A5022991788- Computational Drug Discovery Methods
- Chemical Synthesis and Analysis
- Cancer, Lipids, and Metabolism
- Cancer, Hypoxia, and Metabolism
- Click Chemistry and Applications
- Protein Structure and Dynamics
- Microbial Natural Products and Biosynthesis
- Peroxisome Proliferator-Activated Receptors
- Amino Acid Enzymes and Metabolism
- Machine Learning in Materials Science
- Metabolomics and Mass Spectrometry Studies
- Epigenetics and DNA Methylation
- Cholinesterase and Neurodegenerative Diseases
- Cancer-related Molecular Pathways
- Monoclonal and Polyclonal Antibodies Research
- Mass Spectrometry Techniques and Applications
- Adipose Tissue and Metabolism
- Metabolism, Diabetes, and Cancer
- Hepatitis C virus research
- Bioinformatics and Genomic Networks
- HER2/EGFR in Cancer Research
- Liver Disease Diagnosis and Treatment
- Tryptophan and brain disorders
- HIV/AIDS drug development and treatment
- Endoplasmic Reticulum Stress and Disease
Schrodinger (United States)
2015-2024
Merck & Co., Inc., Rahway, NJ, USA (United States)
2014-2015
Massachusetts General Hospital
2014
United States Military Academy
2014
Merck Canada Inc. (Canada)
2010-2014
McGill University
2005-2008
Biotechnology Research Institute
2007-2008
National Research Council Canada
2008
National University of Singapore
2008
TransCanada (Canada)
2007
We present a binding free energy function that consists of force field terms supplemented by solvation terms. used this to calibrate the model along with interaction in self-consistent manner. The motivation for approach was solute dielectric-constant dependence calculated hydration gas-to-water transfer energies is markedly different from (J. Comput. Chem. 2003, 24, 954). Hence, we sought directly context calculation. five parameters were systematically scanned best reproduce absolute set...
Simultaneous inhibition of the acetyl-CoA carboxylase (ACC) isozymes ACC1 and ACC2 results in concomitant fatty acid synthesis stimulation oxidation may favorably affect morbidity mortality associated with obesity, diabetes, liver disease. Using structure-based drug design, we have identified a series potent allosteric protein-protein interaction inhibitors, exemplified by ND-630, that interact within ACC phosphopeptide acceptor dimerization site to prevent inhibit enzymatic activity both...
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...
The hit identification process usually involves the profiling of millions to more recently billions compounds either via traditional experimental high-throughput screens (HTS) or computational virtual (vHTS). We have previously demonstrated that, by coupling reaction-based enumeration, active learning, and free energy calculations, a similarly large-scale exploration chemical space can be extended hit-to-lead process. In this work, we augment that approach large scale enumeration cloud-based...
The lead optimization stage of a drug discovery program generally involves the design, synthesis, and assaying hundreds to thousands compounds. design phase is usually carried out via traditional medicinal chemistry approaches and/or structure-based (SBDD) when suitable structural information available. Two major limitations this approach are (1) difficulty in rapidly designing potent molecules that adhere myriad project criteria, or multiparameter (MPO) problem, (2) relatively small number...
The hit identification stage of a drug discovery program generally involves the design novel chemical scaffolds with desired biological activity against target(s) interest. One common approach is scaffold hopping, which manual based on known matter. major limitation this narrow space exploration, can lead to difficulties in maintaining or improving activity, selectivity, and favorable property space. Another lack preliminary structure-activity relationship (SAR) data around these designs,...
d-Serine is a coagonist of the N-methyl d-aspartate (NMDA) receptor, key excitatory neurotransmitter receptor. In brain, d-serine synthesized from its l-isomer by serine racemase and metabolized D-amino acid oxidase (DAO, DAAO). Many studies have linked decreased concentration and/or increased DAO expression enzyme activity to NMDA dysfunction schizophrenia. Thus, it feasible employ inhibitors for treatment schizophrenia other indications. Powered Schrödinger computational modeling platform,...
Abstract Protein–ligand binding occurs through interactions at the molecular surface. Hence, a proper description of this surface is essential to our understanding process recognition. Recent studies have noted inadequacy using fixed 1.4 Å solvent probe radius generate This assumes that water molecules approach all atoms an equal distance irrespective polarity, which not case. To adequately model protein–water boundary requires change according polarity its contacting atoms, smaller near...
We have been focused on identifying a structurally different next generation inhibitor to MK-5172 (our Ns3/4a protease currently under regulatory review), which would achieve superior pangenotypic activity with acceptable safety and pharmacokinetic profile. These efforts led the discovery of novel class HCV NS3/4a inhibitors containing unique spirocyclic-proline structural motif. The design strategy involved molecular-modeling based approach, optimization series obtain pan-genotypic coverage...
Significant improvements have been made in the past decade to methods that rapidly and accurately predict binding affinity through free energy perturbation (FEP) calculations. This has driven by recent advances small-molecule force fields sampling algorithms combined with availability of low-cost parallel computing. Predictive accuracies ∼1 kcal mol-1 regularly achieved, which are sufficient drive potency optimization modern drug discovery campaigns. Despite robustness these FEP approaches...
We have previously reported the discovery of our P2-P4 macrocyclic HCV NS3/4a protease inhibitor MK-5172, which in combination with NS5a MK-8742 recently received a breakthrough therapy designation from US FDA for treatment chronic infection. Our goal next generation was to achieve pan-genotypic activity while retaining pharmacokinetic profile MK-5172. One areas follow-up investigation involved replacement quinoxaline moiety MK-5172 quinoline and studying effect substitution at 4-position...
We report a new computational technique, PathFinder, that uses retrosynthetic analysis followed by combinatorial synthesis to generate novel compounds in synthetically accessible chemical space. Coupling PathFinder with active learning and cloud-based free energy calculations allows for large-scale potency predictions of on timescale impacts drug discovery. The process is further accelerated using combination population-based statistics techniques. Using this approach, we rapidly optimized...
The hit identification stage of a drug discovery program generally involves the design novel chemical scaffolds with desired biological activity against target(s) interest. One common approach is scaffold hopping, which manual based on known matter. major limitation this narrow space exploration, can lead to difficulties in maintaining or improving activity, selectivity, and favorable property space. Another lack preliminary structure-activity relationship (SAR) data around these designs,...
Despite the success of first, second and third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in treatment non-small cell lung cancer (NSCLC) with classical EGFR mutations (L858R or Exon 19 deletions), disease progression often occurs due to acquisition additional domain that confer TKI resistance. Specifically, both T790M C797S resistance results an variant is resistant all approved TKIs. Herein, we report a physics-based computationally-driven lead...
We report a series of noncovalent, reversible inhibitors cathepsin L that have been designed to explore additional binding interactions with the S′ subsites. The design was based on our previously reported crystal structure suggested possibility engineering increased subsites ((Chowdhury et al. J. Med. Chem. 2002, 45, 5321−5329)). A representative these new has co-crystallized mature L, and solved refined at 2.2 Å. described in this work extend farther into cathepsins than any literature...
Over the past decade, antimicrobial resistance has emerged as a major public health crisis. Glycopeptide antibiotics such vanco-mycin and teicoplanin are clinically important for treatment of Gram-positive bacterial infections. StaL is 3′-phosphoadenosine 5′-phosphosulfate-dependent sulfotransferase capable sulfating cross-linked heptapeptide substrate both <i>in vivo</i> vitro</i>, yielding product A47934, unique teicoplanin-class glycopeptide antibiotic. The sulfonation reaction catalyzed...
Despite the success of first, second and third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in treatment non-small cell lung cancer (NSCLC) with classical EGFR mutations (L858R or Exon 19 deletions), disease progression often occurs due to acquisition additional domain that confer TKI resistance. Specifically, both T790M C797S resistance results an variant is resistant all approved TKIs. Herein, we report a physics-based computationally-driven lead...
Free energy calculations are revolutionizing early-stage drug-discovery campaigns. Robust free methods can rapidly provide accurate on-target and off-target potency predictions to identify promising chemical matter for synthesis, thus, inspiring further rounds of ideation optimization. Here, we present a framework efficiently achieving kinome-wide selectivity that led the discovery novel selective Wee1 kinase inhibitors. With ligand-based relative binding calculations, multiple scaffolds...
Despite the success of first, second, and third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) for non-small cell lung cancer with classical EGFR mutations (L858R or Exon 19 deletions), disease progression occurs due to acquisition T790M C797S resistance. Herein, we report a physics-based computationally driven lead identification approach that identified structurally unique imidazo[3.2-