Publications by authors named "Markus K Dahlgren"

14 Publications

  • Page 1 of 1

OPLS4: Improving Force Field Accuracy on Challenging Regimes of Chemical Space.

J Chem Theory Comput 2021 Jul 7;17(7):4291-4300. Epub 2021 Jun 7.

Schrodinger, Incorporated, 120 West 45th Street, New York, New York 10036, United States.

We report on the development and validation of the OPLS4 force field. OPLS4 builds upon our previous work with OPLS3e to improve model accuracy on challenging regimes of drug-like chemical space that includes molecular ions and sulfur-containing moieties. A novel parametrization strategy for charged species, which can be extended to other systems, is introduced. OPLS4 leads to improved accuracy on benchmarks that assess small-molecule solvation and protein-ligand binding.
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http://dx.doi.org/10.1021/acs.jctc.1c00302DOI Listing
July 2021

Reaction-Based Enumeration, Active Learning, and Free Energy Calculations To Rapidly Explore Synthetically Tractable Chemical Space and Optimize Potency of Cyclin-Dependent Kinase 2 Inhibitors.

J Chem Inf Model 2019 09 22;59(9):3782-3793. Epub 2019 Aug 22.

Schrödinger Inc. , 120 West 45th Street, 17th floor , New York , New York 10036 , United States.

The hit-to-lead and lead optimization processes usually involve the design, synthesis, and profiling of thousands of analogs prior to clinical candidate nomination. A hit finding campaign may begin with a virtual screen that explores millions of compounds, if not more. However, this scale of computational profiling is not frequently performed in the hit-to-lead or lead optimization phases of drug discovery. This is likely due to the lack of appropriate computational tools to generate synthetically tractable lead-like compounds in silico, and a lack of computational methods to accurately profile compounds prospectively on a large scale. Recent advances in computational power and methods provide the ability to profile much larger libraries of ligands than previously possible. Herein, we report a new computational technique, referred to as "PathFinder", that uses retrosynthetic analysis followed by combinatorial synthesis to generate novel compounds in synthetically accessible chemical space. In this work, the integration of PathFinder-driven compound generation, cloud-based FEP simulations, and active learning are used to rapidly optimize R-groups, and generate new cores for inhibitors of cyclin-dependent kinase 2 (CDK2). Using this approach, we explored >300 000 ideas, performed >5000 FEP simulations, and identified >100 ligands with a predicted IC < 100 nM, including four unique cores. To our knowledge, this is the largest set of FEP calculations disclosed in the literature to date. The rapid turnaround time, and scale of chemical exploration, suggests that this is a useful approach to accelerate the discovery of novel chemical matter in drug discovery campaigns.
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http://dx.doi.org/10.1021/acs.jcim.9b00367DOI Listing
September 2019

OPLS3e: Extending Force Field Coverage for Drug-Like Small Molecules.

J Chem Theory Comput 2019 Mar 4;15(3):1863-1874. Epub 2019 Mar 4.

Schrodinger, Inc. , 120 West 45th Street , New York , New York 10036 , United States.

Building upon the OPLS3 force field we report on an enhanced model, OPLS3e, that further extends its coverage of medicinally relevant chemical space by addressing limitations in chemotype transferability. OPLS3e accomplishes this by incorporating new parameter types that recognize moieties with greater chemical specificity and integrating an on-the-fly parametrization approach to the assignment of partial charges. As a consequence, OPLS3e leads to greater accuracy against performance benchmarks that assess small molecule conformational propensities, solvation, and protein-ligand binding.
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http://dx.doi.org/10.1021/acs.jctc.8b01026DOI Listing
March 2019

OPLS3: A Force Field Providing Broad Coverage of Drug-like Small Molecules and Proteins.

J Chem Theory Comput 2016 Jan 1;12(1):281-96. Epub 2015 Dec 1.

Department of Chemistry, Columbia University , 3000 Broadway, New York, New York 10027, United States.

The parametrization and validation of the OPLS3 force field for small molecules and proteins are reported. Enhancements with respect to the previous version (OPLS2.1) include the addition of off-atom charge sites to represent halogen bonding and aryl nitrogen lone pairs as well as a complete refit of peptide dihedral parameters to better model the native structure of proteins. To adequately cover medicinal chemical space, OPLS3 employs over an order of magnitude more reference data and associated parameter types relative to other commonly used small molecule force fields (e.g., MMFF and OPLS_2005). As a consequence, OPLS3 achieves a high level of accuracy across performance benchmarks that assess small molecule conformational propensities and solvation. The newly fitted peptide dihedrals lead to significant improvements in the representation of secondary structure elements in simulated peptides and native structure stability over a number of proteins. Together, the improvements made to both the small molecule and protein force field lead to a high level of accuracy in predicting protein-ligand binding measured over a wide range of targets and ligands (less than 1 kcal/mol RMS error) representing a 30% improvement over earlier variants of the OPLS force field.
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http://dx.doi.org/10.1021/acs.jctc.5b00864DOI Listing
January 2016

Accurate and reliable prediction of relative ligand binding potency in prospective drug discovery by way of a modern free-energy calculation protocol and force field.

J Am Chem Soc 2015 Feb 12;137(7):2695-703. Epub 2015 Feb 12.

Schrödinger, Inc. , 120 West 45th Street, New York, New York 10036, United States.

Designing tight-binding ligands is a primary objective of small-molecule drug discovery. Over the past few decades, free-energy calculations have benefited from improved force fields and sampling algorithms, as well as the advent of low-cost parallel computing. However, it has proven to be challenging to reliably achieve the level of accuracy that would be needed to guide lead optimization (∼5× in binding affinity) for a wide range of ligands and protein targets. Not surprisingly, widespread commercial application of free-energy simulations has been limited due to the lack of large-scale validation coupled with the technical challenges traditionally associated with running these types of calculations. Here, we report an approach that achieves an unprecedented level of accuracy across a broad range of target classes and ligands, with retrospective results encompassing 200 ligands and a wide variety of chemical perturbations, many of which involve significant changes in ligand chemical structures. In addition, we have applied the method in prospective drug discovery projects and found a significant improvement in the quality of the compounds synthesized that have been predicted to be potent. Compounds predicted to be potent by this approach have a substantial reduction in false positives relative to compounds synthesized on the basis of other computational or medicinal chemistry approaches. Furthermore, the results are consistent with those obtained from our retrospective studies, demonstrating the robustness and broad range of applicability of this approach, which can be used to drive decisions in lead optimization.
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http://dx.doi.org/10.1021/ja512751qDOI Listing
February 2015

Illuminating HIV gp120-Ligand Recognition through Computationally-Driven Optimization of Antibody-Recruiting Molecules.

Chem Sci 2014 Jun;5(6):2311-2317

Department of Chemistry, Yale University, New Haven, Connecticut 06520 ; Department of Pharmacology, Yale School of Medicine, New Haven, Connecticut 06510.

Here we report on the structure-based optimization of antibody-recruiting molecules targeting HIV gp120 (ARM-H). These studies have leveraged a combination of medicinal chemistry, biochemical and cellular assay analysis, and computation. Our findings have afforded an optimized analog of ARM-H, which is ~1000 fold more potent in gp120-binding and MT-2 antiviral assays than our previously reported derivative. Furthermore, computational analysis, taken together with experimental data, provides evidence that azaindole- and indole-based attachment inhibitors bind gp120 at an accessory hydrophobic pocket beneath the CD4-binding site and can also adopt multiple unique binding modes in interacting with gp120. These results are likely to prove highly enabling in the development of novel HIV attachment inhibitors, and more broadly, they suggest novel applications for ARMs as probes of conformationally flexible systems.
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http://dx.doi.org/10.1039/C4SC00484ADOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4217211PMC
June 2014

Virtual screening reveals allosteric inhibitors of the Toxoplasma gondii thymidylate synthase-dihydrofolate reductase.

Bioorg Med Chem Lett 2014 Feb 31;24(4):1232-5. Epub 2013 Dec 31.

Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA; Department of Molecular Biophysics & Biochemistry, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA. Electronic address:

The parasite Toxoplasma gondii can lead to toxoplasmosis in those who are immunocompromised. To combat the infection, the enzyme responsible for nucleotide synthesis thymidylate synthase-dihydrofolate reductase (TS-DHFR) is a suitable drug target. We have used virtual screening to determine novel allosteric inhibitors at the interface between the two TS domains. Selected compounds from virtual screening inhibited TS activity. Thus, these results show that allosteric inhibition by small drug-like molecules can occur in T. gondii TS-DHFR and pave the way for new and potent species-specific inhibitors.
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http://dx.doi.org/10.1016/j.bmcl.2013.12.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3946055PMC
February 2014

Characterization of biaryl torsional energetics and its treatment in OPLS all-atom force fields.

J Chem Inf Model 2013 May 13;53(5):1191-9. Epub 2013 May 13.

Department of Chemistry, Yale University, New Haven, Connecticut 06520-8107, United States.

The frequency of biaryl substructures in a database of approved oral drugs has been analyzed. This led to designation of 20 prototypical biaryls plus 10 arylpyridinones for parametrization in the OPLS all-atom force fields. Bond stretching, angle-bending, and torsional parameters were developed to reproduce the MP2 geometries and torsional energy profiles. The transferability of the new parameters was tested through their application to three additional biaryls. The torsional energetics for the 33 biaryl molecules are analyzed and factors leading to preferences for planar and nonplanar geometries are identified. For liquid biphenyl, the computed density and heat of vaporization at the boiling point (255 °C) are also reported.
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http://dx.doi.org/10.1021/ci4001597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3707137PMC
May 2013

Virtual screening and optimization yield low-nanomolar inhibitors of the tautomerase activity of Plasmodium falciparum macrophage migration inhibitory factor.

J Med Chem 2012 Nov 26;55(22):10148-59. Epub 2012 Oct 26.

Department of Chemistry, Yale University , New Haven, Connecticut 06520-8107, USA.

The Plasmodium falciparum orthologue of the human cytokine, macrophage migratory inhibitory factor (PfMIF), is produced by the parasite during malaria infection and modulates the host's immune response. As for other MIF orthologues, PfMIF has tautomerase activity, whose inhibition may influence the cytokine activity. To identify small-molecule inhibitors of the tautomerase activity of PfMIF, virtual screening has been performed by docking 2.1 million compounds into the enzymatic site. Assaying of 17 compounds identified four as active. Substructure search for the most potent of these compounds, a 4-phenoxypyridine analogue, identified four additional compounds that were purchased and also shown to be active. Thirty-one additional analogues were then designed, synthesized, and assayed. Three were found to be potent PfMIF tautomerase inhibitors with K(i) of ∼40 nM; they are also highly selective with K(i) > 100 μM for human MIF.
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http://dx.doi.org/10.1021/jm301269sDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3509768PMC
November 2012

Pre-clinical pharmacokinetics and anti-chlamydial activity of salicylidene acylhydrazide inhibitors of bacterial type III secretion.

J Antibiot (Tokyo) 2012 Aug 6;65(8):397-404. Epub 2012 Jun 6.

Department of Chemistry, Umeå University, Sweden.

Salicylidene acylhydrazides belong to a class of compounds shown to inhibit bacterial type III secretion (T3S) in pathogenic Gram-negative bacteria. This class of compounds also inhibits growth and replication of Chlamydiae, strict intracellular bacteria that possess a T3S system. In this study a library of 58 salicylidene acylhydrazides was screened to identify inhibitors of Chlamydia growth. Compounds inhibiting growth of both Chlamydia trachomatis and Chlamydophila pneumoniae were tested for cell toxicity and seven compounds were selected for preliminary pharmacokinetic analysis in mice using cassette dosing. Two compounds, ME0177 and ME0192, were further investigated by individual pharmacokinetic analysis. Compound ME0177 had a relatively high peak plasma concentration (C(max)) and area under curve and therefore may be considered for systemic treatment of Chlamydia infections. The other compound, ME0192, had poor pharmacokinetic properties but the highest anti-chlamydial activity in vitro and therefore was tested for topical treatment in a mouse vaginal infection model. ME0192 administered vaginally significantly reduced the infectious burden of C. trachomatis and the number of infected mice.
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http://dx.doi.org/10.1038/ja.2012.43DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3428607PMC
August 2012

Synthesis of [4-(2-hydroxyphenyl)thiazol-2-yl]methanones as potential bioisosteres of salicylidene acylhydrazides.

Molecules 2010 Aug 31;15(9):6019-34. Epub 2010 Aug 31.

Department of Chemistry, Umeå University, Umeå, Sweden.

A focused library of [4-(2-hydroxyphenyl)thiazol-2-yl]methanones was prepared in a four-step synthesis with the aim to obtain potent inhibitors of type III secretion in Gram-negative bacteria. The compounds are potential bioisosteres of salicylidene acylhydrazides that are a known class of type III secretion inhibitors.
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http://dx.doi.org/10.3390/molecules15096019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6257736PMC
August 2010

Synthesis of 2-(2-aminopyrimidine)-2,2-difluoroethanols as potential bioisosters of salicylidene acylhydrazides.

Molecules 2010 Jun 21;15(6):4423-38. Epub 2010 Jun 21.

Department of Chemistry, Umeå University, SE-90187 Umeå, Sweden.

Salicylidene acylhydrazides are inhibitors of type III secretion in several gram-negative pathogens. To further develop the salicylidene acylhydrazides, scaffold hopping was applied to replace the core fragment of the compounds. The novel 2-(2-amino-pyrimidine)-2,2-difluoroethanol scaffold was identified as a possible analog to the salicylidene acylhydrazide core structure. The synthesis of a library of 2-(2-amino-pyrimidine)-2,2-difluoro-ethanols is described in this paper.
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http://dx.doi.org/10.3390/molecules15064423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6264576PMC
June 2010

Statistical molecular design of a focused salicylidene acylhydrazide library and multivariate QSAR of inhibition of type III secretion in the Gram-negative bacterium Yersinia.

Bioorg Med Chem 2010 Apr 18;18(7):2686-703. Epub 2010 Feb 18.

Department of Chemistry, Umeå University, SE-901 87 Umeå, Sweden.

A combined application of statistical molecular design (SMD), quantitative structure-activity relationship (QSAR) modeling and prediction of new active compounds was effectively used to develop salicylidene acylhydrazides as inhibitors of type III secretion (T3S) in the Gram-negative pathogen Yersinia pseudotuberculosis. SMD and subsequent synthesis furnished 50 salicylidene acylhydrazides in high purity. Based on data from biological evaluation in T3S linked assays 18 compounds were classified as active and 25 compounds showed a dose-dependent inhibition. The 25 compounds were used to compute two multivariate QSAR models and two multivariate discriminant analysis models were computed from both active and inactive compounds. Three of the models were used to predict 4416 virtual compounds in consensus and eight new compounds were selected as an external test set. Synthesis and biological evaluation of the test set in Y. pseudotuberculosis and the intracellular pathogen Chlamydia trachomatis validated the models. Y. pseudotuberculosis and C. trachomatis cell-based infection models showed that compounds identified in this study are selective and non-toxic inhibitors of T3S dependent virulence.
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http://dx.doi.org/10.1016/j.bmc.2010.02.022DOI Listing
April 2010

Design, synthesis, and multivariate quantitative structure-activity relationship of salicylanilides--potent inhibitors of type III secretion in Yersinia.

J Med Chem 2007 Nov 2;50(24):6177-88. Epub 2007 Nov 2.

Department of Chemistry, Umeå University, SE-901 87 Umeå, Sweden.

Analogues to the salicylanilide N-(4-Chlorophenyl)-2-acetoxy-3,5-diiodobenzamide, 1a, an inhibitor of type III secretion (T3S) in Yersinia, were selected, synthesized, and biologically evaluated in three cycles. First, a set of analogues with variations in the salicylic acid ring moiety was synthesized to probe possible structural variation. A basic structure-activity relationship was established and then used to cherry-pick compounds from a principal component analysis score plot of salicylanilides to generate a second set. A third set with increased likelihood of biological activity was designed using D-optimal onion design. A quantitative structure-activity relationship model using hierarchical partial least-square regression to latent structures (Hi-PLS) was computed using PLS score vectors of building blocks correlated to the % inhibition of T3S as a response. A PLS discriminant analysis (PLS-DA) model was derived using the same descriptor set as that for the Hi-PLS model. Both models were validated with an external test set.
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http://dx.doi.org/10.1021/jm070741bDOI Listing
November 2007
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