Showing papers by "David L. Mobley published in 2015"

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

Abstract: 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.

Guidelines for the analysis of free energy calculations

Abstract: Free energy calculations based on molecular dynamics simulations show considerable promise for applications ranging from drug discovery to prediction of physical properties and structure-function studies. But these calculations are still difficult and tedious to analyze, and best practices for analysis are not well defined or propagated. Essentially, each group analyzing these calculations needs to decide how to conduct the analysis and, usually, develop its own analysis tools. Here, we review and recommend best practices for analysis yielding reliable free energies from molecular simulations. Additionally, we provide a Python tool, alchemical-analysis.py, freely available on GitHub as part of the pymbar package (located at http://github.com/choderalab/pymbar), that implements the analysis practices reviewed here for several reference simulation packages, which can be adapted to handle data from other packages. Both this review and the tool covers analysis of alchemical calculations generally, including free energy estimates via both thermodynamic integration and free energy perturbation-based estimators. Our Python tool also handles output from multiple types of free energy calculations, including expanded ensemble and Hamiltonian replica exchange, as well as standard fixed ensemble calculations. We also survey a range of statistical and graphical ways of assessing the quality of the data and free energy estimates, and provide prototypes of these in our tool. We hope this tool and discussion will serve as a foundation for more standardization of and agreement on best practices for analysis of free energy calculations.

Is Ring breaking feasible in relative binding free energy calculations

Abstract: Our interest is relative binding free energy (RBFE) calculations based on molecular simulations. These are promising tools for lead optimization in drug discovery, computing changes in binding free energy due to modifications of a lead compound. However, in the "alchemical" framework for RBFE calculations, some types of mutations have the potential to introduce error into the computed binding free energies. Here we explore the magnitude of this error in several different model binding calculations. We find that some of the calculations involving ring breaking have significant errors, and these errors are especially large in bridged ring systems. Since the error is a function of ligand strain, which is unpredictable in advance, we believe that ring breaking should be avoided when possible.

Predicting the excess solubility of acetanilide, acetaminophen, phenacetin, benzocaine, and caffeine in binary water/ethanol mixtures via molecular simulation.

Abstract: We present a general framework to predict the excess solubility of small molecular solids (such as pharmaceutical solids) in binary solvents via molecular simulation free energy calculations at infinite dilution with conventional molecular models. The present study used molecular dynamics with the General AMBER Force Field to predict the excess solubility of acetanilide, acetaminophen, phenacetin, benzocaine, and caffeine in binary water/ethanol solvents. The simulations are able to predict the existence of solubility enhancement and the results are in good agreement with available experimental data. The accuracy of the predictions in addition to the generality of the method suggests that molecular simulations may be a valuable design tool for solvent selection in drug development processes.

A Python tool to set up relative free energy calculations in GROMACS

Abstract: Free energy calculations based on molecular dynamics (MD) simulations have seen a tremendous growth in the last decade. However, it is still difficult and tedious to set them up in an automated manner, as the majority of the present-day MD simulation packages lack that functionality. Relative free energy calculations are a particular challenge for several reasons, including the problem of finding a common substructure and mapping the transformation to be applied. Here we present a tool, alchemical-setup.py, that automatically generates all the input files needed to perform relative solvation and binding free energy calculations with the MD package GROMACS. When combined with Lead Optimization Mapper (LOMAP; Liu et al. in J Comput Aided Mol Des 27(9):755-770, 2013), recently developed in our group, alchemical-setup.py allows fully automated setup of relative free energy calculations in GROMACS. Taking a graph of the planned calculations and a mapping, both computed by LOMAP, our tool generates the topology and coordinate files needed to perform relative free energy calculations for a given set of molecules, and provides a set of simulation input parameters. The tool was validated by performing relative hydration free energy calculations for a handful of molecules from the SAMPL4 challenge (Mobley et al. in J Comput Aided Mol Des 28(4):135-150, 2014). Good agreement with previously published results and the straightforward way in which free energy calculations can be conducted make alchemical-setup.py a promising tool for automated setup of relative solvation and binding free energy calculations.

Correction to Small Molecule Hydration Free Energies in Explicit Solvent: An Extensive Test of Fixed-Charge Atomistic Simulations.

Abstract: Our previous work1 presented a curated database of calculated and experimental hydration free energies, along with input files and structures of the molecules involved. The set ostensibly consisted of 504 molecules, but in fact contained several duplicates as we detail below, as well as errors in the identity of some of the compounds considered, and mistakes in the experimental values of others. Here, we detail the mistakes in our original set, and also refer future users of the set to the FreeSolv database2, available in versioned form via http://www.escholarship.org/uc/item/6sd403pz. for the authoritative version of the database previously contained in the supporting information of this paper. The mistakes in our original set, detailed fully below, were not substantial enough to affect any of our overall conclusions or require re-calculation of statistics on the entire set. However, since the full set including input files is deposited in the Supporting Information of our work1 and has been used fairly widely as a basis for follow-up studies, these issues are important to note for the record. We fully expect that as the field moves forward and does additional work curating hydration free energy data, further issues (especially with the experimental data) may be uncovered. Since journal article Supporting Information does not provide a practical means for database updates (the only means for doing so is via errata), we plan to incorporate the results of any new curation into new versions of the FreeSolv database rather than by submitting an erratum to this paper and making an update to the Supporting Information. Specific issues we corrected relating to our database were: Several molecules were present as duplicates under alternate names: 2-methylbut-2-ene and 2-methyl-but-2-ene; 3-methylbut-l-ene and 3-methyl-but-1-ene; benzonitrile and cyanobenzene; 2-methoxy-2-methyl-propane and methyl-tert-butyl-ether. In FreeSolv, only one of each is retained We also removed a duplicate butanal which had an incorrect experimental value We removed “triacetyl glycerol” which was not the intended molecule (the intended molecule was “glycerol triacetate” which is still present in FreeSolv) We corrected the experimental value for hexafluoropropene, which had incorrectly been the value for hexafluoro-propan-2-ol Additional curation of experimental values was done via cross-comparison with J. Peter Guthrie's database (in preparation), resulting in updates to experimental values for 4-propylphenol, 4-bromophenol, 3-hydroxybenzaldehyde, 2-methoxyethanol, and dimethyl sulfoxide (methanesulfinylmethane). A number of IUPAC names were standardized A small correction was made to the experimental value of 1,3-butadiene, correcting the results of a typo in the cited Hine & Mookerjee work. Experimental values for 2,6-dichlorosyrangaldehyde and 3,5-dichloro-2,6-methoxyphenol were updated with better-curated values. The experimental value for (2E)-hex-2-enal was corrected very slightly More detail on these corrections is provided in the documentation distributed with FreeSolv2. In summary: None of the conclusions in our original study need revision, but the set of calculated and experimental hydration free energies provided in the Supporting Information is now obsolete and is replaced by FreeSolv (http://www.escholarship.org/uc/item/6sd403pz).

A proposal for regularly updated review/survey articles: "Perpetual Reviews"

Abstract: Author(s): Mobley, David L; Zuckerman, Daniel M | Abstract: We advocate the publication of review/survey articles that will be updated regularly, both in traditional journals and novel venues. We call these "perpetual reviews." This idea naturally builds on the dissemination and archival capabilities present in the modern internet, and indeed perpetual reviews exist already in some forms. Perpetual review articles allow authors to maintain over time the relevance of non-research scholarship that requires a significant investment of effort. Further, such reviews published in a purely electronic format without space constraints can also permit more pedagogical scholarship and clearer treatment of technical issues that remain obscure in a brief treatment.