Relating the shape of protein binding sites to binding affinity profiles: is there an association?

Simon, Zoltán; Vigh-Smeller, Margit; Peragovics, Ágnes; Csukly, Gábor; Zahoránszky-Kőhalmi, Gergely; Rauscher, Anna Á; Jelinek, Balázs; Hári, Péter; Bitter, István; Málnási-Csizmadia, András; Czobor, Pál
January 2010
BMC Structural Biology;2010, Vol. 10, p32
Academic Journal
Background: Various pattern-based methods exist that use in vitro or in silico affinity profiles for classification and functional examination of proteins. Nevertheless, the connection between the protein affinity profiles and the structural characteristics of the binding sites is still unclear. Our aim was to investigate the association between virtual drug screening results (calculated binding free energy values) and the geometry of protein binding sites. Molecular Affinity Fingerprints (MAFs) were determined for 154 proteins based on their molecular docking energy results for 1,255 FDA-approved drugs. Protein binding site geometries were characterized by 420 PocketPicker descriptors. The basic underlying component structure of MAFs and binding site geometries, respectively, were examined by principal component analysis; association between principal components extracted from these two sets of variables was then investigated by canonical correlation and redundancy analyses. Results: PCA analysis of the MAF variables provided 30 factors which explained 71.4% of the total variance of the energy values while 13 factors were obtained from the PocketPicker descriptors which cumulatively explained 94.1% of the total variance. Canonical correlation analysis resulted in 3 statistically significant canonical factor pairs with correlation values of 0.87, 0.84 and 0.77, respectively. Redundancy analysis indicated that PocketPicker descriptor factors explain 6.9% of the variance of the MAF factor set while MAF factors explain 15.9% of the total variance of PocketPicker descriptor factors. Based on the salient structures of the factor pairs, we identified a clearcut association between the shape and bulkiness of the drug molecules and the protein binding site descriptors. Conclusions: This is the first study to investigate complex multivariate associations between affinity profiles and the geometric properties of protein binding sites. We found that, except for few specific cases, the shapes of the binding pockets have relatively low weights in the determination of the affinity profiles of proteins. Since the MAF profile is closely related to the target specificity of ligand binding sites we can conclude that the shape of the binding site is not a pivotal factor in selecting drug targets. Nonetheless, based on strong specific associations between certain MAF profiles and specific geometric descriptors we identified, the shapes of the binding sites do have a crucial role in virtual drug design for certain drug categories, including morphine derivatives, benzodiazepines, barbiturates and antihistamines.


Related Articles

  • Benzodiazepines. Smith, Andrew; Rawlins, M.D. // British Medical Journal;8/13/1977, Vol. 2 Issue 6084, p447 

    Investigates the safety and effectiveness of benzodiazepines. Advantages of benzodiazepines over barbiturates; Disadvantages of benzodiazepines; Problems encountered in using dichloralphenazone.

  • Naloxone blocks anxiolytic-like effects of benzodiazepines in Swiss but not in Balb/c mice. Belzung, C.; Ågmo, Anders // Psychopharmacology;1997, Vol. 132 Issue 2, p195 

    Abstract The ability of naloxone to block the effects of the benzodiazepines chlordiazepoxide and diazepam was evaluated in Swiss and Balb/c mice subjected to the light/dark choice test of anxiety or to a choice paradigm for measuring spontaneous exploratory behaviour. In Swiss mice, naloxone (5...

  • Treatment of refractory seizures in eclampsia with propofol: A case report. Dam, A. K.; Mishra, J. C.; Shome, P. K. // Indian Journal of Critical Care Medicine;Oct-Dec2003, Vol. 7 Issue 4, p283 

    We describe the management of a case of refractory status epilepticus evolving in post-partum eclampsia. The seizures were refractory to therapy with benzodiazepines, MgSO4, barbiturates and phenytoin, but responded rapidly to propofol infusion.

  • Transitioning INTO TWILIGHT. Miller, Teri // Healthcare Traveler;Mar2005, Vol. 12 Issue 9, p32 

    Explains procedural sedation (PS) that uses a combination of medications, including benzodiazepine and analgesic or nonbarbiturate hypnotic agents. Four phases of sedation; Medical history and physical conditions that should be considered when preparing patients for sedation; Advantages and...

  • Sleeping pills.  // Mayo Clinic Health Letter;Jan2008, Vol. 26 Issue 1, p4 

    The article presents a guide to choosing sleeping pills. People with sleep-onset insomnia or sleep-maintenance insomnia ought to consult doctors before taking sleep medications. Some considerations in choosing sleeping pills include history of liver or kidney disease and depression. Sleeping...

  • truth serum.  // Taber's Cyclopedic Medical Dictionary;2005, p2244 

    A definition of the term "truth serum" is presented. It is one of several hypnotic drugs that have the effect of causing a person on questioning to talk freely and without inhibition. In actual practice, serum is not provided. Instead, a shortacting barbiturate or benzodiazepine is given...

  • Positive screening tests for barbiturates in urine samples in the York area over a 1-year period. Holbrook, Ian; Sinclair, Margaret; Turley, Paul; Tetlow, Tony // Annals of Clinical Biochemistry;Sep2001, Vol. 38 Issue 5, p559 

    Following the screening of urine samples for a panel of drugs over a period of 1 year, a peak was observed during December 1999 and January 2000 in the numbers of samples testing positive for both morphine and barbiturates. This increase may be due to the adulteration of street heroin with...

  • Drug Treatment of Primary Insomnia: A Meta-Analysis of Polysomnographic Randomized Controlled Trials. Winkler, Alexander; Auer, Charlotte; Doering, Bettina; Rief, Winfried // CNS Drugs;Sep2014, Vol. 28 Issue 9, p799 

    Context: Although insomnia is a frequent health complaint that is often treated with drugs, little is known about differences in treatment efficacy of various drug classes on objective versus subjective outcome measures. Objective: Our aim was to compare treatment efficacy of classical...

  • Fatal drug poisonings in a Swedish general population. Jönsson, Anna K.; Spigset, Olav; Tjäderborn, Micaela; Druid, Henrik; Hägg, Staffan // BMC Clinical Pharmacology;2009, Vol. 9, Special section p1 

    Background: Pharmaceutical drug poisonings have previously been reported using single sources of information, either hospital data or forensic data, which might not reveal the true incidence. We therefore aimed to estimate the incidence of suspected fatal drug poisonings, defined as poisonings...


Read the Article


Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics