological actions in intracellular signaling systems, making it an emerging target for diseases such as diabetes mellitus, cancer, chronic inflammation, bipolar disorders and Alzheimer’s disease. It is important to inhibit GSK-3 selectively and the net effect of the GSK-3 inhibitors thus should […]

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A marriage made in torsional space: using GALAHAD models to drive pharmacophore multiplet searches

Pharmacophore multiplets are useful tools for 3D database searching, with the queries used ordinarily being derived from ensembles of random conformations of active ligands. It seems reasonable to expect that their usefulness can be augmented by instead using queries derived from single ligand conformations obtained from aligned ligands. Comparisons of pharmacophore multiplet searching using random […]

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3D-QSAR and Molecular Docking Studies on Derivatives of MK-0457, GSK1070916 and SNS-314 as Inhibitors against Aurora B Kinase

Development of anticancer drugs targeting Aurora B, an important member of the serine/threonine kinases family, has been extensively focused on in recent years. In this work, by applying an integrated computational method, including comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), homology modeling and molecular docking, we investigated the structural determinants of […]

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