- ItemComputationally Designed Enzyme Models to Replace Natural Enzymes in Prodrug Approaches(2012-11-16) Karaman, RafikThe striking efficiency of enzyme catalysis has inspired many organic chemists to explore enzyme mechanisms by studying certain intra molecular processes such as enzyme models which proceed faster than their intermolecular counterparts. This research brings about the important question of whether enzyme models will replace natural enzymes in the conversion of prodrugs to their parental drugs. Enzymes are mandatory for the inter conversion of many prodrugs to their parental drugs. Among the most important enzymes in the bioconversion of prodrugs are amides (ex. trypsin, chymotrypsin, elastase, carboxypeptidase, and aminopeptidase) and ester-based prodrugs (ex. paraoxonase, carboxylesterase, acetylcholinesterase and cholinesterase). Most of these enzymes are hydrolytic enzymes, however, non-hydrolytic enzymes, including all cytochrome P450 enzymes, are also capable of catalyzing the bioconversion of ester and amide-based prodrugs .
- ItemDiclofenac Codrugs and Prodrugs-Three Decades of Design(WJPPS,Dr. T Pal, 2015-06-08) Dweib, khuloud; Jumaa, Salma; Thawabteh, Ameen; Scrano, Laura; Bufo, Sabino A.; Mecca, Gennaro; Karaman, RafikProdrugs or predrugs are inactive molecules which become active after in vivo conversion to release the active parent drug. The prodrug’s cleavage can be catalyzed by metabolic enzymes or can occur by chemical means without the involvement of enzymes. Prodrugs are designed to improve undesirable physicochemical and pharmacokinetic properties of their parent drugs. Non-steroidal anti-inflammatory (NSAIDs) drugs are among the most commonly used drugs for treatment of pain, inflammation and fever. Despite their frequent use, these agents suffer from gastrointestinal side effects that limit their use for those patients with gastrointestinal conditions. This mini review discusses the design, synthesis and pharmacological effects of prodrugs and codrugs of the non-steroidal anti-inflammatory (NSAIDs) Diclofenac sodium or potassium. It argues that the prodrug approach has the potential to eliminate Diclofenac associated gastrointestinal complications, increases its bioavailability and masks its bitter taste.
- ItemA Novel Mathematical Equation For Calculating The Number of ATP Molecules Generated From Sugars In Cells(WJPR,Tara Pal,WJPR, 2015-05-23) Karaman, Rafik; Khawaja, YahyaAdenosine triphosphate (ATP) is critical for all life from the simplest to the most complex. All organisms from the microscopic to humans utilize ATP as the source for their primary energy currency. This manuscript describes a novel method to calculate the number of ATP molecules generated from the consumption of any sugar (having 3-7 carbons). This calculation method based on the oxidation states of the sugar’s carbons. The time needed to calculate the number of ATP molecules by this method is less than 2 minutes whereas that required by the current (regular) method is many hours and even days in some cases. In addition, the current method requires drawing all biochemical processes that the sugar undergoes upon its cellular respiration (oxidation) while our method described herein does not.
- ItemAntibacterial Predrugs-from 1899 till 2015(WJPPS,Dr. T Pal, 2015-07-08) Elayyan, Sabrin; Karaman, Donia; Mecca, Gennaro; Scrano, Laura; Bufo, Sabino A.; Karaman, RafikThe predrug (prodrug) term involves chemically modified inert compound which upon an administration releases the active parent drug to elicit its pharmacological response within the body. For many years, the predrug strategy has been extensively developed to solve many unwanted drug properties. This approach has several advantages over conventional drug administration and it has the potential to be quite effective method for the treatment of diseases in the future. In this mini-review we describe a number of antibacterial agents‘ predrugs, and the ways by which predrug strategy was exploited to overcome many pharmaceutical and pharmacokinetic problems that the parent active antibacterial drugs suffer from such as, low bioavailability by increasing or decreasing lipophilicity, site selectivity for higher absorption and less toxicity, short duration of action to increase patient compliance, rapid metabolism to increase oral bioavailability and masking bitter sensation which is crucial for geriatric and pediatric patient compliance.
- ItemProdrugs targeting the central nervous system (cns)(2015-08-07) Salameh, Falasteen; Karaman, Donia; Karaman, RafikThe classical approach for delivery of drugs into the central nervous system (CNS) is associated with adverse effects and it has many limitations. Therefore, extensive efforts have been done in searching and developing novel methods for achieving such delivery. This minireview discusses the design and synthesis of selected targeting prodrugs for the treatment of conditions related to impairment in the CNS such as Parkinson‘s and Alzheimer‘s diseases. Such approaches include targeting prodrugs which are designed to interact with unique cellular conditions at the target site, especially the availability of certain enzymes and transporters at these sites. In addition, part of this mini-review is devoted to prodrugs design based on enzyme models that have been invoked to understand how enzymes catalyzebiotransformation. In this approach, the prodrugs design isdone using quantum molecular orbital and molecular mechanics methods. The equations obtained from correlations of experimental and calculated rate values for some intramolecular processes are used to predict parameters for other intramolecular processes that can be utilized as prodrugs linkers. In this approach, there is no need for enzymes to catalyze the conversion of the prodrug to its active parent drug and the conversion rate of the prodrug is dependent only on those factors playing dominant role in the rate-limiting step of the process.