All Scientific Publications

  • Accurate Binding Free Energy Predictions in Fragment Optimization

    J. Chem. Inf. Model. 2015, 55, 11, 2411–2420

    Predicting protein–ligand binding free energies is a central aim of computational structure-based drug design (SBDD) — improved accuracy in binding free energy predictions could significantly reduce costs and accelerate project timelines in lead discovery and optimization. The recent development and validation of advanced free energy calculation methods represents a major step toward this goal. Accurately

  • On the Rational Design of Zeolite Clusters

    ACS Catal. 2015, 5, 5, 2859–2865

    We have applied density functional theory calculations to systematically investigate zeolite cluster-size convergence for two acid-zeolite-catalyzed processes related to the conversion of biomass: (1) the keto–enol tautomerization of acetone in HZSM-5 and HY and (2) the protonation and ring opening of furan in HZSM-5. We have used these reactions as platforms to study two different

  • Improving Docking Results via Reranking of Ensembles of Ligand Poses in Multiple X-ray Protein Conformations with MM-GBSA

    J. Chem. Inf. Model. 2014, 54, 10, 2697–2717

    There is a tendency in the literature to be critical of scoring functions when docking programs perform poorly. The assumption is that existing scoring functions need to be enhanced or new ones developed in order to improve the performance of docking programs for tasks such as pose prediction and virtual screening. However, failures can result

  • Novel Procedure for Modeling Ligand/Receptor Induced Fit Effects

    J. Med. Chem. 2006, 49, 2, 534–553

    Most ReadWidely Cited

    We present a novel protein−ligand docking method that accurately accounts for both ligand and receptor flexibility by iteratively combining rigid receptor docking (Glide) with protein structure prediction (Prime) techniques. While traditional rigid-receptor docking methods are useful when the receptor structure does not change substantially upon ligand binding, success is limited when the protein must be

  • Allosteric Inhibition of the NS2B-NS3 Protease from Dengue Virus

    ACS Chem. Biol. 2013, 8, 12, 2744–2752

    Dengue virus is the flavivirus that causes dengue fever, dengue hemorrhagic disease, and dengue shock syndrome, which are currently increasing in incidence worldwide. Dengue virus protease (NS2B-NS3pro) is essential for dengue virus infection and is thus a target of therapeutic interest. To date, attention has focused on developing active-site inhibitors of NS2B-NS3pro. The flat and

  • Improving the Resistance Profile of Hepatitis C NS3/4A Inhibitors: Dynamic Substrate Envelope Guided Design

    J. Chem. Theory Comput. 2013, 9, 12, 5693–5705

    Drug resistance is a principal concern in the treatment of quickly evolving diseases. The viral protease NS3/4A is a primary drug target for the hepatitis C virus (HCV) and is known to evolve resistance mutations in response to drug therapy. At the molecular level, drug resistance reflects a subtle change in the balance of molecular

  • Water Networks Contribute to Enthalpy/Entropy Compensation in Protein–Ligand Binding

    J. Am. Chem. Soc. 2013, 135, 41, 15579–15584

    The mechanism (or mechanisms) of enthalpy–entropy (H/S) compensation in protein–ligand binding remains controversial, and there are still no predictive models (theoretical or experimental) in which hypotheses of ligand binding can be readily tested. Here we describe a particularly well-defined system of protein and ligands—human carbonic anhydrase (HCA) and a series of benzothiazole sulfonamide ligands with

  • Protein and Ligand Preparation: Parameters, Protocols, and Influence on Virtual Screening Enrichments

    J Comput Aided Mol Des design 27 (3), 221-234

    Widely Cited

    Structure-based virtual screening plays an important role in drug discovery and complements other screening approaches. In general, protein crystal structures are prepared prior to docking in order to add hydrogen atoms, optimize hydrogen bonds, remove atomic clashes, and perform other operations that are not part of the x-ray crystal structure refinement process. In addition, ligands

  • Structure-Based Virtual Screening of MT2 Melatonin Receptor: Influence of Template Choice and Structural Refinement

    J. Chem. Inf. Model. 2013, 53, 4, 821–835

    Developing GPCR homology models for structure-based virtual screening requires the choice of a suitable template and refinement of binding site residues. We explored this systematically for the MT2 melatonin receptor, with the aim to build a receptor homology model that is optimized for the enrichment of active melatoninergic ligands. A set of 12 MT2 melatonin receptor models

  • Type II Kinase Inhibitors Show an Unexpected Inhibition Mode against Parkinson’s Disease-Linked LRRK2 Mutant G2019S

    Biochemistry 2013, 52, 10, 1725–1736

    A number of well-known type II inhibitors (ATP-noncompetitive) that bind kinases in their DFG-out conformation were tested against wild-type LRRK2 and the most common Parkinson’s disease-linked mutation, G2019S. We found that traditional type II inhibitors exhibit surprising variability in their inhibition mechanism between the wild type (WT) and the G2019S mutant of LRRK2. The type

  • Close Intramolecular Sulfur–Oxygen Contacts: Modified Force Field Parameters for Improved Conformation Generation

    Journal of Computer-Aided Molecular Design volume 26, pages1195–1205(2012)

    The Cambridge Structural Database (CSD) offers an excellent data source to study small molecule conformations and molecular interactions. We have analyzed 130 small molecules from the CSD containing an intramolecular sulfur–oxygen distance less than the sum of their van der Waals (vdW) radii. Close S···O distances are observed in several important medicinal chemistry motifs (e.g.

  • Improving the Prediction of Absolute Solvation Free Energies Using the Next Generation OPLS Force Field

    J. Chem. Theory Comput. 2012, 8, 8, 2553–2558

    Explicit solvent molecular dynamics free energy perturbation simulations were performed to predict absolute solvation free energies of 239 diverse small molecules. We use OPLS2.0, the next generation OPLS force field, and compare the results with popular small molecule force fields—OPLS_2005, GAFF, and CHARMm-MSI. OPLS2.0 produces the best correlation with experimental data (R2 = 0.95, slope =

  • Exploring Protein Flexibility: Incorporating Structural Ensembles From Crystal Structures and Simulation into Virtual Screening Protocols

    J. Phys. Chem. B 2012, 116, 23, 6952–6959

    The capacity of proteins to adapt their structure in response to various perturbations including covalent modifications, and interactions with ligands and other proteins plays a key role in biological processes. Here, we explore the ability of molecular dynamics (MD), replica exchange molecular dynamics (REMD), and a library of structures of crystal-ligand complexes, to sample the

  • Rational Approaches to Improving Selectivity in Drug Design

    J. Med. Chem. 2012, 55, 4, 1424–1444

    Widely Cited

    Appropriate tuning of binding selectivity is a primary objective in the discovery and optimization of a compound on the path toward developing a drug. The environment in which drugs act is complex, with many potential interaction partners. Proteins, DNA, RNA, lipids, sugars, metabolites, and other small molecules all have the potential to interact with a

  • Thermodynamic Analysis of Water Molecules at the Surface of Proteins and Applications to Binding Site Prediction and Characterization

    Proteins: Structure, Function, and Bioinformatics 80 (3), 871-883

    Water plays an essential role in determining the structure and function of all biological systems. Recent methodological advances allow for an accurate and efficient estimation of the thermodynamic properties of water molecules at the surface of proteins. In this work, we characterize these thermodynamic properties and relate them to various structural and functional characteristics of

  • Mechanism of the Hydrophobic Effect in the Biomolecular Recognition of Arylsulfonamides by Carbonic Anhydrase

    PNAS November 1, 2011 108 (44) 17889-17894

    Widely Cited

    The hydrophobic effect—a rationalization of the insolubility of nonpolar molecules in water—is centrally important to biomolecular recognition. Despite extensive research devoted to the hydrophobic effect, its molecular mechanisms remain controversial, and there are still no reliably predictive models for its role in protein–ligand binding. Here we describe a particularly well-defined system of protein and ligands—carbonic

  • Prediction of Absolute Solvation Free Energies using Molecular Dynamics Free Energy Perturbation and the OPLS Force Field

    J. Chem. Theory Comput. 2010, 6, 5, 1509–1519

    Widely Cited

    The accurate prediction of protein−ligand binding free energies is a primary objective in computer-aided drug design. The solvation free energy of a small molecule provides a surrogate to the desolvation of the ligand in the thermodynamic process of protein−ligand binding. Here, we use explicit solvent molecular dynamics free energy perturbation to predict the absolute solvation

  • Probing the α‐Helical Structural Stability of Stapled p53 Peptides: Molecular Dynamics Simulations and Analysis

    Chemical Biology & Drug Design, 75 (4), 348-359

    Widely Cited

    Reactivation of the p53 cell apoptosis pathway through inhibition of the p53‐hDM2 interaction is a viable approach to suppress tumor growth in many human cancers and stabilization of the helical structure of synthetic p53 analogs via a hydrocarbon cross‐link (staple) has been found to lead to increased potency and inhibition of protein–protein binding (J. Am.

  • Computational Approaches for Fragment-Based and De Novo Design

    Current Topics in Medicinal Chemistry 10 (1), 14-32

    Fragment-based and de novo design strategies have been used in drug discovery for years. The methodologies for these strategies are typically discussed separately, yet the applications of these techniques overlap substantially. We present a review of various fragment-based discovery and de novo design protocols with an emphasis on successful applications in real-world drug discovery projects.