Ceforanide

Chikungunya virus (CHIKV) a re-emerging mosquito-borne alpha virus causes significant distress which is further accentuated in the lack of specific therapeutics or a preventive vaccine, mandating accelerated research for anti-CHIKV therapeutics. In recent years, drug repositioning has gained recognition for the curative interventions for its cost and time efficacy. CHIKV envelope proteins are considered to be the promising targets for drug discovery because of their essential role in viral attachment and entry in the host cells. In the current study, we propose structure-based virtual screening of drug molecule on the crystal structure of mature Chikungunya envelope protein (PDB 3N41) using a library of FDA approved drug molecules. Several cephalosporin drugs docked successfully within two binding sites prepared at E1-E2 interface of CHIKV envelop protein complex with significantly low binding energies. Cefmenoxime, ceforanide, cefotetan, cefonicid sodium and cefpiramide were identified as top leads with a cumulative score of -67.67, -64.90, -63.78, -61.99, and - 61.77, forming electrostatic, hydrogen and hydrophobic bonds within both the binding sites. These shortlisted leads could be potential inhibitors of E1-E2 hetero dimer in CHIKV, hence might disrupt the integrity of envelope glycoprotein leading to loss of its ability to form mature viral particles and gain entry into the host.

1. Christopher J. Harrison, MD* 2. Denise Bratcher, DO* 1. *Children's Mercy Hospitals and Clinics, Pediatric Infectious Diseases, University of Missouri at Kansas City, Kansas City, Mo After completing this article, readers should be able to: 1. Describe the mechanism of action of cephalosporins. 2. Delineate the two most common mechanisms of resistance to penicillins. 3. Discuss the most common adverse effects of common cephalosporins. 4. List which cephalosporins have activity against Pseudomonas. Cephalosporins are beta-lactam antimicrobials that share mechanisms of action and a similar structure with penicillins (Figure⇓). Penicillins and cephalosporins have the same four-member “core” beta-lactam ring, but cephalosporins have an additional atom in the side ring. Modified side chains on either ring alter antimicrobial activity, resistance to beta-lactamases, or pharmacokinetics. Penicillin-susceptible pathogens usually are cephalosporin-susceptible. Exceptions are Listeria and Pasteurella sp. Cephalosporins have activity against common gram-negative organisms such as Escherichia coli , nontypeable Haemophilus influenzae (ntHi), and methicillin-susceptible Staphylococcus aureus (MSSA), but all methicillin-resistant S aureus (MRSA) and enterococci are cephalosporin-resistant. Because of minimal use or current unavailability, we will not discuss cephalothin, moxalactam, cefamandole, cefonicid, ceforanide, ceftizoxime, cefoperazone, cefpirome, cefmetazole, or cefotetan. Figure. Cephalosporin versus penicillin ring structures. The solid arrows indicate the core four-member beta-lactam ring within both penicillins and cephalosporins. Open arrows indicate the five- and six-member side rings for penicillins and cephalosporins, respectively. R indicates additional side chain sites where substitutions of various chemical groups produce different antimicrobial spectra, pharmacokinetics, or stability to beta-lactamases. To help understand the mechanism of action of cephalosporins, rigid bacterial cell walls can be considered as a series of repeating interlocking units reminiscent of floor tiles. During replication, a bacterium removes “tiles” circumferentially to allow cell division via a pinching-like action, while quickly placing new “tiles” at the ends of what have become two bacteria. This process requires enzymes to interlock replacement tiles. Such enzymes are the targets of beta-lactam antibiotics and are called penicillin-binding proteins (PBPs). Antibiotic action requires binding to PBPs, preventing them from closing the …