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1.
Nat Protoc ; 16(10): 4799-4832, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34561691

RESUMO

Structure-based docking screens of large compound libraries have become common in early drug and probe discovery. As computer efficiency has improved and compound libraries have grown, the ability to screen hundreds of millions, and even billions, of compounds has become feasible for modest-sized computer clusters. This allows the rapid and cost-effective exploration and categorization of vast chemical space into a subset enriched with potential hits for a given target. To accomplish this goal at speed, approximations are used that result in undersampling of possible configurations and inaccurate predictions of absolute binding energies. Accordingly, it is important to establish controls, as are common in other fields, to enhance the likelihood of success in spite of these challenges. Here we outline best practices and control docking calculations that help evaluate docking parameters for a given target prior to undertaking a large-scale prospective screen, with exemplification in one particular target, the melatonin receptor, where following this procedure led to direct docking hits with activities in the subnanomolar range. Additional controls are suggested to ensure specific activity for experimentally validated hit compounds. These guidelines should be useful regardless of the docking software used. Docking software described in the outlined protocol (DOCK3.7) is made freely available for academic research to explore new hits for a range of targets.

2.
Science ; 373(6554): 541-547, 2021 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-34326236

RESUMO

Repurposing drugs as treatments for COVID-19, the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has drawn much attention. Beginning with sigma receptor ligands and expanding to other drugs from screening in the field, we became concerned that phospholipidosis was a shared mechanism underlying the antiviral activity of many repurposed drugs. For all of the 23 cationic amphiphilic drugs we tested, including hydroxychloroquine, azithromycin, amiodarone, and four others already in clinical trials, phospholipidosis was monotonically correlated with antiviral efficacy. Conversely, drugs active against the same targets that did not induce phospholipidosis were not antiviral. Phospholipidosis depends on the physicochemical properties of drugs and does not reflect specific target-based activities-rather, it may be considered a toxic confound in early drug discovery. Early detection of phospholipidosis could eliminate these artifacts, enabling a focus on molecules with therapeutic potential.


Assuntos
Antivirais/farmacologia , COVID-19/tratamento farmacológico , Reposicionamento de Medicamentos , Lipidoses/induzido quimicamente , Fosfolipídeos/metabolismo , SARS-CoV-2/efeitos dos fármacos , Células A549 , Animais , Antivirais/química , Antivirais/uso terapêutico , Antivirais/toxicidade , COVID-19/virologia , Cátions , Chlorocebus aethiops , Relação Dose-Resposta a Droga , Feminino , Humanos , Camundongos , Testes de Sensibilidade Microbiana , SARS-CoV-2/fisiologia , Tensoativos/química , Tensoativos/farmacologia , Tensoativos/toxicidade , Células Vero , Replicação Viral/efeitos dos fármacos
3.
J Chem Inf Model ; 61(2): 699-714, 2021 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-33494610

RESUMO

Enrichment of ligands versus property-matched decoys is widely used to test and optimize docking library screens. However, the unconstrained optimization of enrichment alone can mislead, leading to false confidence in prospective performance. This can arise by over-optimizing for enrichment against property-matched decoys, without considering the full spectrum of molecules to be found in a true large library screen. Adding decoys representing charge extrema helps mitigate over-optimizing for electrostatic interactions. Adding decoys that represent the overall characteristics of the library to be docked allows one to sample molecules not represented by ligands and property-matched decoys but that one will encounter in a prospective screen. An optimized version of the DUD-E set (DUDE-Z), as well as Extrema and sets representing broad features of the library (Goldilocks), is developed here. We also explore the variability that one can encounter in enrichment calculations and how that can temper one's confidence in small enrichment differences. The new tools and new decoy sets are freely available at http://tldr.docking.org and http://dudez.docking.org.


Assuntos
Benchmarking , Ligantes , Modelos Moleculares , Estudos Prospectivos , Ligação Proteica
4.
Cell ; 182(6): 1574-1588.e19, 2020 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-32946782

RESUMO

Hallucinogens like lysergic acid diethylamide (LSD), psilocybin, and substituted N-benzyl phenylalkylamines are widely used recreationally with psilocybin being considered as a therapeutic for many neuropsychiatric disorders including depression, anxiety, and substance abuse. How psychedelics mediate their actions-both therapeutic and hallucinogenic-are not understood, although activation of the 5-HT2A serotonin receptor (HTR2A) is key. To gain molecular insights into psychedelic actions, we determined the active-state structure of HTR2A bound to 25-CN-NBOH-a prototypical hallucinogen-in complex with an engineered Gαq heterotrimer by cryoelectron microscopy (cryo-EM). We also obtained the X-ray crystal structures of HTR2A complexed with the arrestin-biased ligand LSD or the inverse agonist methiothepin. Comparisons of these structures reveal determinants responsible for HTR2A-Gαq protein interactions as well as the conformational rearrangements involved in active-state transitions. Given the potential therapeutic actions of hallucinogens, these findings could accelerate the discovery of more selective drugs for the treatment of a variety of neuropsychiatric disorders.


Assuntos
Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/química , Alucinógenos/química , Receptor 5-HT2A de Serotonina/química , Receptor 5-HT2A de Serotonina/metabolismo , Animais , Microscopia Crioeletrônica , Cristalografia por Raios X , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/metabolismo , Expressão Gênica , Células HEK293 , Alucinógenos/farmacologia , Alucinógenos/uso terapêutico , Humanos , Ligantes , Dietilamida do Ácido Lisérgico/química , Dietilamida do Ácido Lisérgico/farmacologia , Metiotepina/química , Metiotepina/metabolismo , Modelos Químicos , Mutação , Conformação Proteica em alfa-Hélice , Receptor 5-HT2A de Serotonina/genética , Proteínas Recombinantes , Serotonina/metabolismo , Spodoptera
5.
Nature ; 566(7743): 224-229, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30728502

RESUMO

Despite intense interest in expanding chemical space, libraries containing hundreds-of-millions to billions of diverse molecules have remained inaccessible. Here we investigate structure-based docking of 170 million make-on-demand compounds from 130 well-characterized reactions. The resulting library is diverse, representing over 10.7 million scaffolds that are otherwise unavailable. For each compound in the library, docking against AmpC ß-lactamase (AmpC) and the D4 dopamine receptor were simulated. From the top-ranking molecules, 44 and 549 compounds were synthesized and tested for interactions with AmpC and the D4 dopamine receptor, respectively. We found a phenolate inhibitor of AmpC, which revealed a group of inhibitors without known precedent. This molecule was optimized to 77 nM, which places it among the most potent non-covalent AmpC inhibitors known. Crystal structures of this and other AmpC inhibitors confirmed the docking predictions. Against the D4 dopamine receptor, hit rates fell almost monotonically with docking score, and a hit-rate versus score curve predicted that the library contained 453,000 ligands for the D4 dopamine receptor. Of 81 new chemotypes discovered, 30 showed submicromolar activity, including a 180-pM subtype-selective agonist of the D4 dopamine receptor.


Assuntos
Agonistas de Dopamina/química , Agonistas de Dopamina/isolamento & purificação , Simulação de Acoplamento Molecular/métodos , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/isolamento & purificação , Inibidores de beta-Lactamases/química , Inibidores de beta-Lactamases/isolamento & purificação , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/química , Cristalografia por Raios X , Humanos , Ligantes , Aprendizado de Máquina , Observação , Receptores de Dopamina D4/agonistas , Receptores de Dopamina D4/química , Receptores de Dopamina D4/metabolismo , beta-Lactamases/química
6.
J Med Chem ; 61(15): 6830-6845, 2018 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-29990431

RESUMO

To investigate large library docking's ability to find molecules with joint activity against on-targets and selectivity versus antitargets, the dopamine D2 and serotonin 5-HT2A receptors were targeted, seeking selectivity against the histamine H1 receptor. In a second campaign, κ-opioid receptor ligands were sought with selectivity versus the µ-opioid receptor. While hit rates ranged from 40% to 63% against the on-targets, they were just as good against the antitargets, even though the molecules were selected for their putative lack of binding to the off-targets. Affinities, too, were often as good or better for the off-targets. Even though it was occasionally possible to find selective molecules, such as a mid-nanomolar D2/5-HT2A ligand with 21-fold selectivity versus the H1 receptor, this was the exception. Whereas false-negatives are tolerable in docking screens against on-targets, they are intolerable against antitargets; addressing this problem may demand new strategies in the field.


Assuntos
Simulação de Acoplamento Molecular , Receptor 5-HT2A de Serotonina/metabolismo , Receptores de Dopamina D2/metabolismo , Avaliação Pré-Clínica de Medicamentos , Ligantes , Conformação Proteica , Receptor 5-HT2A de Serotonina/química , Receptores de Dopamina D2/química , Especificidade por Substrato
7.
J Med Chem ; 61(13): 5609-5622, 2018 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-29906114

RESUMO

First-generation epidermal growth factor receptor (EGFR) inhibitors, gefitinib and erlotinib, have achieved initially marked clinical efficacy for nonsmall cell lung cancer (NSCLC) patients with EGFR activating mutations. However, their clinical benefit was limited by the emergence of acquired resistance mutations. In most cases (approximately 60%), the resistance was caused by the secondary EGFR T790M gatekeeper mutation. Thus, it is still desirable to develop novel third-generation EGFR inhibitors to overcome T790M mutation while sparing wild-type (WT) EGFR. Herein, a series of pyrimido[4,5- d]pyrimidine-2,4(1 H,3 H)-dione derivatives were designed and synthesized, among which the most potent compound 20g not only demonstrated significant inhibitory activity and selectivity for EGFRL858R/T790M and H1975 cells in vitro but also displayed outstanding antitumor efficiency in H1975 xenograft mouse model. The encouraging mutant-selective results at both in vitro and in vivo levels suggested that 20g might be used as a promising lead compound for further structural optimization as potent and selective EGFRL858R/T790M inhibitors.


Assuntos
Desenho de Fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Mutação , Pirimidinas/síntese química , Pirimidinas/farmacologia , Linhagem Celular Tumoral , Técnicas de Química Sintética , Simulação por Computador , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/química , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Simulação de Acoplamento Molecular , Conformação Proteica , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/química , Pirimidinas/metabolismo , Relação Estrutura-Atividade
8.
Sci Rep ; 7(1): 3830, 2017 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-28630494

RESUMO

Epidermal growth factor receptor (EGFR) T790M acquired drug-resistance mutation has become a major clinical challenge for the therapy of non-small cell lung cancer. Here, we applied a structure-guided approach on the basis of the previous reported EGFR inhibitor (compound 9), and designed a series of C4-alkyl-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one derivatives as novel mutant-selective EGFR inhibitors. Finally, the most representative compound 20a was identified, which showed high selectivity at both enzymatic and cellular levels against EGFRL858R/T790M (H1975 cell lines) over EGFRWT (A431 cell lines). The representative compound 20a also showed promising antitumor efficiency in the in vivo antitumor efficacy study of H1975 xenograft mouse model driven by EGFRL858R/T790M. These results provide a new scaffold for the treatment of dual-mutant-driven non-small cell lung cancer.


Assuntos
Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/química , Inibidores de Proteínas Quinases/química , Substituição de Aminoácidos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Carcinoma Pulmonar de Células não Pequenas/genética , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/química , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/genética , Mutação de Sentido Incorreto , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Inibidores de Proteínas Quinases/farmacologia
9.
Oncotarget ; 7(40): 64967-64976, 2016 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-27533458

RESUMO

Blocking the interaction of human programmed death 1 (hPD-1) and its ligand hPD-L1 has been a promising immunotherapy in cancer treatment. In this paper, using a computational de novo peptide design method, we designed several hPD-1 binding peptides. The most potent peptide Ar5Y_4 showed a KD value of 1.38 ± 0.39 µM, comparable to the binding affinity of the cognate hPD-L1. A Surface Plasmon Resonance (SPR) competitive binding assay result indicated that Ar5Y_4 could inhibit the interaction of hPD-1/hPD-L1. Moreover, Ar5Y_4 could restore the function of Jurkat T cells which had been suppressed by stimulated HCT116 cells. Peptides described in this paper provide promising biologic candidates for cancer immunotherapy or diagnostics.


Assuntos
Carcinoma/terapia , Imunoterapia/métodos , Peptídeos/farmacologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Linfócitos T/imunologia , Antígeno B7-H1/metabolismo , Carcinoma/imunologia , Biologia Computacional , Células HCT116 , Humanos , Células Jurkat , Ativação Linfocitária , Terapia de Alvo Molecular , Peptídeos/síntese química , Receptor de Morte Celular Programada 1/metabolismo , Ligação Proteica/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Ressonância de Plasmônio de Superfície , Linfócitos T/efeitos dos fármacos
10.
J Med Chem ; 59(13): 6187-200, 2016 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-27266526

RESUMO

FLT3 has been validated as a therapeutic target for the treatment of acute myeloid leukemia (AML). In this paper, we describe for the first time, pteridin-7(8H)-one as a scaffold for potent FLT3 inhibitors derived from structural optimizations on irreversible EGFR inhibitors. The representative inhibitor (31) demonstrates single-digit nanomolar inhibition against FLT3 and subnanomolar KD for drug-resistance FLT3 mutants. In profiling of the in vitro tumor cell lines, it shows good selectivity against AML cells harboring FLT3-ITD mutations over other leukemia and solid tumor cell lines. The mechanism of action study illustrates that pteridin-7(8H)-one derivatives suppress the phosphorylation of FLT3 and its downstream pathways, thereby inducing G0/G1 cell cycle arrest and apoptosis in AML cells. In in vivo studies, 31 significantly suppresses the tumor growth in MV4-11 xenograft model. Overall, we provide a structurally distinct chemical scaffold with which to develop FLT3 mutants-selective inhibitors for AML treatment.


Assuntos
Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Pteridinas/química , Pteridinas/farmacologia , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Tirosina Quinase 3 Semelhante a fms/genética , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Simulação de Acoplamento Molecular , Mutação , Fosforilação/efeitos dos fármacos , Tirosina Quinase 3 Semelhante a fms/metabolismo
11.
Bioorg Med Chem ; 23(17): 5672-80, 2015 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-26211460

RESUMO

A novel series of naphthalimide-cyclam conjugates were designed and synthesized. Among them, compounds 4c, 4d, 8c and 8d which bearing long lipophilic alkyl chains, displayed comparable or more potent cytotoxic activities against human tumor cell lines than amonafide. Furthermore, the four compounds were proved to possess strong inhibition against both topoisomerase I and II. The representative compound 8c exhibited moderate DNA intercalation activity. Molecular modeling studies identified the possible interaction of compound 8c with the molecular target by forming topoisomerase/DNA/drug ternary complex. Finally, derivatives with long lipophilic alkyl chains could efficiently induce apoptosis.


Assuntos
Compostos Heterocíclicos/metabolismo , Naftalimidas/metabolismo , Inibidores da Topoisomerase II/farmacologia , Apoptose , Humanos , Estrutura Molecular
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