A5017942901- Computational Drug Discovery Methods
- Protein Structure and Dynamics
- Machine Learning in Materials Science
- Chemical Synthesis and Analysis
- Mass Spectrometry Techniques and Applications
- Enzyme Structure and Function
- Click Chemistry and Applications
- Crystallization and Solubility Studies
- RNA and protein synthesis mechanisms
- Crystallography and molecular interactions
- Monoclonal and Polyclonal Antibodies Research
- X-ray Diffraction in Crystallography
- Microbial Natural Products and Biosynthesis
- Receptor Mechanisms and Signaling
- Chronic Lymphocytic Leukemia Research
- Chronic Myeloid Leukemia Treatments
- Various Chemistry Research Topics
- DNA and Nucleic Acid Chemistry
- Retinal Imaging and Analysis
- Free Radicals and Antioxidants
- Fungal Plant Pathogen Control
- Cholinesterase and Neurodegenerative Diseases
- Melanoma and MAPK Pathways
- Protein purification and stability
- Inorganic and Organometallic Chemistry
Schrodinger (United States)
2016-2025
Thomas Jefferson University
2012-2017
Ophthalmology Consultants
2007-2017
Columbia University
2007-2014
Olympic College
2010
University of Cincinnati
2008
University of Florida
2006
Pfizer (United States)
2001
Abstract The ff94 force field that is commonly associated with the Amber simulation package one of most widely used parameter sets for biomolecular simulation. After a decade extensive use and testing, limitations in this field, such as over‐stabilization α‐helices, were reported by us other researchers. This led to number attempts improve these parameters, resulting variety “Amber” fields significant difficulty determining which should be particular application. We show several continue...
The parametrization and validation of the OPLS3 force field for small molecules proteins are reported. Enhancements with respect to previous version (OPLS2.1) include addition off-atom charge sites represent halogen bonding aryl nitrogen lone pairs as well a complete refit peptide dihedral parameters better model native structure proteins. To adequately cover medicinal chemical space, employs over an order magnitude more reference data associated parameter types relative other commonly used...
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 advent low-cost parallel computing. However, it has proven to be challenging reliably achieve level accuracy that would needed guide lead optimization (∼5× in binding affinity) for wide range protein targets. Not surprisingly, widespread commercial application simulations been...
We report on the development and validation of OPLS4 force field. builds upon our previous work with OPLS3e to improve model accuracy challenging regimes drug-like chemical space that includes molecular ions sulfur-containing moieties. A novel parametrization strategy for charged species, which can be extended other systems, is introduced. leads improved benchmarks assess small-molecule solvation protein–ligand binding.
Building upon the OPLS3 force field we report on an enhanced model, OPLS3e, that further extends its coverage of medicinally relevant chemical space by addressing limitations in chemotype transferability. OPLS3e accomplishes this incorporating new parameter types recognize moieties with greater specificity and integrating on-the-fly parametrization approach to assignment partial charges. As a consequence, leads accuracy against performance benchmarks assess small molecule conformational...
A novel energy model (VSGB 2.0) for high resolution protein structure modeling is described, which features an optimized implicit solvent as well physics-based corrections hydrogen bonding, π-π interactions, self-contact and hydrophobic interactions. Parameters of the VSGB 2.0 were fit to a crystallographic database 2239 single side chain 100 11-13 residue loop predictions. Combined with advanced method sampling robust algorithm protonation state assignment, was validated by predicting 115...
The thermodynamic properties and phase behavior of water in confined regions can vary significantly from that observed the bulk. This is particularly true for systems which confinement on molecular-length scale. In this study, we use molecular dynamics simulations a powerful solvent analysis technique based inhomogenous solvation theory to investigate molecules solvate protein active sites. Our indicate sites are characterized by hydrophobic enclosure correlated hydrogen bonds induce...
Understanding the underlying physics of binding small-molecule ligands to protein active sites is a key objective computational chemistry and biology. It widely believed that displacement water molecules from site by ligand principal (if not dominant) source free energy. Although continuum theories hydration are routinely used describe contributions solvent affinity complex, it still an unsettled question as whether or these solvation molecular with sufficient accuracy reliably rank...
Although many popular docking programs include a facility to account for covalent ligands, large-scale systematic validation studies of inhibitors have been sparse. In this paper, we present the development and novel approach scoring inhibitors, which consists conventional noncovalent docking, heuristic formation attachment point, structural refinement protein–ligand complex. This combines strengths program Glide protein structure modeling Prime does not require any parameter fitting study...
A principal goal of drug discovery project is to design molecules that can tightly and selectively bind the target protein receptor. Accurate prediction protein-ligand binding free energies therefore central importance in computational chemistry computer aided design. Multiple recent improvements computing power, classical force field accuracy, enhanced sampling methods, simulation setup have enabled accurate reliable calculations protein-ligands energies, position energy play a guiding role...
Ligand docking is a widely used tool for lead discovery and binding mode prediction based drug discovery. The greatest challenges in occur when the receptor significantly reorganizes upon small molecule binding, thereby requiring an induced fit (IFD) approach which allowed to move order bind ligand optimally. IFD methods have had some success but suffer from lack of reliability. Complementing with all-atom molecular dynamics (MD) straightforward solution principle not practice due severe...
Accurate and reliable calculation of protein-ligand binding affinities remains a hotbed computer-aided drug design research. Despite the potentially large impact FEP (free energy perturbation) may have in projects, practical applications industrial contexts been limited. In this work, we use recently developed method, FEP/REST perturbation/replica exchange with solute tempering), to calculate relative for set congeneric ligands CDK2 receptor. We compare results traditional FEP/MD (molecular...
With the advent of make-on-demand commercial libraries, number purchasable compounds available for virtual screening and assay has grown explosively in recent years, with several libraries eclipsing one billion compounds. Today's are larger more diverse, enabling discovery more-potent hit unlocking new areas chemical space, represented by core scaffolds. Applying physics-based silico methods an exhaustive manner, where every molecule library must be enumerated evaluated independently, is...
We present a reliable and accurate solution to the induced fit docking problem for protein–ligand binding by combining ligand-based pharmacophore docking, rigid receptor protein structure prediction with explicit solvent molecular dynamics simulations. This novel methodology in detailed retrospective prospective testing succeeded determine modes root-mean-square deviation within 2.5 Å over 90% of cross-docking cases. further demonstrate these predicted ligand–receptor structures were...
In the hit identification stage of drug discovery, a diverse chemical space needs to be explored identify initial hits. Contrary empirical scoring functions, absolute protein–ligand binding free-energy perturbation (ABFEP) provides theoretically more rigorous and accurate description thermodynamics could, in principle, greatly improve rates virtual screening. this work, we describe an implementation reliable ABFEP method FEP+. We validated on eight congeneric compound series protein...
Computational techniques can speed up the identification of hits and accelerate development candidate molecules for drug discovery. Among predicting relative binding affinities, most consistently accurate is free energy perturbation (FEP), a class rigorous physics-based methods. However, uncertainty remains about how FEP ever be. Here, we present what believe to be largest publicly available dataset proteins congeneric series small molecules, assess accuracy leading workflow. To ascertain...
Predicting protein–ligand binding free energies is a central aim of computational structure-based drug design (SBDD) — improved accuracy in energy predictions could significantly reduce costs and accelerate project timelines lead discovery optimization. The recent development validation advanced calculation methods represents major step toward this goal. Accurately predicting the relative changes modifications to ligands especially valuable field fragment-based design, since fragment screens...
The rapid growth of structural information for G-protein-coupled receptors (GPCRs) has led to a greater understanding their structure, function, selectivity, and ligand binding. Although novel ligands have been identified using methods such as virtual screening, computationally driven lead optimization possible only in isolated cases because challenges associated with predicting binding free energies related compounds. Here, we provide systematic characterization the performance free-energy...
Improving the binding affinity of a chemical series by systematically probing one its exit vectors is medicinal chemistry activity that can benefit from molecular modeling input. Herein, we compare effectiveness four approaches in prioritizing building blocks with better potency: selection chemist, manual modeling, docking followed filtering, and free energy calculations (FEP). Our study focused on identifying novel substituents for apolar S2 pocket cathepsin L was conducted entirely...
The accurate prediction of protein-ligand binding free energies remains a significant challenge central importance in computational biophysics and structure-based drug design. Multiple recent advances including the development greatly improved protein ligand molecular mechanics force fields, more efficient enhanced sampling methods, low-cost powerful GPU computing clusters have enabled reliable predictions relative through energy perturbation (FEP) methods. However, existing FEP methods can...
Water plays an essential role in determining the structure and function of all biological systems. Recent methodological advances allow for accurate efficient estimation thermodynamic properties water molecules at surface proteins. In this work, we characterize these relate them to various structural functional characteristics protein. We find that high-energy hydration sites often exist near protein motifs typically characterized as hydrophilic, such backbone amide groups. also waters...
Abstract The prevention of blood coagulation is important in treating thromboembolic disorders, and several serine proteases involved the cascade have been classified as pharmaceutically relevant. Whereas structure‐based drug design has contributed to development some protease inhibitors, traditional computational methods not able fully describe structure–activity relationships (SAR). Here, we study SAR for a number by using method that calculates thermodynamic properties (enthalpy entropy)...
The hit-to-lead and lead optimization processes usually involve the design, synthesis, profiling of thousands analogs prior to clinical candidate nomination. A hit finding campaign may begin with a virtual screen that explores millions compounds, if not more. However, this scale computational is frequently performed in or phases drug discovery. This likely due lack appropriate tools generate synthetically tractable lead-like compounds silico, methods accurately profile prospectively on large...
In drug discovery programs, modifications that change the net charge of ligands are often considered to improve binding potency and solubility, or address other ADME/Tox problems. Accurate calculation free-energy changes associated with charge-changing perturbations remains a great challenge central importance in computational discovery. The finite size effects periodic boundary condition lattice summation employed common molecular dynamics simulations introduce artifacts electrostatic...