Hit-to-Lead: Hit Validation and Assessment

Hevener, Kirk E.; Pesavento, Russell P.; Ren, Jin; Lee, Hyun; Ratia, Kiira; Johnson, Michael E.

doi:10.1016/bs.mie.2018.09.022

Cited by 32 publications

(31 citation statements)

References 142 publications

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“…Further optimization can be made to improve the results, using strategies like Fragment-Based Drug Discovery (FBDD) [ 50 ]. In addition, Fragment Molecular Orbital (FMO) [ 51 , 52 ] can be used to optimize the hit to make it more effective.…”

Section: Resultsmentioning

confidence: 99%

Searching Hit Potential Antimicrobials in Natural Compounds Space against Biofilm Formation

2020

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Biofilms are communities of microorganisms that can colonize biotic and abiotic surfaces and thus play a significant role in the persistence of bacterial infection and resistance to antimicrobial. About 65% and 80% of microbial and chronic infections are associated with biofilm formation, respectively. The increase in infections by multi-resistant bacteria instigates the need for the discovery of novel natural-based drugs that act as inhibitory molecules. The inhibition of diguanylate cyclases (DGCs), the enzyme implicated in the synthesis of the second messenger, cyclic diguanylate (c-di-GMP), involved in the biofilm formation, represents a potential approach for preventing the biofilm development. It has been extensively studied using PleD protein as a model of DGC for in silico studies as virtual screening and as a model for in vitro studies in biofilms formation. This study aimed to search for natural products capable of inhibiting the Caulobacter crescentus enzyme PleD. For this purpose, 224,205 molecules from the natural products ZINC15 database, have been evaluated through molecular docking and molecular dynamic simulation. Our results suggest trans-Aconitic acid (TAA) as a possible starting point for hit-to-lead methodologies to obtain new inhibitors of the PleD protein and hence blocking the biofilm formation.

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Section: Resultsmentioning

confidence: 99%

Searching Hit Potential Antimicrobials in Natural Compounds Space against Biofilm Formation

2020

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“…Thus, a validation step is required. Hit-validation is therefore the process of confirming, or validating, that the molecule(s) identified previously have on target activity and selectivity [ 367 , 368 ]. One of the highest-impacts of NMR on drug discovery is the use as a hit-validation tool.…”

Section: Nmr Methods For Drug Discovery and Drug Developmentmentioning

confidence: 99%

“…Of course, NMR is not the sole technique used for drug validation. Most often, NMR drug validation is coupled with additional methods [ 367 ] such as surface plasmon resonance (SPR) [ 376 , 377 ] X-ray crystallography [ 377 , 378 , 379 ], isothermal calorimetry (ITC) [ 379 ], UV-Vis and/or fluorescence spectroscopy [ 380 ].…”

Section: Nmr Methods For Drug Discovery and Drug Developmentmentioning

confidence: 99%

“…NMR can be also coupled with multiple biophysical techniques to validate a molecule’s ability to inhibit protein-protein interactions (PPIs) [ 367 ]. An example of the combination of NMR with SPR and X-ray crystallography can be found in the work of Fry et al, where the authors sought to understand how the nutlin molecule inhibits MDM2-p53, a protein-protein interaction that has been an important cancer therapy target for several years [ 381 , 382 , 383 ].…”

Section: Nmr Methods For Drug Discovery and Drug Developmentmentioning

confidence: 99%

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NMR as a “Gold Standard” Method in Drug Design and Discovery

et al. 2020

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Studying disease models at the molecular level is vital for drug development in order to improve treatment and prevent a wide range of human pathologies. Microbial infections are still a major challenge because pathogens rapidly and continually evolve developing drug resistance. Cancer cells also change genetically, and current therapeutic techniques may be (or may become) ineffective in many cases. The pathology of many neurological diseases remains an enigma, and the exact etiology and underlying mechanisms are still largely unknown. Viral infections spread and develop much more quickly than does the corresponding research needed to prevent and combat these infections; the present and most relevant outbreak of SARS-CoV-2, which originated in Wuhan, China, illustrates the critical and immediate need to improve drug design and development techniques. Modern day drug discovery is a time-consuming, expensive process. Each new drug takes in excess of 10 years to develop and costs on average more than a billion US dollars. This demonstrates the need of a complete redesign or novel strategies. Nuclear Magnetic Resonance (NMR) has played a critical role in drug discovery ever since its introduction several decades ago. In just three decades, NMR has become a “gold standard” platform technology in medical and pharmacology studies. In this review, we present the major applications of NMR spectroscopy in medical drug discovery and development. The basic concepts, theories, and applications of the most commonly used NMR techniques are presented. We also summarize the advantages and limitations of the primary NMR methods in drug development.

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“…Discovery (FBDD) [43] or Fragment Molecular Orbital (FMO) [44,45] can be use to optimized the hit to become an effective lead.…”

Section: Ligand Residues Involve In the H-bond Formation With The Majmentioning

confidence: 99%

Searching Hit Potential Antimicrobials in Natural Compounds Space Against Biofilm Formation

Pestana¹,

Leyva²,

Yosa³

2020

Preprint

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Biofilms are communities of microorganisms that can colonize biotic and abiotic surfaces playing a significant role in the persistence of bacterial infection and antibiotic resistance. About 65% and 80% of microbial and chronic infections are produced by biofilm formation. The increase in infections by multi-resistant bacteria draws attention to the discovery of new drugs based on natural inhibitory molecules. The inhibition of diguanylate cyclases (DGCs), the enzyme implicated in the synthesis of the second messenger, cyclic diguanylate (c-di-GMP), involved the biofilm formation, represents a potential method for preventing the biofilm development. It has been extensively studied using PleD protein as a model of DGC for in silico studies as virtual screening and as a model for in vitro studies in biofilms formation. In the present study 224205 molecules from natural products database, ZINC15 has been evaluated through molecular docking and molecular dynamic simulation, our result suggests trans-Aconitic acid (TAA) as a possible starting point for hit-to-lead methodologies to obtain new molecules capable of inhibiting the PleD protein and hence blocking the biofilm formation.

show abstract

Hit-to-Lead: Hit Validation and Assessment

Cited by 32 publications

References 142 publications

Searching Hit Potential Antimicrobials in Natural Compounds Space against Biofilm Formation

Searching Hit Potential Antimicrobials in Natural Compounds Space against Biofilm Formation

NMR as a “Gold Standard” Method in Drug Design and Discovery

Searching Hit Potential Antimicrobials in Natural Compounds Space Against Biofilm Formation

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