Computational methods for the prediction of ‘drug-likeness’

Clark, David E.; Pickett, Stephen D.

doi:10.1016/s1359-6446(99)01451-8

Cited by 520 publications

(341 citation statements)

References 52 publications

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“…In silico studies Lipinski's rule of five (the effect of lipophilic and steric parameters) [31][32][33] . As a part of our study; the compliance of compounds to the Lipinski's rule of five was evaluated 31 .…”

Section: Antitumor Activitymentioning

confidence: 99%

“…As a part of our study; the compliance of compounds to the Lipinski's rule of five was evaluated 31 . In addition, the polar surface area (PSA) of the compounds was also calculated (Table 5), since it is another key property that has been linked to drug bioavailability, where passively absorbed compounds with a PSA4140 Å 2 are thought to have low oral bioavailability 32 . The results disclosed in Table 5 show that all of the synthesized compounds comply with these rules.…”

Section: Antitumor Activitymentioning

confidence: 99%

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Synthesis and potential antitumor activity of 7-(4-substituted piperazin-1-yl)-4-oxoquinolines based on ciprofloxacin and norfloxacin scaffolds: in silico studies

Abdel‐Aziz

El‐Azab

Alanazi

et al. 2015

Journal of Enzyme Inhibition and Medicinal Chemistry

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The potential antitumor activities of a series of 7-(4-substituted piperazin-1-yl)fluoroquinolone derivatives (1-14a,b) using ciprofloxacin and norfloxacin as scaffolds are described. These compounds exhibit potent and broad spectrum antitumor activities using 60 human cell lines in addition to the inherent antibacterial activity. Compounds 1a, 2a, 3b, 6b and 7a were found to be the most potent, while 2b, 5b, and 6a were found to have an average activity. The results of this study demonstrated that compounds 1a, 2a, 3b, 6b and 7a (mean GI 50 ; 2.63-3.09 mM) are nearly 7-fold more potent compared with the positive control 5-fluorouracil (mean GI 50 ; 22.60 mM). More interestingly, compounds 1a, 2a, 3b, 6b and 7a have an almost antitumor activity similar to gefitinib (mean GI 50 ; 3.24 mM) and are nearly 2-fold more potent compared to erlotinib (mean GI 50 ; 7.29 mM). In silico study and ADME-Tox prediction methodology were used to study the antitumor activity of the most active compounds and to identify the structural features required for antitumor activity.

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Section: Antitumor Activitymentioning

confidence: 99%

Section: Antitumor Activitymentioning

confidence: 99%

Synthesis and potential antitumor activity of 7-(4-substituted piperazin-1-yl)-4-oxoquinolines based on ciprofloxacin and norfloxacin scaffolds: in silico studies

Abdel‐Aziz

El‐Azab

Alanazi

et al. 2015

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…1). In addition, for potential applications in the brain, the blood-brain barrier (BBB) permeability of compounds is essential (2,25,26). For BBB penetration, molecules should satisfy the restrictive terms of Lipinski's rules [low molecular weight (MW ≤ 450); relatively lipophilic (clogP, calculated logarithm of the octanol/water partition coefficient, ≤5); hydrogen-bond donor atoms (HBD ≤ 5); hydrogen-bond acceptor atoms (HBA ≤ 10); small polar surface area (PSA ≤ 90 Å 2 )] along with calculated logBB values (Table S1).…”

mentioning

confidence: 99%

Design of small molecules that target metal-Aβ species and regulate metal-induced Aβ aggregation and neurotoxicity

Choi

Braymer

Nanga

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

252

420

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The accumulation of metal ions and amyloid-β (Aβ) aggregates found in the brain of patients with Alzheimer's disease (AD) has been suggested to be involved in AD pathogenesis. To investigate metal-Aβ-associated pathways in AD, development of chemical tools to target metal-Aβ species is desired. Only a few efforts, however, have been reported. Here, we report bifunctional small molecules, N-(pyridin-2-ylmethyl)aniline (L2-a) and N 1 ,N 1 -dimethyl-N 4 -(pyridin-2-ylmethyl)benzene-1,4-diamine (L2-b) that can interact with both metal ions and Aβ species, as determined by spectroscopic methods including high-resolution NMR spectroscopy. Using the bifunctional compound L2-b, metal-induced Aβ aggregation and neurotoxicity were modulated in vitro as well as in human neuroblastoma cells. Furthermore, treatment of human AD brain tissue homogenates containing metal ions and Aβ species with L2-b showed disassembly of Aβ aggregates. Therefore, our studies presented herein demonstrate the value of bifunctional compounds as chemical tools for investigating metal-Aβ-associated events and their mechanisms in the development and pathogenesis of AD and as potential therapeutics.amyloid-β peptide | copper | zinc | reactive oxygen species | rational structure-based design M ore than 24 million people worldwide have Alzheimer's disease (AD), a devastating and fatal form of dementia (1-3). The key pathological markers in AD are amyloid-β (Aβ) plaques and neurofibrillary tangles, the accumulation of which is accompanied by oxidative stress, inflammation, and neurodegeneration. The "amyloid hypothesis" in AD states that Aβ, generated via cleavage of the amyloid precursor protein (APP) by β-and γ-secretases, is a proximal causative agent (1-4). It is, however, still unclear which morphological Aβ species, from soluble small oligomers to large fibrils, are central to AD pathogenesis (1-5).In addition to Aβ aggregate deposits, dyshomeostasis and miscompartmentalization of metal ions such as Fe, Cu, and Zn ions clearly occur in AD brains (1-4, 6-10). Some studies suggest that highly concentrated metal ions play an important role in Aβ aggregate deposition and neurotoxicity including the formation of reactive oxygen species (ROS) such as hydrogen peroxide (H 2 O 2 ) (1-4, 6-13). The role of metal ions in AD and molecular mechanisms of metal-Aβ-associated pathological pathways, however, are not fully understood. Using traditional metal chelating agents, potential regulation of metal-induced Aβ aggregation and neurotoxicity has been shown in vitro and in vivo (1-4, 6, 10, 13-17). Some compounds such as clioquinol (CQ) and an 8-hydroxyquinoline derivative (PBT2) have moved into clinical trials and showed improved cognition. Long-term use of CQ is, however, limited by an adverse side effect, subacute myelo-optic neuropathy (18). Although these traditional metal chelators have yet to be available as therapeutic agents, the studies using these compounds show the possible involvement of metal ions in AD pathogenesis.To elucidate the pathological ...

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“…58 In general, compounds with molecular weight less than 500, HBAH less than 10, HBDH less than 5 and a logP value of less than 5 are treated as orally bioavailable with favorable ADME profile. 59,60 The determined ADME properties of compounds 5a-o are given in Table 4. All the trial compounds exhibited favorable ADME properties and no violation of Lipinski's rule was observed.…”

Section: Molecular Docking Studies Of Compounds 5a-omentioning

confidence: 99%

Synthesis and in vitro Bio-activity Evaluation of N4-benzyl Substituted 5-Chloroisatin- 3-thiosemicarbazones as Urease and Glycation Inhibitors

Pervez¹,

Khan²,

Iqbal³

et al. 2018

ACSi

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A series of fifteen N 4 -benzyl substituted 5-chloroisatin-3-thiosemicarbazones 5a-o were synthesized and screened mainly for their antiurease and antiglycation effects. Lemna aequinocitalis growth and Artemia salina assays were carried out to determine their phytotoxicity and cytotoxicity potential. All the compounds proved to be extremely effective urease inhibitors, demonstrating enzyme inhibition much better than the reference inhibitor, thiourea (IC 50 values 1.31 ± 0.06 to 3.24 ± 0.15 vs. 22.3 ± 1.12 μM). On the other hand, eight out of fifteen compounds tested, i.e. 5b, 5c, 5h-k, 5m and 5n were found to be potent glycation inhibitors. Of these, five viz. 5c, 5h-j and 5n proved to be exceedingly efficient, displaying glycation inhibition greater than the reference inhibitor, rutin (IC 50 values 114.51 ± 1.08 to 229.94 ± 3.40 vs. 294.5 ± 1.5 μM).

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Computational methods for the prediction of ‘drug-likeness’

Cited by 520 publications

References 52 publications

Synthesis and potential antitumor activity of 7-(4-substituted piperazin-1-yl)-4-oxoquinolines based on ciprofloxacin and norfloxacin scaffolds: in silico studies

Synthesis and potential antitumor activity of 7-(4-substituted piperazin-1-yl)-4-oxoquinolines based on ciprofloxacin and norfloxacin scaffolds: in silico studies

Design of small molecules that target metal-Aβ species and regulate metal-induced Aβ aggregation and neurotoxicity

Synthesis and in vitro Bio-activity Evaluation of N4-benzyl Substituted 5-Chloroisatin- 3-thiosemicarbazones as Urease and Glycation Inhibitors

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