Ligand-biased ensemble receptor docking (LigBEnD): a hybrid ligand/receptor structure-based approach.

Ligand docking to flexible protein molecules can be efficiently carried out through ensemble docking to multiple protein conformations, either from experimental X-ray structures or from in silico simulations. The success of ensemble docking often requires the careful selection of complementary protein conformations, through docking and scoring of known co-crystallized ligands. False positives, in which a ligand in a wrong pose achieves a better docking score than that of native pose, arise as additional protein conformations are added. In the current study, we developed a new ligand-biased ensemble receptor docking method and composite scoring function which combine the use of ligand-based atomic property field (APF) method with receptor structure-based docking. This method helps us to correctly dock 30 out of 36 ligands presented by the D3R docking challenge. For the six mis-docked ligands, the cognate receptor structures prove to be too different from the 40 available experimental Pocketome conformations used for docking and could be identified only by receptor sampling beyond experimentally explored conformational subspace

Non-bisphosphonate inhibitors of isoprenoid biosynthesis identified via computer-aided drug design.

The relaxed complex scheme, a virtual-screening methodology that accounts for protein receptor flexibility, was used to identify a low-micromolar, non-bisphosphonate inhibitor of farnesyl diphosphate synthase. Serendipitously, we also found that several predicted farnesyl diphosphate synthase inhibitors were low-micromolar inhibitors of undecaprenyl diphosphate synthase. These results are of interest because farnesyl diphosphate synthase inhibitors are being pursued as both anti-infective and anticancer agents, and undecaprenyl diphosphate synthase inhibitors are antibacterial drug leads

Basic Enhancement Strategies When Using Bayesian Optimization for Hyperparameter Tuning of Deep Neural Networks

Compared to the traditional machine learning models, deep neural networks (DNN) are known to be highly sensitive to the choice of hyperparameters. While the required time and effort for manual tuning has been rapidly decreasing for the well developed and commonly used DNN architectures, undoubtedly DNN hyperparameter optimization will continue to be a major burden whenever a new DNN architecture needs to be designed, a new task needs to be solved, a new dataset needs to be addressed, or an existing DNN needs to be improved further. For hyperparameter optimization of general machine learning problems, numerous automated solutions have been developed where some of the most popular solutions are based on Bayesian Optimization (BO). In this work, we analyze four fundamental strategies for enhancing BO when it is used for DNN hyperparameter optimization. Specifically, diversification, early termination, parallelization, and cost function transformation are investigated. Based on the analysis, we provide a simple yet robust algorithm for DNN hyperparameter optimization - DEEP-BO (Diversified, Early-termination-Enabled, and Parallel Bayesian Optimization). When evaluated over six DNN benchmarks, DEEP-BO mostly outperformed well-known solutions including GP-Hedge, BOHB, and the speed-up variants that use Median Stopping Rule or Learning Curve Extrapolation. In fact, DEEP-BO consistently provided the top, or at least close to the top, performance over all the benchmark types that we have tested. This indicates that DEEP-BO is a robust solution compared to the existing solutions. The DEEP-BO code is publicly available at <uri>https://github.com/snu-adsl/DEEP-BO</uri>

Towards 'smart lasers': self-optimisation of an ultrafast pulse source using a genetic algorithm

Short-pulse fibre lasers are a complex dynamical system possessing a broad space of operating states that can be accessed through control of cavity parameters. Determination of target regimes is a multi-parameter global optimisation problem. Here, we report the implementation of a genetic algorithm to intelligently locate optimum parameters for stable single-pulse mode-locking in a Figure-8 fibre laser, and fully automate the system turn-on procedure. Stable ultrashort pulses are repeatably achieved by employing a compound fitness function that monitors both temporal and spectral output properties of the laser. Our method of encoding photonics expertise into an algorithm and applying machine-learning principles paves the way to self-optimising `smart' optical technologies

Computational structure‐based drug design: Predicting target flexibility

The role of molecular modeling in drug design has experienced a significant revamp in the last decade. The increase in computational resources and molecular models, along with software developments, is finally introducing a competitive advantage in early phases of drug discovery. Medium and small companies with strong focus on computational chemistry are being created, some of them having introduced important leads in drug design pipelines. An important source for this success is the extraordinary development of faster and more efficient techniques for describing flexibility in three‐dimensional structural molecular modeling. At different levels, from docking techniques to atomistic molecular dynamics, conformational sampling between receptor and drug results in improved predictions, such as screening enrichment, discovery of transient cavities, etc. In this review article we perform an extensive analysis of these modeling techniques, dividing them into high and low throughput, and emphasizing in their application to drug design studies. We finalize the review with a section describing our Monte Carlo method, PELE, recently highlighted as an outstanding advance in an international blind competition and industrial benchmarks.We acknowledge the BSC-CRG-IRB Joint Research Program in Computational Biology. This work was supported by a grant from the Spanish Government CTQ2016-79138-R.J.I. acknowledges support from SVP-2014-068797, awarded by the Spanish Government.Peer ReviewedPostprint (author's final draft

Identification of G-quadruplex DNA/RNA binders: Structure-based virtual screening and biophysical characterization

Background Recent findings demonstrated that, in mammalian cells, telomere DNA (Tel) is transcribed into telomeric repeat-containing RNA (TERRA), which is involved in fundamental biological processes, thus representing a promising anticancer target. For this reason, the discovery of dual (as well as selective) Tel/TERRA G-quadruplex (G4) binders could represent an innovative strategy to enhance telomerase inhibition. Methods Initially, docking simulations of known Tel and TERRA active ligands were performed on the 3D coordinates of bimolecular G4 Tel DNA (Tel2) and TERRA (TERRA2). Structure-based pharmacophore models were generated on the best complexes and employed for the virtual screening of ~ 257,000 natural compounds. The 20 best candidates were submitted to biophysical assays, which included circular dichroism and mass spectrometry at different K+ concentrations. Results Three hits were here identified and characterized by biophysical assays. Compound 7 acts as dual Tel2/TERRA2 G4-ligand at physiological KCl concentration, while hits 15 and 17 show preferential thermal stabilization for Tel2 DNA. The different molecular recognition against the two targets was also discussed. Conclusions Our successful results pave the way to further lead optimization to achieve both increased selectivity and stabilizing effect against TERRA and Tel DNA G4s. General significance The current study combines for the first time molecular modelling and biophysical assays applied to bimolecular DNA and RNA G4s, leading to the identification of innovative ligand chemical scaffolds with a promising anticancer profile. This article is part of a Special Issue entitled "G-quadruplex" Guest Editor: Dr. Concetta Giancola and Dr. Daniela Montesarchio