IN SILICO DRUG DISCOVERY FOR NDM -1 METALLO β LACTAMASE INHIBITORS for KLEBSIELLA PUEUMONIAE

Abstract

In every region of the world, antibiotic resistance is increasing to dangerously high levels. Our ability to cure widespread infectious diseases is being threatened by the emergence of new resistance mechanisms. Klebsiella pneumoniae is one of the most prevalent nosocomial Gram-negative bacteria in the world. NDM-1 is a brand-new class of metallo-{beta}-lactamase (MBL) that makes the bacteria almost total resistant to all {beta}-lactam antibiotics, including penicillins, cephalosporins and carbapenems. Dangerous infections could develop if NDM-1 switches to a bacterium that is already resistant to antibiotics. It could be untreatable and spread quickly among humans. Using the available insilico tools, in the present research work, an attempt has been made to develop inhibitors for NDM-1 {beta} Lactamase of K. pneumoniae. In the present study, 8 standard ligands were identified and docked against the NDM-1 protein using PyRx. Among these standards, Sulfonamide was selected as the best compound and virtual screening of a large number of sulfonamide moieties was conducted with the identified active site in NDM-1 protein using PyRx. On analyzing the obtained results, about 60 molecules were selected as best hits for Docking studies and ADMET studies. On analyzing the ADMET properties and binding energies of the top hits, (3Z)-N-hydroxypenta-1,3-diene-2-sulfonamide (Pubchem CID 118156306) and N-hydroxyfuran-2-sulfonamide (Pubchem CID 46175386). Molecular dynamics simulations were carried out on the complxes formed by these 2 compounds with target protein and the results showed the complexes were stable which validated the earlier findings. Based on the findings of the study, it was concluded that (3Z)-N-hydroxypenta-1,3-diene-2-sulfonamide (Pubchem CID 118156306) and N-hydroxyfuran-2-sulfonamide (Pubchem CID 46175386) had the potential to be used as lead candidates against infections caused by K. pneumoniae producing NDM-1 strains.