475 research outputs found
A sobering assessment of small-molecule force field methods for low energy conformer predictions
We have carried out a large scale computational investigation to assess the utility of common small-molecule force fields for computational screening of low energy conformers of typical organic molecules. Using statistical analyses on the energies and relative rankings of up to 250 diverse conformers of 700 different molecular structures, we find that energies from widely used classical force fields (MMFF94, UFF, and GAFF) show unconditionally poor energy and rank correlation with semiempirical (PM7) and KohnâSham density functional theory (DFT) energies calculated at PM7 and DFT optimized geometries. In contrast, semiempirical PM7 calculations show significantly better correlation with DFT calculations and generally better geometries. With these results, we make recommendations to more reliably carry out conformer screening
Atomic radius and charge parameter uncertainty in biomolecular solvation energy calculations
Atomic radii and charges are two major parameters used in implicit solvent
electrostatics and energy calculations. The optimization problem for charges
and radii is under-determined, leading to uncertainty in the values of these
parameters and in the results of solvation energy calculations using these
parameters. This paper presents a new method for quantifying this uncertainty
in implicit solvation calculations of small molecules using surrogate models
based on generalized polynomial chaos (gPC) expansions. There are relatively
few atom types used to specify radii parameters in implicit solvation
calculations; therefore, surrogate models for these low-dimensional spaces
could be constructed using least-squares fitting. However, there are many more
types of atomic charges; therefore, construction of surrogate models for the
charge parameter space requires compressed sensing combined with an iterative
rotation method to enhance problem sparsity. We demonstrate the application of
the method by presenting results for the uncertainties in small molecule
solvation energies based on these approaches. The method presented in this
paper is a promising approach for efficiently quantifying uncertainty in a wide
range of force field parameterization problems, including those beyond
continuum solvation calculations.The intent of this study is to provide a way
for developers of implicit solvent model parameter sets to understand the
sensitivity of their target properties (solvation energy) on underlying choices
for solute radius and charge parameters
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Complex macrocycle exploration: parallel, heuristic, and constraint-based conformer generation using ForceGen.
ForceGen is a template-free, non-stochastic approach for 2D to 3D structure generation and conformational elaboration for small molecules, including both non-macrocycles and macrocycles. For conformational search of non-macrocycles, ForceGen is both faster and more accurate than the best of all tested methods on a very large, independently curated benchmark of 2859 PDB ligands. In this study, the primary results are on macrocycles, including results for 431 unique examples from four separate benchmarks. These include complex peptide and peptide-like cases that can form networks of internal hydrogen bonds. By making use of new physical movements ("flips" of near-linear sub-cycles and explicit formation of hydrogen bonds), ForceGen exhibited statistically significantly better performance for overall RMS deviation from experimental coordinates than all other approaches. The algorithmic approach offers natural parallelization across multiple computing-cores. On a modest multi-core workstation, for all but the most complex macrocycles, median wall-clock times were generally under a minute in fast search mode and under 2 min using thorough search. On the most complex cases (roughly cyclic decapeptides and larger) explicit exploration of likely hydrogen bonding networks yielded marked improvements, but with calculation times increasing to several minutes and in some cases to roughly an hour for fast search. In complex cases, utilization of NMR data to constrain conformational search produces accurate conformational ensembles representative of solution state macrocycle behavior. On macrocycles of typical complexity (up to 21 rotatable macrocyclic and exocyclic bonds), design-focused macrocycle optimization can be practically supported by computational chemistry at interactive time-scales, with conformational ensemble accuracy equaling what is seen with non-macrocyclic ligands. For more complex macrocycles, inclusion of sparse biophysical data is a helpful adjunct to computation
QM7-X: A comprehensive dataset of quantum-mechanical properties spanning the chemical space of small organic molecules
We introduce QM7-X, a comprehensive dataset of 42 physicochemical properties
for 4.2 M equilibrium and non-equilibrium structures of small organic
molecules with up to seven non-hydrogen (C, N, O, S, Cl) atoms. To span this
fundamentally important region of chemical compound space (CCS), QM7-X includes
an exhaustive sampling of (meta-)stable equilibrium structures - comprised of
constitutional/structural isomers and stereoisomers, e.g., enantiomers and
diastereomers (including cis-/trans- and conformational isomers) - as well as
100 non-equilibrium structural variations thereof to reach a total of
4.2 M molecular structures. Computed at the tightly converged
quantum-mechanical PBE0+MBD level of theory, QM7-X contains global (molecular)
and local (atom-in-a-molecule) properties ranging from ground state quantities
(such as atomization energies and dipole moments) to response quantities (such
as polarizability tensors and dispersion coefficients). By providing a
systematic, extensive, and tightly-converged dataset of quantum-mechanically
computed physicochemical properties, we expect that QM7-X will play a critical
role in the development of next-generation machine-learning based models for
exploring greater swaths of CCS and performing in silico design of molecules
with targeted properties
Reaction between Peroxy and Alkoxy Radicals Can Form Stable Adducts
Peroxy (RO2) and alkoxy (RO) radicals are prototypical intermediates in any hydrocarbon oxidation. In this work, we use computational methods to (1) study the mechanism and kinetics of the RO2 + OH reaction for previously unexplored âRâ structures (R = CH(O)CH2 and R = CH3C(O)) and (2) investigate a hitherto unaccounted channel of molecular growth, Râ˛O2 + RO. On the singlet surface, these reactions rapidly form ROOOH and Râ˛OOOR adducts, respectively. The former decomposes to RO + HO2 and R(O)OH + O2 products, while the main decomposition channel for the latter is back to the reactant radicals. Decomposition rates of Râ˛OOOR adducts varied between 103 and 0.015 sâ1 at 298 K and 1 atm. The most long-lived Râ˛OOOR adducts likely account for some fraction of the elemental compositions detected in the atmosphere that are commonly assigned to stable covalently bound dimers.Peer reviewe
Ligand-based drug design : I. conformational studies of GBR 12909 analogs as cocaine antagonists; II. 3d-QSAR studies of salvinorin a analogs as kappa opioid agonists
Ligand-based drug design (LBDD) techniques are applied when the structure of the receptor is unknown but when a series of compounds or ligands have been identified that show the biological activity of the interest. Generally, availability of a series of compounds with high activity, with no activity, and also with a range of intermediate activities for the desired biological target is required. It is common that structures of membrane-bound proteins (for example, monoamine transporter proteins and opioid receptor proteins) are unknown as these proteins are notoriously difficult to crystallize.
In Part I of this study, analogs of the flexible dopamine reuptake inhibitor, GBR 12909, may have potential usefulness in the treatment of cocaine abuse. As a first step in the 3D-QSAR modeling of the dopamine transporter (DAT)/serotonin transporter (SERT) selectivity of these compounds, conformational analysis of a piperazine and related piperidine analog of GBR12909 is performed. These analogs have eight rotatable bonds and are somewhat easier to deal with computationally than the parent compound. Ensembles of conformers consisting of local minima on the potential energy surface of the molecule were generated in the vacuum phase and implicit solvent (also known as continuum solvent) by random search conformational analysis using the molecular mechanics methods and the Tripos and MMFF94 force fields. These conformer populations were classified by relative energy, molecular shape, and their behavior in 2D torsional angle space in order to evaluate their sensitivity to the choice of charges and force field. Some differences were noted in the conformer populations due to differences in the treatment of the tertiary amine nitrogen and ether oxygen atom types by the force fields.
In Part II of this study, 3D-QSAR studies of salvinorin A analogs as kappa opioid (K) receptor agonists were performed. Salvinorin A is a naturally-occurring diterpene from the plant Salvia divinorum which activates the kappa opioid receptor (KOR) selectively and potently. It is the only known natural non-nitrogenous agent active at the human KOR. Salvinorin A may represent a novel lead compound with possible potential in the treatment of addiction and pain. The primary aim of the current study was to develop Comparative Molecular Field Analysis (CoMFA) models to clarify the correlation between the molecular features of the 2-position analogs of salvinorin A and their KOR binding affinity. The final, stable CoMFA model has predictivity given by q2 of 0.62 and fit given by r2 of 0.86. The steric and electrostatic contributions were 47% and 53%, respectively. The CoMFA contour map indicated that the presence of a negative environment and steric region near the 2-position would lead to improved binding affinity at the KOR. Novel salvinorin A analogs with improved binding affinity were predicted based on the stable and predictive CoMFA model. Novel analogs were synthesized by Dr. Thomas Prisinzano of the University of Iowa and preliminary biological results are available from the Rothman laboratory at the National Institute on Drug Abuse. These novel analogs appear to be KOR selective
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