Certara’s Best of Blogs 2016

A selection of short essays from our blog, written to empower our customers with modeling and simulation (M&S) and regulatory writing solutions in order to help them solve the toughest drug development problems. Certara staff contributions range in topic from pharmacometrics to systems biology to the growing importance of regulatory writing and sharing clinical trial results.

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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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A 3D QSAR model of 17β-HSD1 inhibitors based on a thieno[2,3-d]pyrimidin-4(3H)-one core applying molecular

The 17ß-hydroxysteroid dehydrogenase type 1 (17ß-HSD1) enzyme plays a crucial role in female hormonal regulation by catalysing the NADPH-dependent reduction of the less potent estrone E1 into the biologically active estradiol E2. Because 17ß-HSD1 is a key enzyme in E2 biosynthesis, it has emerged as an attractive drug target for inhibitor development. Herein we report […]

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A Systematic Quantitative Approach to Rational Drug Design and Discovery of Novel Human Carbonic Anhydrase IX Inhibitors

Drug design involves the design of small molecules that are complementary in shape and charge to the biomolecular target with which they interact and therefore will bind to it. Three-dimensional quantitative structure-activity relationship (3D-QSAR) studies were performed for a series of carbonic anhydrase IX inhibitors using comparative molecular field analysis (CoMFA) and comparative molecular similarity […]

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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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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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3D-QSAR Studies on Substituted Benzimidazole Derivatives as Angiotensin II-AT1 Receptor Antagonist

This study investigated 3D quantitative structure-activity relationships (QSAR) for a range of substituted benzimidazole derivatives as AngII-AT1 receptor antagonists by comparative molecular field analysis (CoMFA) and comparative molecular similarity indices (CoMSIA). The alignment strategy was used for these compounds by means of Distill function defined in SYBYL X 1.2. The best CoMFA and CoMSIA models […]

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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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Acute Toxicity and n-octanol/Water Partition Coefficients of Substituted Thiophenols: Determination and QSAR Analysis

The acute toxicity (-log EC50) to Photobacterium phosphoreum and the n-octanol/water partition coefficient (log Kow) of 31 kinds of substituted thiophenols were determined at 298.15K. The -log EC50 values of studied chemicals are between 4.26 and 5.89. Their log Kow values are between 1.34 and 4.02. Comparative molecular field (CoMFA) and comparative molecular similarity index […]

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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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Binding Conformation of 2-oxoamide Inhibitors to Group IVA Cytosolic Phospholipase A2 Determined by Molecular Docking Combined with Molecular Dynamics

The Group IVA cytosolic phospholipase A2 (GIVA cPLA2) plays a central role in inflammation. Long chain 2-oxoamides constitute a class of potent GIVA cPLA2 inhibitors that exhibit potent in vivo anti-inflammatory and analgesic activity. We have now gained insight into the binding of 2-oxoamide inhibitors in the GIVA cPLA2 active site through a combination of […]

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An Integrated Computational Workflow for Efficient and Quantitative Modeling of Renin Inhibitors

A new integrated computational workflow that couples the strength of the molecular overlay methods to achieve rapid and automated alignments along with 3D-QSAR techniques like CoMFA and CoMSIA for quantitative binding affinity prediction is presented. The results obtained from such techniques are compared with rule-based Topomer CoMFA method, where possible.  

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3D-quantitative Structure-activity Relationship and Docking Studies of the Tachykinin NK3 Receptor

The tachykinin NK(3) receptor (NK(3)R) is a novel drug target for schizophrenia and drug abuse. Since few non-peptide antagonists of this G protein-coupled receptor are available, we have initiated this study to gain a better understanding of the structure-activity relationships of NK(3) antagonist compounds. We developed a 3D comparative molecular similarity index analysis (CoMSIA) model […]

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3,4,5-trisubstituted-1,2,4-4H-triazoles as WT and Y188L Mutant HIV-1 Non-nucleoside Reverse Transcriptase Inhibitors: Docking-based CoMFA and CoMSIA Analyses

3,4,5-Trisubstituted-1,2,4-4H-triazoles (TTs) have recently been identified as a new class of potent non-nucleoside HIV-1 reverse transcriptase (RT) inhibitors. Two series of triazoles have been studied, one of which was also screened against the Y188L mutant. A computational strategy based on molecular docking studies followed by comparative molecular fields analysis (CoMFA) and comparative molecular similarity indices […]

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A Discovery of Novel Mycobacterium Tuberculosis Pantothenate Synthetase Inhibitors Based on the Molecular Mechanism of Actinomycin D Inhibition

Mycobacterium tuberculosis pantothenate synthetase is a potential anti-tuberculosis target, and a high-throughput screening system was previously developed to identify its inhibitors. Using a similar system, we screened a small library of compounds and identified actinomycin D (ActD) as a weak inhibitor of pantothenate synthetase. A new method was established to discover more effective inhibitors by […]

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Capturing Structure-activity Relationships from Chemogenomic Spaces

Modeling off-target effects is one major goal of chemical biology, particularly in its applications to drug discovery. Here, we describe a new approach that allows the extraction of structure-activity relationships from large chemogenomic spaces starting from a single chemical structure. Several public source databases, offering a vast amount of data on structure and activity for […]

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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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3D-QSAR Studies on Caspase-mediated Apoptosis Activity of Phenolic Analogs

Phenols and its analogues are known to induce caspase-mediated apoptosis activity and cytotoxicity on various cancer cell lines. In the current work, two types of molecular field analysis techniques were used to perform the three dimension quantitative structure activity relationship (3D-QSAR) modeling between structural characters and anticancer activity of two sets of phenolic compounds, which […]

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