Known drug space as a metric in exploring the boundaries of drug-like chemical space

Mirza, Amin; Desai, R. K.; Reynisson, Jóhannes

doi:10.1016/j.ejmech.2009.08.014

Cited by 37 publications

(23 citation statements)

References 48 publications

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“…Known drug space (KDS) is a related concept to drug-like chemical space [13,14]. KDS incorporates all small molecules currently marketed based on the idea that compounds that have passed clinical trials and stay in medical use have acceptable pharmacokinetic profiles.…”

Section: Introductionmentioning

confidence: 99%

Characteristics of known drug space. Natural products, their derivatives and synthetic drugs

Bade¹,

Chan²,

Reynisson³

2010

European Journal of Medicinal Chemistry

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112

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Section: Introductionmentioning

confidence: 99%

Characteristics of known drug space. Natural products, their derivatives and synthetic drugs

Bade¹,

Chan²,

Reynisson³

2010

European Journal of Medicinal Chemistry

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112

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“…The question therefore arises whether these properties can be used as molecular descriptors in defining useful regions in chemical space in aid of successful development of drug candidates? In this work the concept of Known Drug Space (KDS)13,26,27 is used in conjunction with DFT to determine whether using DM, POL, IP and EA can improve the definition of favourable areas in chemical space for drug discovery and development.…”

Section: Introductionmentioning

confidence: 99%

Defining Known Drug Space Using DFT

Matuszek

Reynisson

2015

Molecular Informatics

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A density functional theory (DFT) study was performed on a collection of clinically approved drugs, or Known Drug Space (KDS), to determine the statistical distribution of four properties: dipole moment (DM), polarisability (POL), ionisation potential (IP) and electron affinity (EA). The DM and POL are linked to cell permeability of drugs whereas IP and EA reflect their redox stability thus ease of metabolism. A benchmarking exercise showed a good correlation between experimental values and their predicted counterparts. It was found that KDS occupies the volume of chemical space defined by: DM≤10 D, POL≤68 Å(3) , IP 6.0-9.0 V and EA-1.5-2.0 eV. Only 16 % of the drugs are outside one or more of these parameters. Three categories based on known oral absorption and bioavailability (low/medium/high) were established and compared. Predominately, drugs designated as 'low' were found outside the established parameters. The properties were compared with mainstream molecular descriptors and a strong correlation was seen for POL to MW (r(2) =0.899), which can explain the success of the latter since POL reflects the ability of molecules to interact with polar and non-polar environments such as water and interior of a membrane.

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“…Salicylic acid derivatives are known to have a great potencial as bioactive molecules. To determine the possibility of theoretical hitting of synthesized compounds into «drug like space» ADME analysis was performed ,. Towards this goal the bioavailability of compounds was estimated by Schrödinger Suite (QikProp) program .…”

Section: Resultsmentioning

confidence: 99%

Synthesis and Biological Activity of 4‐Cycloaminopolyfluorosalicylic Acids

et al. 2019

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A series of novel 4-cycloamino-substituted polyfluorosalicylic acids, their esters and amides have been synthesized by the reactions of alkyl polyfluorosalicylates with morpholine, Nmethylpiperazine, pyrrolidine and proline. It was observed that esters of polyfluorosalicylic acids under prolonged heating with amines could undergo one pot nucleophilic substitution of fluorine and intramolecular acidic hydrolysis owing to catalysis by the neighboring hydroxyl group. According to ADME calculations, the synthesized compounds are suitable for drug-design. 4-(N-Methylpiperazinyl)-substituted polylfluorosalicylic acids were found to have good analgesic activity while 4morphonyl-containing analogs revealed moderate anti-inflammatory action. In addition, the presence of amine fragment in polyfluorosalicylates reduced acute toxicity comparing to nonsubstituted polyfluorosalicylic acids. The molecular docking of the most active compounds was carried out into the tyrosine site of cyclooxygenase-1.

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Known drug space as a metric in exploring the boundaries of drug-like chemical space

Cited by 37 publications

References 48 publications

Characteristics of known drug space. Natural products, their derivatives and synthetic drugs

Characteristics of known drug space. Natural products, their derivatives and synthetic drugs

Defining Known Drug Space Using DFT

Synthesis and Biological Activity of 4‐Cycloaminopolyfluorosalicylic Acids

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