Molecular design opportunities presented by solvent‐exposed regions of target proteins

Solvent‐exposed regions, or solvent‐filled pockets, within or adjacent to the ligand‐binding sites of drug‐target proteins provide opportunities for substantial modifications of existing small‐molecular drug molecules without serious loss of activity. In this review, we present recent selected examples of exploitation of solvent‐exposed regions of proteins in drug design and development from the recent medicinal‐chemistry literature.

[1]  Structure-Based Design of Highly Selective and Potent G Protein-Coupled Receptor Kinase 2 Inhibitors Based on Paroxetine. , 2017, Journal of medicinal chemistry.

[2]  T. Lu,et al.  Structure-based design, synthesis, and evaluation of 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine derivatives as novel c-Met inhibitors. , 2017, European journal of medicinal chemistry.

[3]  E. De Clercq,et al.  Discovery of small molecular inhibitors targeting HIV-1 gp120-CD4 interaction drived from BMS-378806. , 2014, European journal of medicinal chemistry.

[4]  B. Gryder,et al.  Histone deacetylase inhibitors equipped with estrogen receptor modulation activity. , 2013, Journal of medicinal chemistry.

[5]  William L Jorgensen,et al.  Optimization of diarylazines as anti-HIV agents with dramatically enhanced solubility. , 2013, Bioorganic & medicinal chemistry letters.

[6]  Dongwei Kang,et al.  Further Exploring Solvent-Exposed Tolerant Regions of Allosteric Binding Pocket for Novel HIV-1 NNRTIs Discovery. , 2018, ACS medicinal chemistry letters.

[7]  Fei Xu,et al.  Evaluation of molecular modeling of agonist binding in light of the crystallographic structure of an agonist-bound A₂A adenosine receptor. , 2012, Journal of medicinal chemistry.

[8]  I. Churcher Protac-Induced Protein Degradation in Drug Discovery: Breaking the Rules or Just Making New Ones? , 2017, Journal of medicinal chemistry.

[9]  Deepak Bandyopadhyay,et al.  DNA-Encoded Library Screening Identifies Benzo[b][1,4]oxazepin-4-ones as Highly Potent and Monoselective Receptor Interacting Protein 1 Kinase Inhibitors. , 2016, Journal of medicinal chemistry.

[10]  C. Schiffer,et al.  Structural and Thermodynamic Effects of Macrocyclization in HCV NS3/4A Inhibitor MK-5172. , 2016, ACS chemical biology.

[11]  M. Kutzler,et al.  Bifunctional Chimera That Coordinately Targets Human Immunodeficiency Virus 1 Envelope gp120 and the Host-Cell CCR5 Coreceptor at the Virus-Cell Interface. , 2018, Journal of medicinal chemistry.

[12]  Ping Chen,et al.  Imidazoquinoxaline Src-family kinase p56Lck inhibitors: SAR, QSAR, and the discovery of (S)-N-(2-chloro-6-methylphenyl)-2-(3-methyl-1-piperazinyl)imidazo- [1,5-a]pyrido[3,2-e]pyrazin-6-amine (BMS-279700) as a potent and orally active inhibitor with excellent in vivo antiinflammatory activity. , 2004, Journal of medicinal chemistry.

[13]  Peng Zhan,et al.  Designed multiple ligands: an emerging anti-HIV drug discovery paradigm. , 2009, Current pharmaceutical design.

[14]  Stephanie Hamilton,et al.  Dimeric zanamivir conjugates with various linking groups are potent, long-lasting inhibitors of influenza neuraminidase including H5N1 avian influenza. , 2005, Journal of medicinal chemistry.

[15]  Liu Liu,et al.  Discovery of a Small-Molecule Degrader of Bromodomain and Extra-Terminal (BET) Proteins with Picomolar Cellular Potencies and Capable of Achieving Tumor Regression , 2017, Journal of medicinal chemistry.

[16]  Chang Kai Soh,et al.  Design, Synthesis, and Preclinical Evaluation of Fused Pyrimidine-Based Hydroxamates for the Treatment of Hepatocellular Carcinoma. , 2018, Journal of medicinal chemistry.

[17]  C. Cywin,et al.  Novel nonnucleoside inhibitors of HIV-1 reverse transcriptase. 7. 8-Arylethyldipyridodiazepinones as potent broad-spectrum inhibitors of wild-type and mutant enzymes. , 1998, Journal of medicinal chemistry.

[18]  M. Soellner,et al.  Development of a chimeric c-Src kinase and HDAC inhibitor. , 2013, ACS medicinal chemistry letters.

[19]  Stephen P. Jackson,et al.  Deubiquitylating enzymes and drug discovery: emerging opportunities , 2017, Nature Reviews Drug Discovery.

[20]  C. Salomon,et al.  Pharmacophore and structure-activity relationships of integrase inhibition within a dual inhibitor scaffold of HIV reverse transcriptase and integrase. , 2010, Bioorganic & medicinal chemistry.

[21]  Jian Ding,et al.  Discovery of novel 2,4-diarylaminopyrimidine analogues (DAAPalogues) showing potent inhibitory activities against both wild-type and mutant ALK kinases. , 2015, Journal of medicinal chemistry.

[22]  Adam Nelson,et al.  Embarking on a Chemical Space Odyssey. , 2017, Journal of medicinal chemistry.

[23]  Ching-Chow Chen,et al.  Design and synthesis of dual-action inhibitors targeting histone deacetylases and 3-hydroxy-3-methylglutaryl coenzyme A reductase for cancer treatment. , 2013, Journal of medicinal chemistry.

[24]  P. Acharya,et al.  Interfacial cavity filling to optimize CD4-mimetic miniprotein interactions with HIV-1 surface glycoprotein. , 2013, Journal of medicinal chemistry.

[25]  B. Gryder,et al.  Selectively targeting prostate cancer with antiandrogen equipped histone deacetylase inhibitors. , 2013, ACS chemical biology.

[26]  P. Zhan,et al.  Update on Recent Developments in Small Molecular HIV-1 RNase H Inhibitors (2013-2016): Opportunities and Challenges. , 2018, Current medicinal chemistry.

[27]  Peng Zhan,et al.  Heterocycle-thioacetic acid motif: a privileged molecular scaffold with potent, broad-ranging pharmacological activities. , 2013, Current pharmaceutical design.

[28]  Zhenquan Hu,et al.  Discovery of 1-(4-(4-Amino-3-(4-(2-morpholinoethoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)phenyl)-3-(5-(tert-butyl)isoxazol-3-yl)urea (CHMFL-FLT3-213) as a Highly Potent Type II FLT3 Kinase Inhibitor Capable of Overcoming a Variety of FLT3 Kinase Mutants in FLT3-ITD Positive AML. , 2017, Journal of medicinal chemistry.

[29]  Søren L Pedersen,et al.  Peptide Half-Life Extension: Divalent, Small-Molecule Albumin Interactions Direct the Systemic Properties of Glucagon-Like Peptide 1 (GLP-1) Analogues. , 2017, Journal of medicinal chemistry.

[30]  J. Roche,et al.  Synthesis and biological evaluation of glucuronide prodrugs of the histone deacetylase inhibitor CI-994 for application in selective cancer chemotherapy. , 2008, Bioorganic & medicinal chemistry.

[31]  W. Hol,et al.  Characterization and crystal structure of a high-affinity pentavalent receptor-binding inhibitor for cholera toxin and E. coli heat-labile enterotoxin. , 2002, Journal of the American Chemical Society.

[32]  Mark E Flanagan,et al.  Discovery and development of Janus kinase (JAK) inhibitors for inflammatory diseases. , 2014, Journal of medicinal chemistry.

[33]  L. Lazzarato,et al.  Synthesis and Biological Evaluation of the First Example of NO-Donor Histone Deacetylase Inhibitor. , 2013, ACS medicinal chemistry letters.

[34]  M. Coumar,et al.  Structural Biology Insight for the Design of Sub-type Selective Aurora Kinase Inhibitors. , 2015, Current cancer drug targets.

[35]  E. De Clercq,et al.  Discovery of Thiophene[3,2-d]pyrimidine Derivatives as Potent HIV-1 NNRTIs Targeting the Tolerant Region I of NNIBP. , 2017, ACS medicinal chemistry letters.

[36]  Q. You,et al.  Design, synthesis, and initial evaluation of affinity-based small molecular probe for detection of WDR5. , 2018, Bioorganic chemistry.

[37]  K. Berka,et al.  Discovery of N2-(4-Amino-cyclohexyl)-9-cyclopentyl- N6-(4-morpholin-4-ylmethyl-phenyl)- 9H-purine-2,6-diamine as a Potent FLT3 Kinase Inhibitor for Acute Myeloid Leukemia with FLT3 Mutations. , 2018, Journal of medicinal chemistry.

[38]  Jian Zhang,et al.  Efficient drug discovery by rational lead hybridization based on crystallographic overlay. , 2019, Drug discovery today.

[39]  M. Lehner,et al.  Biphenyl Pyridazinone Derivatives as Inhaled PDE4 Inhibitors: Structural Biology and Structure-Activity Relationships. , 2016, Journal of medicinal chemistry.

[40]  J. Majoral,et al.  Present drug-likeness filters in medicinal chemistry during the hit and lead optimization process: how far can they be simplified? , 2018, Drug discovery today.

[41]  C. Verlinde,et al.  Protein heterodimerization through ligand-bridged multivalent pre-organization: enhancing ligand binding toward both protein targets. , 2005, Journal of the American Chemical Society.

[42]  F. Cao,et al.  Discovery of a Highly Potent, Cell-Permeable Macrocyclic Peptidomimetic (MM-589) Targeting the WD Repeat Domain 5 Protein (WDR5)-Mixed Lineage Leukemia (MLL) Protein-Protein Interaction. , 2017, Journal of medicinal chemistry.

[43]  M. Geng,et al.  Design, synthesis and pharmacological evaluation of ALK and Hsp90 dual inhibitors bearing resorcinol and 2,4-diaminopyrimidine motifs. , 2018, European journal of medicinal chemistry.

[44]  W. L. Jorgensen,et al.  A remote arene-binding site on prostate specific membrane antigen revealed by antibody-recruiting small molecules. , 2010, Journal of the American Chemical Society.

[45]  Andrew D. Huber,et al.  Double-Winged 3-Hydroxypyrimidine-2,4-diones: Potent and Selective Inhibition against HIV-1 RNase H with Significant Antiviral Activity. , 2017, Journal of medicinal chemistry.

[46]  C. Verlinde,et al.  Nonspanning bivalent ligands as improved surface receptor binding inhibitors of the cholera toxin B pentamer. , 2004, Chemistry & biology.

[47]  Dima Kozakov,et al.  How Proteins Bind Macrocycles , 2014, Nature chemical biology.

[48]  V. Brabec,et al.  A Photoactivatable Platinum(IV) Complex Targeting Genomic DNA and Histone Deacetylases. , 2015, Angewandte Chemie.

[49]  Alexander S. Bayden,et al.  The Roles of Water in the Protein Matrix: A Largely Untapped Resource for Drug Discovery. , 2017, Journal of medicinal chemistry.

[50]  ビー・ナラシムフル・ナイドゥ,et al.  Inhibitors of human immunodeficiency virus replication , 2014 .

[51]  Matthew P Jacobson,et al.  Probing the Physicochemical Boundaries of Cell Permeability and Oral Bioavailability in Lipophilic Macrocycles Inspired by Natural Products. , 2015, Journal of medicinal chemistry.

[52]  M. E. Alvarez-Sánchez,et al.  Polyamine Transport and Synthesis in Trichomonas vaginalis: Potential Therapeutic Targets. , 2017, Current pharmaceutical design.

[53]  S. Catinella,et al.  Discovery and Optimization of Thiazolidinyl and Pyrrolidinyl Derivatives as Inhaled PDE4 Inhibitors for Respiratory Diseases. , 2017, Journal of medicinal chemistry.

[54]  Christopher G. Parker,et al.  Antibody-recruiting molecules: an emerging paradigm for engaging immune function in treating human disease. , 2012, ACS chemical biology.

[55]  Yuquan Wei,et al.  Discovery of Novel Dual Histone Deacetylase and Mammalian Target of Rapamycin Target Inhibitors as a Promising Strategy for Cancer Therapy. , 2019, Journal of Medicinal Chemistry.

[56]  W. L. Jorgensen,et al.  Energetics of displacing water molecules from protein binding sites: consequences for ligand optimization. , 2009, Journal of the American Chemical Society.

[57]  Asier Unciti-Broceta,et al.  AXL Inhibitors in Cancer: A Medicinal Chemistry Perspective. , 2015, Journal of medicinal chemistry.

[58]  Peng Zhan,et al.  Structure-Based Optimization of Thiophene[3,2-d]pyrimidine Derivatives as Potent HIV-1 Non-nucleoside Reverse Transcriptase Inhibitors with Improved Potency against Resistance-Associated Variants. , 2017, Journal of medicinal chemistry.

[59]  J. Duan,et al.  Thiotetrazole alkynylacetanilides as potent and bioavailable non-nucleoside inhibitors of the HIV-1 wild type and K103N/Y181C double mutant reverse transcriptases. , 2007, Bioorganic & medicinal chemistry letters.

[60]  Markus K. Dahlgren,et al.  Illuminating HIV gp120-Ligand Recognition through Computationally-Driven Optimization of Antibody-Recruiting Molecules. , 2014, Chemical science.

[61]  D. Tourwé,et al.  Side Chain Cyclized Aromatic Amino Acids: Great Tools as Local Constraints in Peptide and Peptidomimetic Design. , 2016, Journal of medicinal chemistry.

[62]  Y. Li,et al.  Discovery of Novel Indoleamine 2,3-Dioxygenase 1 (IDO1) and Histone Deacetylase (HDAC) Dual Inhibitors. , 2018, ACS medicinal chemistry letters.

[63]  Yung Chang Hsu,et al.  3D‐QSAR‐Assisted Drug Design: Identification of a Potent Quinazoline‐Based Aurora Kinase Inhibitor , 2013, ChemMedChem.

[64]  J. Duan,et al.  Novel 8-substituted dipyridodiazepinone inhibitors with a broad-spectrum of activity against HIV-1 strains resistant to non-nucleoside reverse transcriptase inhibitors. , 2005, Journal of Medicinal Chemistry.

[65]  B. Villoutreix,et al.  Analysis of solvent-exposed and buried co-crystallized ligands: a case study to support the design of novel protein-protein interaction inhibitors. , 2019, Drug discovery today.

[66]  G. Whitesides,et al.  Water networks contribute to enthalpy/entropy compensation in protein-ligand binding. , 2013, Journal of the American Chemical Society.

[67]  P. Zhan,et al.  The development of HEPT-type HIV non-nucleoside reverse transcriptase inhibitors and its implications for DABO family. , 2012, Current pharmaceutical design.

[68]  Murugaiah A. M. Subbaiah,et al.  Design strategies in the prodrugs of HIV-1 protease inhibitors to improve the pharmaceutical properties. , 2017, European journal of medicinal chemistry.

[69]  Yuan Luo,et al.  Design, Synthesis, and Biological Evaluation of Substituted Pyrimidines as Potential Phosphatidylinositol 3-Kinase (PI3K) Inhibitors. , 2016, Journal of medicinal chemistry.

[70]  X Liu,et al.  Rationally designed multitarget anti-HIV agents. , 2013, Current medicinal chemistry.

[71]  Anthony D. Keefe,et al.  DNA-encoded chemistry: enabling the deeper sampling of chemical space , 2016, Nature Reviews Drug Discovery.

[72]  G. Gao,et al.  Structure-Based Tetravalent Zanamivir with Potent Inhibitory Activity against Drug-Resistant Influenza Viruses. , 2016, Journal of medicinal chemistry.

[73]  J. Ovádi,et al.  Chemically Induced Degradation of Sirtuin 2 (Sirt2) by a Proteolysis Targeting Chimera (PROTAC) Based on Sirtuin Rearranging Ligands (SirReals). , 2017, Journal of medicinal chemistry.

[74]  Peng Zhan,et al.  Design, Synthesis, and Evaluation of Thiophene[3,2-d]pyrimidine Derivatives as HIV-1 Non-nucleoside Reverse Transcriptase Inhibitors with Significantly Improved Drug Resistance Profiles. , 2016, Journal of medicinal chemistry.

[75]  L. Boone,et al.  Antiviral Activity of GW678248, a Novel Benzophenone Nonnucleoside Reverse Transcriptase Inhibitor , 2005, Antimicrobial Agents and Chemotherapy.

[76]  Guoqiang Dong,et al.  Discovery of Janus Kinase 2 (JAK2) and Histone Deacetylase (HDAC) Dual Inhibitors as a Novel Strategy for the Combinational Treatment of Leukemia and Invasive Fungal Infections. , 2018, Journal of medicinal chemistry.

[77]  Klaus R. Liedl,et al.  Enthalpic and Entropic Contributions to Hydrophobicity , 2016, Journal of chemical theory and computation.

[78]  O. Abián,et al.  A look at ligand binding thermodynamics in drug discovery , 2017, Expert opinion on drug discovery.

[79]  M. Cummings,et al.  Structure-based macrocyclization yields hepatitis C virus NS5B inhibitors with improved binding affinities and pharmacokinetic properties. , 2012, Angewandte Chemie.

[80]  O. Rabal,et al.  Design, Synthesis, and Biological Evaluation of First-in-Class Dual Acting Histone Deacetylases (HDACs) and Phosphodiesterase 5 (PDE5) Inhibitors for the Treatment of Alzheimer's Disease. , 2016, Journal of medicinal chemistry.

[81]  X. Zhai,et al.  Discovery of novel 2,4-diarylaminopyrimidine analogues as ALK and ROS1 dual inhibitors to overcome crizotinib-resistant mutants including G1202R. , 2018, European journal of medicinal chemistry.

[82]  Felice C. Lightstone,et al.  Accounting for water molecules in drug design , 2011, Expert opinion on drug discovery.

[83]  M. Geng,et al.  Discovery of 2,4-diarylaminopyrimidines bearing a resorcinol motif as novel ALK inhibitors to overcome the G1202R resistant mutation. , 2018, European journal of medicinal chemistry.

[84]  M. Sturlese,et al.  AquaMMapS: An Alternative Tool to Monitor the Role of Water Molecules During Protein–Ligand Association , 2018, ChemMedChem.

[85]  Lyn H Jones,et al.  Cell permeable affinity- and activity-based probes. , 2015, Future medicinal chemistry.

[86]  William L Jorgensen,et al.  Extension into the entrance channel of HIV-1 reverse transcriptase--crystallography and enhanced solubility. , 2013, Bioorganic & medicinal chemistry letters.

[87]  D. Stefanidis,et al.  Orally bioavailable prodrugs of a BCS class 2 molecule, an inhibitor of HIV-1 reverse transcriptase. , 2008, Bioorganic & medicinal chemistry letters.

[88]  Ludger A. Wessjohann,et al.  What can a chemist learn from nature’s macrocycles? – A brief, conceptual view , 2005, Molecular Diversity.

[89]  David M. Wilson,et al.  Fragment-based discovery of bromodomain inhibitors part 2: optimization of phenylisoxazole sulfonamides. , 2012, Journal of medicinal chemistry.

[90]  Yun Song,et al.  Targeting the CoREST complex with dual histone deacetylase and demethylase inhibitors , 2018, Nature Communications.

[91]  Q. You,et al.  Design, Synthesis, and Initial Evaluation of Affinity-Based Small-Molecule Probes for Fluorescent Visualization and Specific Detection of Keap1. , 2016, Journal of medicinal chemistry.

[92]  E. Olejniczak,et al.  Optimization of Potent and Selective Tricyclic Indole Diazepinone Myeloid Cell Leukemia-1 Inhibitors Using Structure-Based Design. , 2018, Journal of medicinal chemistry.

[93]  Petra Schneider,et al.  De Novo Design at the Edge of Chaos. , 2016, Journal of medicinal chemistry.

[94]  S. Hymowitz,et al.  Potent and selective Bruton's tyrosine kinase inhibitors: discovery of GDC-0834. , 2015, Bioorganic & medicinal chemistry letters.

[95]  Peter D. Kwong,et al.  Structure-Based Design, Synthesis and Validation of CD4-Mimetic Small Molecule Inhibitors of HIV-1 Entry: Conversion of a Viral Entry Agonist to an Antagonist , 2014, Accounts of chemical research.

[96]  A. Oyelere,et al.  Dual targeting of histone deacetylase and topoisomerase II with novel bifunctional inhibitors. , 2012, Journal of medicinal chemistry.

[97]  Soon-Sun Hong,et al.  Identification of 4-Phenoxyquinoline Based Inhibitors for L1196M Mutant of Anaplastic Lymphoma Kinase by Structure-Based Design. , 2017, Journal of medicinal chemistry.

[98]  G. Klebe,et al.  Paying the Price of Desolvation in Solvent-Exposed Protein Pockets: Impact of Distal Solubilizing Groups on Affinity and Binding Thermodynamics in a Series of Thermolysin Inhibitors. , 2017, Journal of medicinal chemistry.

[99]  Jing Wang,et al.  The Advantages of Targeted Protein Degradation Over Inhibition: An RTK Case Study. , 2017, Cell chemical biology.

[100]  S. Sasaki,et al.  Structure-Based Design and Synthesis of 3-Amino-1,5-dihydro-4H-pyrazolopyridin-4-one Derivatives as Tyrosine Kinase 2 Inhibitors. , 2016, Journal of medicinal chemistry.

[101]  Lihong Hu,et al.  Design, synthesis and biological evaluation of indolin-2-one-based derivatives as potent, selective and efficacious inhibitors of FMS-like tyrosine kinase3 (FLT3). , 2017, European journal of medicinal chemistry.

[102]  Peng Zhan,et al.  HIV‐1 NNRTIs: structural diversity, pharmacophore similarity, and impliations for drug design , 2013, Medicinal research reviews.

[103]  M. Naito,et al.  Development of Protein Degradation Inducers of Androgen Receptor by Conjugation of Androgen Receptor Ligands and Inhibitor of Apoptosis Protein Ligands. , 2017, Journal of medicinal chemistry.

[104]  Jonathan Hall,et al.  Tankyrase 1 Inhibitors with Drug-like Properties Identified by Screening a DNA-Encoded Chemical Library. , 2015, Journal of medicinal chemistry.

[105]  T. Engber,et al.  Novel diamino derivatives of [1,2,4]triazolo[1,5-a][1,3,5]triazine as potent and selective adenosine A2a receptor antagonists. , 2004, Journal of medicinal chemistry.

[106]  Peng Zhan,et al.  Recent advances in the discovery and development of novel HIV-1 NNRTI platforms (Part II): 2009-2013 update. , 2013, Current medicinal chemistry.

[107]  C. Verlinde,et al.  Solution and crystallographic studies of branched multivalent ligands that inhibit the receptor-binding of cholera toxin. , 2002, Journal of the American Chemical Society.

[108]  R. Baron,et al.  Water in Cavity−Ligand Recognition , 2010, Journal of the American Chemical Society.

[109]  Yuta Tanaka,et al.  Discovery of potent Mcl-1/Bcl-xL dual inhibitors by using a hybridization strategy based on structural analysis of target proteins. , 2013, Journal of medicinal chemistry.

[110]  P. Zhan,et al.  Privileged scaffolds or promiscuous binders: a glance of pyrrolo[2,1-f][1,2,4]triazines and related bridgehead nitrogen heterocycles in medicinal chemistry. , 2013, Current pharmaceutical design.

[111]  L. Tari Accounting for solvent in structure-based drug design. , 2012, Methods in molecular biology.

[112]  Peng Zhan,et al.  Novel HIV-1 non-nucleoside reverse transcriptase inhibitors: a patent review (2011 – 2014) , 2014, Expert opinion on therapeutic patents.

[113]  Shuai Lu,et al.  Discovery of 4-((7H-Pyrrolo[2,3-d]pyrimidin-4-yl)amino)-N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrazole-3-carboxamide (FN-1501), an FLT3- and CDK-Kinase Inhibitor with Potentially High Efficiency against Acute Myelocytic Leukemia. , 2018, Journal of medicinal chemistry.

[114]  I. Chaiken,et al.  Peptide Triazole Inactivators of HIV-1 Utilize a Conserved Two-Cavity Binding Site at the Junction of the Inner and Outer Domains of Env gp120. , 2015, Journal of medicinal chemistry.

[115]  Afaf R. Genady,et al.  Preparation and Evaluation of Radiolabeled Antibody Recruiting Small Molecules That Target Prostate-Specific Membrane Antigen for Combined Radiotherapy and Immunotherapy. , 2016, Journal of medicinal chemistry.

[116]  Zhaohui S. Qin,et al.  Targeting MLL1 H3K4 methyltransferase activity in mixed-lineage leukemia. , 2014, Molecular cell.

[117]  P. Workman,et al.  Demonstrating In-Cell Target Engagement Using a Pirin Protein Degradation Probe (CCT367766) , 2017, Journal of medicinal chemistry.

[118]  J. Yen,et al.  Design and Synthesis of Janus Kinase 2 (JAK2) and Histone Deacetlyase (HDAC) Bispecific Inhibitors Based on Pacritinib and Evidence of Dual Pathway Inhibition in Hematological Cell Lines. , 2016, Journal of medicinal chemistry.

[119]  I. Gelman,et al.  Discovery of Novel Dual Mechanism of Action Src Signaling and Tubulin Polymerization Inhibitors (KX2-391 and KX2-361). , 2018, Journal of medicinal chemistry.

[120]  R. Marek,et al.  Water-Tryptophan Interactions: Lone-pair⋅⋅⋅π or O-H⋅⋅⋅π? Molecular Dynamics Simulations of β-Galactosidase Suggest that Both Modes Can Co-exist. , 2018, Chemistry.

[121]  Chi‐Huey Wong,et al.  Synergistic effect of zanamivir-porphyrin conjugates on inhibition of neuraminidase and inactivation of influenza virus. , 2009, Journal of medicinal chemistry.

[122]  Christopher M. Bailey,et al.  Bifunctional inhibition of human immunodeficiency virus type 1 reverse transcriptase: mechanism and proof-of-concept as a novel therapeutic design strategy. , 2013, Journal of medicinal chemistry.

[123]  G. Bottegoni,et al.  Polo-like kinases inhibitors. , 2012, Current medicinal chemistry.

[124]  N. Sach,et al.  Design of potent and selective inhibitors to overcome clinical anaplastic lymphoma kinase mutations resistant to crizotinib. , 2014, Journal of medicinal chemistry.

[125]  C. Heinis,et al.  Drug discovery: tools and rules for macrocycles. , 2014, Nature chemical biology.

[126]  J. Konvalinka,et al.  Design of HIV protease inhibitors based on inorganic polyhedral metallacarboranes. , 2009, Journal of medicinal chemistry.

[127]  D. Williams,et al.  Recent kinase and kinase inhibitor X-ray structures: mechanisms of inhibition and selectivity insights. , 2004, Current medicinal chemistry.

[128]  H. Dyson,et al.  Slow Dynamics of Tryptophan-Water Networks in Proteins. , 2018, Journal of the American Chemical Society.

[129]  C. Stephan,et al.  Protease inhibitor therapy for hepatitis C virus-infection , 2018, Expert opinion on pharmacotherapy.

[130]  Philipp M Cromm,et al.  Targeted Protein Degradation: from Chemical Biology to Drug Discovery. , 2017, Cell chemical biology.

[131]  I. Wilson,et al.  Structure-based optimization and synthesis of antiviral drug Arbidol analogues with significantly improved affinity to influenza hemagglutinin. , 2017, Bioorganic & medicinal chemistry letters.

[132]  M. Yoshikawa,et al.  Discovery of 7-Oxo-2,4,5,7-tetrahydro-6 H-pyrazolo[3,4- c]pyridine Derivatives as Potent, Orally Available, and Brain-Penetrating Receptor Interacting Protein 1 (RIP1) Kinase Inhibitors: Analysis of Structure-Kinetic Relationships. , 2018, Journal of medicinal chemistry.

[133]  T. Engber,et al.  Piperazine derivatives of [1,2,4]triazolo[1,5-a][1,3,5]triazine as potent and selective adenosine A2a receptor antagonists. , 2004, Journal of medicinal chemistry.

[134]  Magid Abou-Gharbia,et al.  Discovery of innovative therapeutics: today's realities and tomorrow's vision. 1. Criticisms faced by the pharmaceutical industry. , 2013, Journal of medicinal chemistry.

[135]  Greg M. Thurber,et al.  Structure-Guided Design and Initial Studies of a Bifunctional MEK/PI3K Inhibitor (ST-168). , 2017, ACS medicinal chemistry letters.

[136]  C. Cywin,et al.  Novel nonnucleoside inhibitors of HIV-1 reverse transcriptase. 8. 8-Aryloxymethyl- and 8-arylthiomethyldipyridodiazepinones. , 1998, Journal of medicinal chemistry.

[137]  Peng Zhan,et al.  Conformational restriction: an effective tactic in 'follow-on'-based drug discovery. , 2014, Future medicinal chemistry.

[138]  H. Lindmark,et al.  Design and Synthesis of Soluble and Cell-Permeable PI3Kδ Inhibitors for Long-Acting Inhaled Administration. , 2017, Journal of medicinal chemistry.

[139]  J. Sodroski,et al.  Small-Molecule CD4-Mimics: Structure-Based Optimization of HIV-1 Entry Inhibition. , 2016, ACS medicinal chemistry letters.

[140]  A. Ciulli,et al.  Molecular recognition of ternary complexes: a new dimension in the structure-guided design of chemical degraders , 2017, Essays in biochemistry.

[141]  B. Admire,et al.  Fragment-Based Discovery of a Dual pan-RET/VEGFR2 Kinase Inhibitor Optimized for Single-Agent Polypharmacology. , 2015, Angewandte Chemie.

[142]  Lei Wang,et al.  Novel Tetrahydropyrido[4,3-d]pyrimidines as Potent Inhibitors of Chaperone Heat Shock Protein 90. , 2016, Journal of medicinal chemistry.

[143]  C. Salomon,et al.  Rationally designed dual inhibitors of HIV reverse transcriptase and integrase. , 2007, Journal of medicinal chemistry.

[144]  Hongyu Zhao,et al.  Medicinal chemistry strategies in follow-on drug discovery. , 2009, Drug discovery today.

[145]  Gregory P Tochtrop,et al.  Target identification strategies in chemical genetics. , 2004, Combinatorial chemistry & high throughput screening.

[146]  Jun Wu,et al.  Novel Bioactive Hybrid Compound Dual Targeting Estrogen Receptor and Histone Deacetylase for the Treatment of Breast Cancer. , 2015, Journal of medicinal chemistry.

[147]  M. Glick,et al.  Design, Synthesis, and Properties of a Potent Inhibitor of Pseudomonas aeruginosa Deacetylase LpxC. , 2017, Journal of medicinal chemistry.

[148]  L. May,et al.  Synthesis and pharmacological evaluation of dual acting ligands targeting the adenosine A2A and dopamine D2 receptors for the potential treatment of Parkinson's disease. , 2015, Journal of medicinal chemistry.

[149]  Robert A. Domaoal,et al.  An antibody-recruiting small molecule that targets HIV gp120. , 2009, Journal of the American Chemical Society.

[150]  William L Jorgensen,et al.  A mechanistic and structural investigation of modified derivatives of the diaryltriazine class of NNRTIs targeting HIV-1 reverse transcriptase. , 2014, Biochimica et biophysica acta.

[151]  Christophe Meyer,et al.  Crystal structures for HIV-1 reverse transcriptase in complexes with three pyridinone derivatives: a new class of non-nucleoside inhibitors effective against a broad range of drug-resistant strains. , 2005, Journal of medicinal chemistry.

[152]  Wei Chen,et al.  Discovery of Novel Multiacting Topoisomerase I/II and Histone Deacetylase Inhibitors. , 2015, ACS medicinal chemistry letters.

[153]  M. Recanatini,et al.  Novel antiproliferative chimeric compounds with marked histone deacetylase inhibitory activity. , 2014, ACS medicinal chemistry letters.

[154]  Chen Jiang,et al.  Biomacromolecules as carriers in drug delivery and tissue engineering , 2017, Acta pharmaceutica Sinica. B.

[155]  J. Bischoff,et al.  Generation of tricyclic imidazo[1,2-a]pyrazines as novel PI3K inhibitors by application of a conformational restriction strategy. , 2017, Bioorganic & medicinal chemistry letters.

[156]  J. Duan,et al.  Novel nevirapine-like inhibitors with improved activity against NNRTI-resistant HIV: 8-heteroarylthiomethyldipyridodiazepinone derivatives. , 2004, Bioorganic & medicinal chemistry letters.

[157]  Z. Leśnikowski Challenges and Opportunities for the Application of Boron Clusters in Drug Design. , 2016, Journal of medicinal chemistry.

[158]  A. Rak,et al.  Discovery and Pharmacokinetic and Pharmacological Properties of the Potent and Selective MET Kinase Inhibitor 1-{6-[6-(4-Fluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl]benzothiazol-2-yl}-3-(2-morpholin-4-ylethyl)urea (SAR125844). , 2016, Journal of medicinal chemistry.

[159]  J. Cheung,et al.  Structure-Based Design, Synthesis, and Biological Evaluation of Highly Selective and Potent G Protein-Coupled Receptor Kinase 2 Inhibitors. , 2016, Journal of medicinal chemistry.

[160]  Jian Ding,et al.  Design and optimization of a series of 1-sulfonylpyrazolo[4,3-b]pyridines as selective c-Met inhibitors. , 2015, Journal of medicinal chemistry.

[161]  Pietro Cozzini,et al.  Simple, intuitive calculations of free energy of binding for protein-ligand complexes. 3. The free energy contribution of structural water molecules in HIV-1 protease complexes. , 2004, Journal of medicinal chemistry.

[162]  C. Luo,et al.  Discovery of 3-(5'-Substituted)-Benzimidazole-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazoles as Potent Fibroblast Growth Factor Receptor Inhibitors: Design, Synthesis, and Biological Evaluation. , 2016, Journal of medicinal chemistry.

[163]  M. Lehner,et al.  4-Amino-7,8-dihydro-1,6-naphthyridin-5(6 H)-ones as Inhaled Phosphodiesterase Type 4 (PDE4) Inhibitors: Structural Biology and Structure-Activity Relationships. , 2018, Journal of medicinal chemistry.

[164]  Peng Zhan,et al.  Novel HIV-1 non-nucleoside reverse transcriptase inhibitors: a patent review (2005 – 2010) , 2011, Expert opinion on therapeutic patents.

[165]  W. Childers,et al.  Discovery of innovative therapeutics: today's realities and tomorrow's vision. 2. Pharma's challenges and their commitment to innovation. , 2014, Journal of medicinal chemistry.

[166]  Peng Zhan,et al.  Identification of Dihydrofuro[3,4- d]pyrimidine Derivatives as Novel HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors with Promising Antiviral Activities and Desirable Physicochemical Properties. , 2019, Journal of medicinal chemistry.

[167]  J. Yen,et al.  Design and Synthesis of Ligand Efficient Dual Inhibitors of Janus Kinase (JAK) and Histone Deacetylase (HDAC) Based on Ruxolitinib and Vorinostat. , 2017, Journal of medicinal chemistry.

[168]  A. Ciulli,et al.  Impact of Target Warhead and Linkage Vector on Inducing Protein Degradation: Comparison of Bromodomain and Extra-Terminal (BET) Degraders Derived from Triazolodiazepine (JQ1) and Tetrahydroquinoline (I-BET726) BET Inhibitor Scaffolds , 2017, Journal of medicinal chemistry.

[169]  F. Totzke,et al.  Optimization of potent DFG-in inhibitors of platelet derived growth factor receptorβ (PDGF-Rβ) guided by water thermodynamics. , 2015, Journal of medicinal chemistry.

[170]  C. Crews Inducing Protein Degradation as a Therapeutic Strategy. , 2018, Journal of medicinal chemistry.

[171]  Peng Zhan,et al.  "Old friends in new guise": exploiting privileged structures for scaffold re-evolution/refining. , 2014, Combinatorial chemistry & high throughput screening.

[172]  J. McCarter,et al.  A "Click Chemistry Platform" for the Rapid Synthesis of Bispecific Molecules for Inducing Protein Degradation. , 2017, Journal of medicinal chemistry.

[173]  Guoqiang Dong,et al.  Dual NAMPT/HDAC Inhibitors as a New Strategy for Multitargeting Antitumor Drug Discovery. , 2018, ACS medicinal chemistry letters.

[174]  R. Morphy,et al.  Designed multiple ligands. An emerging drug discovery paradigm. , 2005, Journal of medicinal chemistry.

[175]  S. Bazzi,et al.  Lone-pair-π interactions: analysis of the physical origin and biological implications. , 2016, Physical chemistry chemical physics : PCCP.

[176]  Heejun Kim,et al.  Privileged structures: efficient chemical "navigators" toward unexplored biologically relevant chemical spaces. , 2014, Journal of the American Chemical Society.

[177]  R. Franzini,et al.  Chemical Space of DNA-Encoded Libraries. , 2016, Journal of medicinal chemistry.

[178]  K. Dill,et al.  Water Is a Cagey Liquid. , 2018, Journal of the American Chemical Society.

[179]  Xianfeng Lin,et al.  Discovery of piperidin-4-yl-aminopyrimidines as HIV-1 reverse transcriptase inhibitors. N-benzyl derivatives with broad potency against resistant mutant viruses. , 2010, Bioorganic & medicinal chemistry letters.

[180]  I. Chaiken,et al.  Macrocyclic Envelope Glycoprotein Antagonists that Irreversibly Inactivate HIV-1 before Host Cell Encounter. , 2015, Journal of medicinal chemistry.

[181]  Zhengqiang Wang,et al.  Synthesis of pyrimidine and quinolone conjugates as a scaffold for dual inhibitors of HIV reverse transcriptase and integrase. , 2008, Bioorganic & medicinal chemistry letters.

[182]  S. Steinbacher,et al.  Discovery of Peptidomimetic Antibody-Drug Conjugate Linkers with Enhanced Protease Specificity. , 2017, Journal of medicinal chemistry.

[183]  Hao-Ze Huang,et al.  Identification and optimization of novel Hsp90 inhibitors with tetrahydropyrido[4,3-d]pyrimidines core through shape-based screening. , 2014, European journal of medicinal chemistry.

[184]  R. Kane,et al.  Polyvalency: a promising strategy for drug design. , 2008, Biotechnology and bioengineering.

[185]  J. Baell,et al.  Design, Synthesis, and Characterization of Cyclic Peptidomimetics of the Inducible Nitric Oxide Synthase Binding Epitope That Disrupt the Protein-Protein Interaction Involving SPRY Domain-Containing Suppressor of Cytokine Signaling Box Protein (SPSB) 2 and Inducible Nitric Oxide Synthase. , 2016, Journal of medicinal chemistry.

[186]  M. Desai,et al.  Synthesis and biological evaluation of phosphonate analogues of nevirapine. , 2013, Bioorganic & medicinal chemistry letters.

[187]  Synthesis and SAR of novel imidazoquinoxaline-based Lck inhibitors: improvement of cell potency. , 2002, Bioorganic & medicinal chemistry letters.

[188]  Nathan Robertson,et al.  Biophysical Mapping of the Adenosine A2A Receptor , 2011, Journal of medicinal chemistry.

[189]  T. Poulos,et al.  Structure-based design and synthesis of N(omega)-nitro-L-arginine-containing peptidomimetics as selective inhibitors of neuronal nitric oxide synthase. Displacement of the heme structural water. , 2007, Journal of medicinal chemistry.

[190]  Zhengqiang Wang,et al.  Design and synthesis of dual inhibitors of HIV reverse transcriptase and integrase: introducing a diketoacid functionality into delavirdine. , 2008, Bioorganic & medicinal chemistry.

[191]  F. Conquet,et al.  Discovery, Structure-Activity Relationship, and Antiparkinsonian Effect of a Potent and Brain-Penetrant Chemical Series of Positive Allosteric Modulators of Metabotropic Glutamate Receptor 4. , 2017, Journal of medicinal chemistry.

[192]  C. Crews,et al.  Lessons in PROTAC Design from Selective Degradation with a Promiscuous Warhead. , 2017, Cell chemical biology.

[193]  K. Scearce-Levie,et al.  Discovery of highly potent, selective, and brain-penetrant aminopyrazole leucine-rich repeat kinase 2 (LRRK2) small molecule inhibitors. , 2014, Journal of medicinal chemistry.