Virtual screening for potential inhibitors of homology modeled Leptospira interrogans MurD ligase

Abstract

The life-threatening infections caused by Leptospira serovars remain a global challenge since long time. Prevention of infection by controlling environmental factors being difficult to practice in developing countries, there is a need for designing potent anti-leptospirosis drugs. ATP-dependent MurD involved in biosynthesis of peptidoglycan was identified as common drug target among pathogenic Leptospira serovars through subtractive genomic approach. Peptidoglycan biosynthesis pathway being unique to bacteria and absent in host represents promising target for antimicrobial drug discovery. Thus, MurD 3D models were generated using crystal structures of 1EEH and 2JFF as templates in Modeller9v7. Structural refinement and energy minimization of the model was carried out in Maestro 9.0 applying OPLS-AA 2001 force field and was evaluated through Procheck, ProSA, PROQ, and Profile 3D. The active site residues were confirmed from the models in complex with substrate and inhibitor. Four published MurD inhibitors (two phosphinics, one sulfonamide, and one benzene 1,3-dicarbixylic acid derivative) were queried against more than one million entries of Ligand.Info Meta-Database to generate in-house library of 1,496 MurD inhibitor analogs. Our approach of virtual screening of the best-ranked compounds with pharmacokinetics property prediction has provided 17 novel MurD inhibitors for developing anti-leptospirosis drug targeting peptidoglycan biosynthesis pathway.

Molecular modelling, docking and dynamics studies of biotin carboxyl carrier protein of acetyl-CoA carboxylase to discover potential inhibitors

“…Therefore, the binding orientations of lead molecules obtained after simulations showed better correlation to their biologically active states. 35,40 MD simulations also quantified stability of the docked complex.…”

“…Maximum of 50 structural analogues of biotin were retrieved from each of eight structural databases of Ligand Info. [33][34][35][36] Consequently, an in-house library of biotin structural analogues was compiled.…”

“…All hydrogens were added to AccB which subsequently minimized with the OPLS 2005 force field and the impact molecular mechanics engine setting the maximum root mean square deviation (RMSD) of 0.30 Å. [35][36][37] Minimization was performed constraining the heavy atoms with the hydrogen torsion parameters turned off, to allow free rotation of the hydrogen atoms. The ligands were prepared to expand protonation and tautomeric states at 7.0±2.0 pH units using LigPrep 38 with Epik.…”

“…42 A three phased subsequent docking protocol was implemented to the prepared protein and ligand dataset to rank the ligands based on their binding affinities towards AccB and to study interactions of the best lead. [33][34][35] Glide high-throughput virtual screening (HTVS), standard precision (SP) and extra precision (XP) methods were applied. [42][43][44] The XP docking method is highly accurate and generates 10000 poses for each ligand during docking and reports the best pose based on the energy term Emodel.…”

Human Rab8b Protein as a Cancer Target - An In Silico Study

“…The RMSD value of Rab8b protein with its template protein 2BCG is 0.31 Å, calculated using the Swiss-Pdb Viewer (SPDBV_4.1.0, the permissible range of RMSD for any protein being ≤ 2 Å) to assess the reliability of the generated model. The low overall RMSD reflects high structural conservation making it a good structure for further use of in silico study [53]. Energy minimization of 3D structure, is vital for protein stability, and was carried out by using protein preparation wizard in Schrödinger suite.…”