A5041554247- Protein Structure and Dynamics
- Computational Drug Discovery Methods
- Enzyme Structure and Function
- Glycosylation and Glycoproteins Research
- Click Chemistry and Applications
- HIV/AIDS drug development and treatment
- Monoclonal and Polyclonal Antibodies Research
- Endoplasmic Reticulum Stress and Disease
- Chemical Synthesis and Analysis
- Machine Learning in Materials Science
- Ubiquitin and proteasome pathways
- Enzyme function and inhibition
- Medical Imaging Techniques and Applications
- Cancer therapeutics and mechanisms
- Receptor Mechanisms and Signaling
- HER2/EGFR in Cancer Research
- HIV Research and Treatment
- Advanced Proteomics Techniques and Applications
- Forensic Toxicology and Drug Analysis
- Pharmacological Receptor Mechanisms and Effects
- Protein Kinase Regulation and GTPase Signaling
- Lung Cancer Treatments and Mutations
- Plant-based Medicinal Research
- Cannabis and Cannabinoid Research
- Bone health and treatments
Leidos (United States)
2020-2025
Frederick National Laboratory for Cancer Research
2020-2025
Leidos Biomedical Research Inc. (United States)
2020-2023
University of California, San Francisco
2015-2021
National Cancer Institute
2020-2021
Stony Brook University
2009-2015
This manuscript presents the latest algorithmic and methodological developments to structure‐based design program DOCK 6.7 focused on an updated internal energy function, new anchor selection control, enhanced minimization options, a footprint similarity scoring symmetry‐corrected root‐mean‐square deviation algorithm, database filter, docking forensic tools. An important strategy during development involved use of three orthogonal metrics for assessment validation: pose reproduction over...
A database consisting of 780 ligand−receptor complexes, termed SB2010, has been derived from the Protein Databank to evaluate accuracy docking protocols for regenerating bound ligand conformations. The goal is provide easily accessible community resources development improved procedures aid virtual screening ligands with a wide range flexibilities. Three core experiments using program DOCK, which employ rigid (RGD), fixed anchor (FAD), and flexible (FLX) protocols, were used gauge...
Fatty acid binding proteins (FABPs), in particular FABP5 and FABP7, have recently been identified by us as intracellular transporters for the endocannabinoid anandamide (AEA). Furthermore, animal studies others shown that elevated levels of endocannabinoids resulted beneficial pharmacological effects on stress, pain inflammation also ameliorate drug withdrawal. Based these observations, we hypothesized FABP7 would provide excellent targets. Thus, performed a virtual screening over one...
Enrichment of ligands versus property-matched decoys is widely used to test and optimize docking library screens. However, the unconstrained optimization enrichment alone can mislead, leading false confidence in prospective performance. This arise by over-optimizing for against decoys, without considering full spectrum molecules be found a true large screen. Adding representing charge extrema helps mitigate electrostatic interactions. that represent overall characteristics docked allows one...
Eukaryotic translation initiation factor 4E (eIF4E) binds the m7GTP cap structure at 5'-end of mRNAs, stimulating proteins implicated in cancer cell growth and metastasis. eIF4E is a notoriously challenging target, most reported inhibitors are negatively charged guanine analogues with negligible permeability. To overcome these challenges, we envisioned covalent targeting strategy. As there no cysteines near binding site, developed docking approach focused on lysine. Taking advantage...
RAF kinases are integral to the RAS-MAPK signaling pathway, and proper RAF1 folding relies on its interaction with chaperone HSP90 cochaperone CDC37. Understanding intricate molecular interactions governing is crucial for comprehending this process. Here, we present a cryo-EM structure of closed-state RAF1-HSP90-CDC37 complex, where C-lobe kinase domain binds one side dimer, an unfolded N-lobe segment threads through center dimer. CDC37 C-lobe, mimicking HxNI motif. We also describe...
Significance Water molecules play a crucial role in protein–ligand binding. Calculating the energetic consequences of displacing water upon ligand binding has challenged field for many years. Inhomogeneous solvation theory (IST) is one most popular methods distinguishing favorable from unfavorable molecules, but little controlled, prospective testing at atomic resolution been done to evaluate method. Here we compare molecular docking screens with and without an IST term gauge its impact on...
We observed a 53% response rate in non-small cell lung cancer (NSCLC) patients treated with vorinostat plus paclitaxel/carboplatin Phase I trial. Studies were undertaken to investigate the mechanism (s) underlying this activity. Growth inhibition was assessed NSCLC cells by MTT assay after 72 hr of continuous drug exposure. Vorinostat (1 microM) inhibited growth by: 17% +/- 7% A549, 28% 6% 128-88T, 39% 8% Calu1 and 41% 201T cells. addition carboplatin or paclitaxel led significantly greater...
Abstract A docking‐rescoring method, based on per‐residue van der Waals (VDW), electrostatic (ES), or hydrogen bond (HB) energies has been developed to aid discovery of ligands that have interaction signatures with a target (footprints) similar reference. Biologically useful references could include known drugs, inhibitors, substrates, transition states, side‐chains mediate protein‐protein interactions. Termed footprint similarity (FPS) score, the as implemented in program DOCK, was...
The success of targeted covalent inhibitors in the global pharmaceutical industry has led to a resurgence drug discovery. However, inhibitor design for flexible binding sites remains difficult task due lack methodological development. Here, we compared docking empirical electrophile screening against highly dynamic target K-RasG12C. While overall hit rate both methods was comparable, were able rapidly progress potent irreversible binder that modifies inactive, GDP-bound state...
Clinical use of ATP-competitive inhibitors the epidermal growth factor receptor (EGFR) kinase domain can lead to an acquired drug resistant mutant L858R&T790M which dramatically reduces binding affinity relative a prevalent cancer causing mutation L858R. In this study, we have used molecular dynamics (MD) computer simulations, free energy calculations (MM-GBSA method), and per-residue footprint analysis characterize three (erlotinib, gefitinib, AEE788) with wildtype EGFR mutants. The goal is...
Significance Many medicinal chemistry programs change ligands incrementally to explore protein binding and optimize affinity. How a accommodates such growing ligand series has received remarkably little structural attention. Here we investigate eight congeneric that grow by single-methylene additions, determining their protein-bound structures X-ray crystallography, how these changes. Rather than changing conformation smoothly complement the ever-larger ligands, site adopts few discrete...
Molecular docking methods are widely used in drug discovery efforts. RAS proteins important cancer targets, and useful systems for evaluating methods, including accounting solvation effects covalent small molecule binding. Water often plays a key role binding to proteins, many inhibitors─including FDA-approved drugs─covalently bind oncogenic proteins. We assembled test set, consisting of 138 protein structures 2 KRAS DNA complex with ligands. In DOCK 6, we have implemented receptor...
De novo design can be used to explore vast areas of chemical space in computational lead discovery. As a complement virtual screening, from‐scratch construction molecules is not limited compounds pre‐existing vendor catalogs. Here, we present an iterative fragment growth method, integrated into the program DOCK, which new are built using rules for allowable connections based on known molecules. The method leverages DOCK's advanced scoring and pruning approaches users define very specific...
Peptide T20, which targets the HIV protein gp41, represents first approved member of class drugs known as membrane fusion inhibitors. However, mechanisms lead to resistance through clinical use T20 are not well-understood because structure bound complex remains undetermined. In this report, an atomic-level model a T20−gp41 embedded in explicit DOPC was constructed, and molecular dynamics simulations, followed by binding energy analysis (MM-GBSA method), were performed delineate structural...
Abstract Scoring functions are a critically important component of computer‐aided screening methods for the identification lead compounds during early stages drug discovery. Here, we present new multigrid implementation footprint similarity (FPS) scoring function that was recently developed in our laboratory which has proven useful bind to protein on per‐residue basis way resembles known reference. The grid‐based FPS method is much faster than its Cartesian‐space counterpart, makes it...
Significance The dynamic nature of biomolecules is typically neglected in docking screens for ligand discovery. key to benefitting from various receptor conformations not only structural but also thermodynamic information. Here, we test a general approach that uses conformational preferences enhanced and conventional molecular dynamics simulations account the cost transitions high-energy states. Including this information as penalty term docking, scoring function, perform retrospective...
To allow DOCK 6 access to unprecedented chemical space for screening billions of small molecules, we have implemented features from 3.7 into 6, including a search routine that traverses precomputed ligand conformations stored in hierarchical database. We tested them on the DUDE-Z and SB2012 test sets. The database is 16 times faster than anchor-and-grow. However, ability reproduce experimental pose 16% worse enrichment performance average similar, but has better 1.7 slower. with post-docking...