Journal of Computer Aided Molecular Design

A fragment-based approach to the SAMPL3 Challenge.

Publication Date: 2012 Jan 31 PMID: 22290624
Authors: Kulp, J. L. 3rd - Blumenthal, S. N. - Wang, Q. - Bryan, R. L. - Guarnieri, F.
Journal: J Comput Aided Mol Des

The success of molecular fragment-based design depends critically on the ability to make predictions of binding poses and of affinity ranking for compounds assembled by linking fragments. The SAMPL3 Challenge provides a unique opportunity to evaluate the performance of a state-of-the-art fragment-based design methodology with respect to these requirements. In this article, we present results derived from linking fragments to predict affinity and pose in the SAMPL3 Challenge. The goal is to demonstrate how incorporating different aspects of modeling protein-ligand interactions impact the accuracy of the predictions, including protein dielectric models, charged versus neutral ligands, DeltaDeltaGs solvation energies, and induced conformational stress. The core method is based on annealing of chemical potential in a Grand Canonical Monte Carlo (GC/MC) simulation. By imposing an initially very high chemical potential and then automatically running a sequence of simulations at successively decreasing chemical potentials, the GC/MC simulation efficiently discovers statistical distributions of bound fragment locations and orientations not found reliably without the annealing. This method accounts for configurational entropy, the role of bound water molecules, and results in a prediction of all the locations on the protein that have any affinity for the fragment. Disregarding any of these factors in affinity-rank prediction leads to significantly worse correlation with experimentally-determined free energies of binding. We relate three important conclusions from this challenge as applied to GC/MC: (1) modeling neutral ligands-regardless of the charged state in the active site-produced better affinity ranking than using charged ligands, although, in both cases, the poses were almost exactly overlaid; (2) simulating explicit water molecules in the GC/MC gave better affinity and pose predictions; and (3) applying a DeltaDeltaGs solvation correction further improved the ranking of the neutral ligands. Using the GC/MC method under a variety of parameters in the blinded SAMPL3 Challenge provided important insights to the relevant parameters and boundaries in predicting binding affinities using simulated annealing of chemical potential calculations.

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Prediction of SAMPL3 host-guest binding affinities: evaluating the accuracy of generalized force-fields.

Publication Date: 2012 Jan 25 PMID: 22274835
Authors: Muddana, H. S. - Gilson, M. K.
Journal: J Comput Aided Mol Des

We used the second-generation mining minima method (M2) to compute the binding affinities of the novel host-guest complexes in the SAMPL3 blind prediction challenge. The predictions were in poor agreement with experiment, and we conjectured that much of the error might derive from the force field, CHARMm with Vcharge charges. Repeating the calculations with other generalized force-fields led to no significant improvement, and we observed that the predicted affinities were highly sensitive to the choice of force-field. We therefore embarked on a systematic evaluation of a set of generalized force fields, based upon comparisons with PM6-DH2, a fast yet accurate semi-empirical quantum mechanics method. In particular, we compared gas-phase interaction energies and entropies for the host-guest complexes themselves, as well as for smaller chemical fragments derived from the same molecules. The mean deviations of the force field interaction energies from the quantum results were greater than 3 kcal/mol and 9 kcal/mol, for the fragments and host-guest systems respectively. We further evaluated the accuracy of force-fields for computing the vibrational entropies and found the mean errors to be greater than 4 kcal/mol. Given these errors in energy and entropy, it is not surprising in retrospect that the predicted binding affinities deviated from the experiment by several kcal/mol. These results emphasize the need for improvements in generalized force-fields and also highlight the importance of systematic evaluation of force-field parameters prior to evaluating different free-energy methods.

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Drug design for ever, from hype to hope.

Publication Date: 2012 Jan 18 PMID: 22252446
Authors: Seddon, G. - Lounnas, V. - McGuire, R. - van den Bergh, T. - Bywater, R. P. - Oliveira, L. - Vriend, G.
Journal: J Comput Aided Mol Des

In its first 25 years JCAMD has been disseminating a large number of techniques aimed at finding better medicines faster. These include genetic algorithms, COMFA, QSAR, structure based techniques, homology modelling, high throughput screening, combichem, and dozens more that were a hype in their time and that now are just a useful addition to the drug-designers toolbox. Despite massive efforts throughout academic and industrial drug design research departments, the number of FDA-approved new molecular entities per year stagnates, and the pharmaceutical industry is reorganising accordingly. The recent spate of industrial consolidations and the concomitant move towards outsourcing of research activities requires better integration of all activities along the chain from bench to bedside. The next 25 years will undoubtedly show a series of translational science activities that are aimed at a better communication between all parties involved, from quantum chemistry to bedside and from academia to industry. This will above all include understanding the underlying biological problem and optimal use of all available data.

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Looking forward into the next 25 years: the 25th anniversary issue of the Journal of Computer-Aided Molecular Design.

Publication Date: 2012 Jan 17 PMID: 22249774
Authors: Stouch, T. R.
Journal: J Comput Aided Mol Des

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Ligand expansion in ligand-based virtual screening using relevance feedback.

Publication Date: 2012 Jan 17 PMID: 22249773
Authors: Abdo, A. - Saeed, F. - Hamza, H. - Ahmed, A. - Salim, N.
Journal: J Comput Aided Mol Des

Query expansion is the process of reformulating an original query to improve retrieval performance in information retrieval systems. Relevance feedback is one of the most useful query modification techniques in information retrieval systems. In this paper, we introduce query expansion into ligand-based virtual screening (LBVS) using the relevance feedback technique. In this approach, a few high-ranking molecules of unknown activity are filtered from the outputs of a Bayesian inference network based on a single ligand molecule to form a set of ligand molecules. This set of ligand molecules is used to form a new ligand molecule. Simulated virtual screening experiments with the MDL Drug Data Report and maximum unbiased validation data sets show that the use of ligand expansion provides a very simple way of improving the LBVS, especially when the active molecules being sought have a high degree of structural heterogeneity. However, the effectiveness of the ligand expansion is slightly less when structurally-homogeneous sets of actives are being sought.

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Computational fragment-based screening using RosettaLigand: the SAMPL3 challenge.

Publication Date: 2012 Jan 15 PMID: 22246345
Authors: Kumar, A. - Zhang, K. Y.
Journal: J Comput Aided Mol Des

SAMPL3 fragment based virtual screening challenge provides a valuable opportunity for researchers to test their programs, methods and screening protocols in a blind testing environment. We participated in SAMPL3 challenge and evaluated our virtual fragment screening protocol, which involves RosettaLigand as the core component by screening a 500 fragments Maybridge library against bovine pancreatic trypsin. Our study reaffirmed that the real test for any virtual screening approach would be in a blind testing environment. The analyses presented in this paper also showed that virtual screening performance can be improved, if a set of known active compounds is available and parameters and methods that yield better enrichment are selected. Our study also highlighted that to achieve accurate orientation and conformation of ligands within a binding site, selecting an appropriate method to calculate partial charges is important. Another finding is that using multiple receptor ensembles in docking does not always yield better enrichment than individual receptors. On the basis of our results and retrospective analyses from SAMPL3 fragment screening challenge we anticipate that chances of success in a fragment screening process could be increased significantly with careful selection of receptor structures, protein flexibility, sufficient conformational sampling within binding pocket and accurate assignment of ligand and protein partial charges.

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The errors of our ways: taking account of error in computer-aided drug design to build confidence intervals for our next 25 years.

Publication Date: 2012 Jan PMID: 22246296
Authors: Stouch, T. R.
Journal: J Comput Aided Mol Des

The future of the advancement as well as the reputation of computer-aided drug design will be guided by a more thorough understanding of the domain of applicability of our methods and the errors and confidence intervals of their results. The implications of error in current force fields applied to drug design are given are given as an example. Even as our science advances and our hardware become increasingly more capable, our software will be perhaps the most important aspect in this realization. Some recommendations for the future are provided. Education of users is essential for proper use and interpretation of computational results in the future.

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The good, the bad and the twisted: a survey of ligand geometry in protein crystal structures.

Publication Date: 2012 Jan 14 PMID: 22246295
Authors: Liebeschuetz, J. - Hennemann, J. - Olsson, T. - Groom, C. R.
Journal: J Comput Aided Mol Des

The protein databank now contains the structures of over 11,000 ligands bound to proteins. These structures are invaluable in applied areas such as structure-based drug design, but are also the substrate for understanding the energetics of intermolecular interactions with proteins. Despite their obvious importance, the careful analysis of ligands bound to protein structures lags behind the analysis of the protein structures themselves. We present an analysis of the geometry of ligands bound to proteins and highlight the role of small molecule crystal structures in enabling molecular modellers to critically evaluate a ligand model's quality and investigate protein-induced strain.

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Are predefined decoy sets of ligand poses able to quantify scoring function accuracy?

Publication Date: 2012 Jan 10 PMID: 22231069
Authors: Korb, O. - Ten Brink, T. - Victor Paul Raj, F. R. - Keil, M. - Exner, T. E.
Journal: J Comput Aided Mol Des

Due to the large number of different docking programs and scoring functions available, researchers are faced with the problem of selecting the most suitable one when starting a structure-based drug discovery project. To guide the decision process, several studies comparing different docking and scoring approaches have been published. In the context of comparing scoring function performance, it is common practice to use a predefined, computer-generated set of ligand poses (decoys) and to reevaluate their score using the set of scoring functions to be compared. But are predefined decoy sets able to unambiguously evaluate and rank different scoring functions with respect to pose prediction performance? This question arose when the pose prediction performance of our piecewise linear potential derived scoring functions (Korb et al. in J Chem Inf Model 49:84-96, 2009) was assessed on a standard decoy set (Cheng et al. in J Chem Inf Model 49:1079-1093, 2009). While they showed excellent pose identification performance when they were used for rescoring of the predefined decoy conformations, a pronounced degradation in performance could be observed when they were directly applied in docking calculations using the same test set. This implies that on a discrete set of ligand poses only the rescoring performance can be evaluated. For comparing the pose prediction performance in a more rigorous manner, the search space of each scoring function has to be sampled extensively as done in the docking calculations performed here. We were able to identify relative strengths and weaknesses of three scoring functions (ChemPLP, GoldScore, and Astex Statistical Potential) by analyzing the performance for subsets of the complexes grouped by different properties of the active site. However, reasons for the overall poor performance of all three functions on this test set compared to other test sets of similar size could not be identified.

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Development of energetic pharmacophore for the designing of 1,2,3,4-tetrahydropyrimidine derivatives as selective cyclooxygenase-2 inhibitors.

Publication Date: 2012 Jan 5 PMID: 22218727
Authors: Lokwani, D. - Shah, R. - Mokale, S. - Shastry, P. - Shinde, D.
Journal: J Comput Aided Mol Des

We present here the Energetic pharmacophore model representing complementary features of the 1,2,3,4-tetrahydropyrimidine for selective cyclooxygenase-2 (COX-2) inhibition. For the development of pharmacophore hypothesis, a total of 43 previously reported compounds were docked on active site of COX-2 enzyme. The generated pharmacophore features were ranked using energetic terms of Glide XP docking for 1,2,3,4-tetrahydropyrimidine scaffold to optimize its structure requirement for COX-2 inhibition. The thirty new 4,5,6-triphenyl-1,2,3,4-tetrahydropyrimidine derivatives were synthesized and assessed for selective COX-2 inhibitory activity. Two compounds 4B1 and 4B11 were found to be potent and selective COX-2 inhibitors. The molecular docking studies revealed that the newly synthesized compounds can be docked into COX-2 binding site and also provide the molecular basis for their activity.

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