A5015984763- HIV/AIDS drug development and treatment
- Protein Structure and Dynamics
- HIV Research and Treatment
- Computational Drug Discovery Methods
- Peptidase Inhibition and Analysis
- Protease and Inhibitor Mechanisms
- Signaling Pathways in Disease
- Pharmacological Receptor Mechanisms and Effects
- Peroxisome Proliferator-Activated Receptors
- HER2/EGFR in Cancer Research
- Cancer, Lipids, and Metabolism
- Cannabis and Cannabinoid Research
- DNA and Nucleic Acid Chemistry
- Chemical Synthesis and Analysis
- Cancer therapeutics and mechanisms
- Monoclonal and Polyclonal Antibodies Research
- Enzyme Structure and Function
- Lung Cancer Treatments and Mutations
- SARS-CoV-2 and COVID-19 Research
- Prostate Cancer Treatment and Research
- Receptor Mechanisms and Signaling
- RNA and protein synthesis mechanisms
- Plant biochemistry and biosynthesis
- Drug Transport and Resistance Mechanisms
- Spectroscopy and Quantum Chemical Studies
Stony Brook University
2016-2025
John Wiley & Sons (United States)
2022
University of Nebraska–Lincoln
2016
State University of New York
2012
Northport VA Medical Center
2011
Statistics Finland
2009
Brookhaven National Laboratory
2006
Scripps Research Institute
2005
University of California, San Francisco
2004
Yale University
1999-2003
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...
With an increasing interest in RNA therapeutics and for targeting to treat disease, there is a need the tools used protein-based drug design, particularly DOCKing algorithms, be extended or adapted nucleic acids. Here, we have compiled test set of RNA-ligand complexes validate ability DOCK suite programs successfully recreate experimentally determined binding poses. optimized parameters minimal scoring function, 70% with less than seven rotatable ligand bonds 26% 13 can recreated within 2 A...
Classical force-field parameters have been developed for amines primarily by fitting to experimental data pure liquids and hydrogen-bond strengths from gas-phase ab initio calculations. The resultant were used calculate relative free energies of hydration ammonia, methylamine, dimethylamine, trimethylamine using energy perturbation calculations in Monte Carlo simulations (MC/FEP). results including the fact that most favorable ΔGhyd occurs methylamine are excellent agreement with data,...
We report unrestrained, all-atom molecular dynamics simulations of HIV-1 protease that sample large conformational changes the active site flaps. In particular, unliganded undergoes multiple conversions between “closed” and “semiopen” forms observed in crystal structures inhibitor-bound protease, respectively, including reversal flap “handedness.” Simulations presence a cyclic urea inhibitor yield stable closed Furthermore, we observe several events which flaps open to much greater degree...
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...
Absolute free energies of hydration (ΔGhyd) for more than 500 neutral and charged compounds have been computed, using Poisson-Boltzmann (PB) Generalized Born (GB) continuum methods plus a solvent-accessible surface area (SA) term, to evaluate the accuracy eight simple point-charge models used in molecular modeling. The goal is develop improved procedures protocols protein-ligand binding calculations virtual screening (docking). best overall PBSA GBSA results, comparison with experimental...
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...
The endocannabinoid anandamide (AEA) is an antinociceptive lipid that inactivated through cellular uptake and subsequent catabolism by fatty acid amide hydrolase (FAAH). Fatty binding proteins (FABPs) are intracellular carriers deliver AEA related N-acylethanolamines (NAEs) to FAAH for hydrolysis. mammalian brain expresses three FABP subtypes: FABP3, FABP5, FABP7. Recent work from our group has revealed pharmacological inhibition of FABPs reduces inflammatory pain in mice. goal the current...
The SARS-CoV-2 coronavirus is an enveloped, positive-sense single-stranded RNA virus that responsible for the COVID-19 pandemic. spike a class I viral fusion glycoprotein extends from surface and entry into host cell primary target of neutralizing antibodies. receptor binding domain (RBD) samples multiple conformations in compromise between evading immune recognition searching host-cell receptor. Using atomistic simulations glycosylated wild-type closed 1-up RBD conformations, we map free...
Lack of target specificity by existing matrix metalloproteinase (MMP) inhibitors has hindered antimetastatic cancer drug discovery. Inhibitors that bind to noncatalytic sites MMPs and disrupt protease signaling function have the potential be more specific selective. In this work, compounds hemopexin (PEX) domain MMP-9 were identified using an in silico docking approach evaluated biochemical biological approaches. Two selected interfere with MMP-9-mediated cell migration proliferation cells...
False negative docking outcomes for highly symmetric molecules are a barrier to the accurate evaluation of programs, scoring functions, and protocols. This work describes an implementation symmetry-corrected root-mean-square deviation (RMSD) method into program DOCK based on Hungarian algorithm solving minimum assignment problem, which dynamically assigns atom correspondence in with symmetry. The adds only trivial amount computation time RMSD calculations is shown increase reported overall...
A new linear interaction energy (LIE) method based on a continuum solvent surface generalized Born (SGB) model is proposed for protein−ligand binding affinity calculations. The SGB-LIE about 1 order of magnitude faster than previously published LIE methods explicit solvents. It has been applied to several sets: HEPT analogues HIV-1 reverse transcriptase (20 ligands), sulfonamide inhibitors human thrombin (seven and various ligands coagulation factor Xa (eight ligands). predictions...
We report unrestrained, all-atom molecular dynamics simulations of HIV-1 protease (HIV-PR) with a continuum solvent model that reproducibly sample closing the active site flaps following manual placement cyclic urea inhibitor into substrate binding open protease. The form was obtained from unbound, semi-open HIV-PR crystal structure, which we recently reported (Hornak, V.; et al. Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 915−920.) to have spontaneously opened during unrestrained dynamics. In...
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 interactions and energetics associated with the binding of 20 HEPT nevirapine nonnucleoside inhibitors HIV-1 reverse transcriptase (RT) have been explored in an effort to establish simulation protocols methods that can be used development more effective anti-HIV drugs. Using crystallographic structures as starting points, all 40 were modeled bound unbound states via Monte Carlo (MC) statistical mechanics methods. Potentially useful descriptors affinity configurationally averaged for each...
Results of Monte Carlo (MC) simulations for more than 200 nonnucleoside inhibitors HIV-1 reverse transcriptase (NNRTIs) representing eight diverse chemotypes have been correlated with their anti-HIV activities in an effort to establish simulation protocols and methods that can be used the development effective drugs. Each inhibitor was modeled a complex protein by itself water, potentially useful descriptors binding affinity were collected during MC simulations. A viable regression equation...
Point mutations in the influenza virus enzyme neuraminidase (NA) have been reported that lead to dramatic loss of activity for known NA inhibitors including FDA approved sialic acid mimics zanamivir and oseltamivir. A more complete understanding molecular basis such resistance is a critical component toward development improved next-generation drugs. In this study, we used explicit solvent all-atom dynamics simulations, free energy calculations (MM-GBSA), residue-based decomposition model...
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...
Pharmacophore modeling incorporates geometric and chemical features of known inhibitors and/or targeted binding sites to rationally identify design new drug leads. In this study, we have encoded a three-dimensional pharmacophore matching similarity (FMS) scoring function into the structure-based program DOCK. Validation characterization method are presented through pose reproduction, crossdocking, enrichment studies. When used alone, FMS dramatically improves reproduction success 93.5% (∼20%...