Design, Conformation, and Crystallography of 2-Naphthyl Phenyl Ethers as Potent Anti-HIV Agents

Lee, Won‐Gil; Chan, Albert H.; Spasov, Krasimir A.; Anderson, Karen S.; Jorgensen, William L.

doi:10.1021/acsmedchemlett.6b00390

Cited by 25 publications

(63 citation statements)

References 21 publications

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“…3c), lack of robust HBs does not preclude tight binding. In fact, a multiplicity of binding modes might be beneficial to preserve binding affinity when the target is mutated, thus averting resistance 30,31 . While the distribution of HB strength between the four types of binding sites that we have defined is quite different (see Supplementary Tables 4 and 5 for statistical tests), individual cases can deviate from the norm (e.g., the allosteric ligand 1YV3 is extremely robust) and more examples will be needed to reach firm conclusion about site-dependence.…”

Section: Resultsmentioning

confidence: 99%

An investigation of structural stability in protein-ligand complexes reveals the balance between order and disorder

2019

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The predominant view in structure-based drug design is that small-molecule ligands, once bound to their target structures, display a well-defined binding mode. However, structural stability (robustness) is not necessary for thermodynamic stability (binding affinity). In fact, it entails an entropic penalty that counters complex formation. Surprisingly, little is known about the causes, consequences and real degree of robustness of protein-ligand complexes. Since hydrogen bonds have been described as essential for structural stability, here we investigate 469 such interactions across two diverse structure sets, comprising of 79 druglike and 27 fragment ligands, respectively. Completely constricted protein-ligand complexes are rare and may fulfill a functional role. Most complexes balance order and disorder by combining a single anchoring point with looser regions. 25% do not contain any robust hydrogen bond and may form loose structures. Structural stability analysis reveals a hidden layer of complexity in protein-ligand complexes that should be considered in ligand design.

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Section: Resultsmentioning

confidence: 99%

An investigation of structural stability in protein-ligand complexes reveals the balance between order and disorder

2019

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“…[245] They had previously discovered an ew class of 2-naphthyl catechol diether derivatives able to inhibit wild-type HIV-1 RT with nanomolar potency. [246] Analysis of the binding mode of inhibitor 48 ( Figure 37) complexed with wild-type HIV-1 RT (PDB ID:5 TER, Figure 38 A) [246] revealed that the chlorine atom attached to the naphtyl moiety was oriented toward Ty r181, the residue commonly replaced with cysteine in drug-resistant strains. Theh ypothesis was that the replacement of this group with aM ichael acceptor could result in covalent binding to the thiol group of Cys181.…”

Section: Covalent Inhibition To Overcome Tyr181cys Resistancementioning

confidence: 99%

A Structural View on Medicinal Chemistry Strategies against Drug Resistance

et al. 2019

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The natural phenomenon of drug resistance represents a generic impairment that hampers the benefits of drugs in all major clinical indications. Antibacterials and antifungals are affected as well as compounds for the treatment of cancer, viral infections or parasitic diseases. Despite the very diverse set of biological targets and organisms involved in the development of drug resistance, underlying molecular processes have been identified to understand the emergence of resistance and to overcome this detrimental mechanism. Detailed structural information of the root causes for drug resistance is nowadays frequently available to design next generation drugs anticipated to suffer less from resistance. This knowledge-based approach is a prerequisite in the fight against the inevitable occurrence of drug resistance to secure the achievements of medicinal chemistry in the future.

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“…[190] EC 50 [245] Zuvor hatte die Forschungsgruppe eine neue Klasse von 2-Naph-thylcatecholdiether-Derivaten entdeckt, welche die Wildtyp-HIV-1-RTm it nanomolarer Affinitäti nhibieren kçnnen. [246] Die Analyse der Cokristallstruktur von Inhibitor 48 (Abbildung 37) mit Wildtyp-HIV-1-RT( PDB ID:5 TER, Abbildung 38 A) [246] zeigte,d ass das an die Naphthylgruppe gebundene Chloratom zu Tyr181 orientiert ist, wobei dieser Rest bei wirkstoffresistenten Stämmen zu Cys mutiert. Deshalb wurde der Ansatz verfolgt, dass der Chlorsubstituent durch einen Michael-Akzeptor ersetzt wird und dadurch eine kovalente Bindung mit der Thiolgruppe von Cys181 gebildet werden kann.…”

Section: Angewandte Chemieunclassified

Eine strukturelle Evaluierung medizinalchemischer Strategien gegen Wirkstoffresistenzen

Agnello¹,

Brand²,

Chellat³

et al. 2019

Angewandte Chemie

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Das natürliche Phänomen der Wirkstoffresistenz stellt eine universelle Beeinträchtigung des Nutzens von pharmazeutischen Wirkstoffen in vielen klinischen Indikationen dar. Antibakterielle und antifungale Wirkstoffe sind dabei ebenso betroffen wie Wirkstoffe zur Behandlung von Krebs, Virusinfektionen oder durch Parasiten hervorgerufene Erkrankungen. Trotz der unterschiedlichen biologischen Zielstrukturen und Organismen, die bei der Entwicklung von Wirkstoffresistenzen involviert sind, konnten grundlegende molekulare Prozesse identifiziert werden, die zum Verständnis des Auftretens von Resistenzen beitragen und die Bekämpfung dieser nachteiligen Mechanismen erlauben. Strukturelle Informationen über die Prinzipien von Wirkstoffresistenzen sind heute vielfältig vorhanden, sodass neue Wirkstoffe entwickelt werden können, die weniger anfällig gegenüber einer Resistenzbildung sein werden. Dieser wissensbasierte Ansatz ist eine Grundlage für den Kampf gegen das unvermeidbare Auftreten von Wirkstoffresistenzen.

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Design, Conformation, and Crystallography of 2-Naphthyl Phenyl Ethers as Potent Anti-HIV Agents

Cited by 25 publications

References 21 publications

An investigation of structural stability in protein-ligand complexes reveals the balance between order and disorder

An investigation of structural stability in protein-ligand complexes reveals the balance between order and disorder

A Structural View on Medicinal Chemistry Strategies against Drug Resistance

Eine strukturelle Evaluierung medizinalchemischer Strategien gegen Wirkstoffresistenzen

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