Computational investigation of potent inhibitors against YsxC: structure-based pharmacophore modeling, molecular docking, molecular dynamics, and binding free energy.

In S. aureus, ribosome biogenesis GTP-binding (YsxC), a GTPase interacts with 50S subunit and 30S subunit of ribosome, and ß' subunit of RNA polymerase and played an important role in protein synthesis. For the identification of potent lead molecules, we have conducted pharmacophore modeling by consideration of pharmacophore features of GTP among YsxC-GTP complex. Virtual screening and molecular docking results displayed that five pharmacokinetic and ADMET filtered molecules-ZINC000006424138, ZINC000095502032, ZINC000225415132, ZINC000095475800, and ZINC000012990761-had higher binding affinities than GTP with YsxC. All the identified molecules shared similar pharmacophore features of GTP and were stabilized via hydrogen bonds and hydrophobic interactions with YsxC. Molecular dynamics analysis revealed that YsxC-inhibitor(s) complexes were lesser dynamics and higher stable than YsxC-GTP complex. Molecular Mechanics/Poisson-Boltzmann Surface Area (MMPBSA) results confirmed that identified molecules bound at the active site (Arg33, Ser34, Asn35, Val36, Lys38, Ser39, Thr40, Thr54, Ser55, Pro58, Lys60, Thr61, Thr144, Lys145, Ser178, and Ile179) of YsxC and formed the lower energy (-190.32 ± 3.46 to -217.03 ± 2.55 kJ/mol) complexes than YsxC-GTP (-157.16 ± 2.89 kJ/mol) complex. The identified molecules in this study can be further tested and utilized to design novel antimicrobial agents for S. aureus.Communicated by Ramaswamy H. Sarma.

Promising antibacterials for LLM of Staphylococcus aureus using virtual screening, molecular docking, dynamics, and MMPBSA.

In S. aureus, lipophilic membrane (LLM) protein is a methicillin resistance factor and is an essential role in peptidoglycan metabolism. The virtual screening of antibacterial molecules against the model of LLM was performed to identify the potent antibacterial molecules. Molecular docking results of pharmacokinetic filtered molecules illustrated that five molecules had higher binding affinities than tunicamycin (TUM) and were stabled via non-covalent interactions (hydrogen bond and hydrophobic interactions) at the active site of LLM. Further, molecular dynamics results revealed that binding of identified antibacterial molecules with LLM resulted in stable LLM-inhibitor(s) complexes. Molecular Mechanics/Position-Boltzmann Surface Area (MMPBSA) analysis showed that LLM-inhibitor(s) complexes had high binding affinities in the range of -213.49 ± 2.24 to -227.42 ± 3.05 kJ/mol. The amino acid residues decomposition analysis confirmed that identified antibacterial molecules bound at the active site (Asn148, Leu149, Asp151, Asp208, His269, His271, and His272) of LLM. Noticeably, the current study found five antibacterial molecules (BDE 27575101, BDE 33638168, BDE 33672484, LAS 51502073, and BDE 25098678) were highly potent than TUM and even than earlier reported molecules. Therefore, here reported antibacterial molecules may be used directly or developed to inhibit LLM of S. aureus.Communicated by Ramaswamy H. Sarma.

Substituted imidazole derivatives as novel cardiovascular agents.

A series of novel substituted imidazole derivatives were synthesized and have been screened in vivo for their hypotensive and acute toxicity activities. Out of seventeen compounds eight compounds (2b, 2c, 3b, 3c, 3f, 4a, 4b and 4c) have shown good hypotensive and bradycardiac responses. Compounds 3b, 3c, 3f and 4c have shown better activity than reference drug clonidine. All the compounds have shown ALD50>1000 mg/kg with maximum in 2e and 4c (>1200 mg/kg).

Synthesis and antihypertensive activity of novel quinazolin-4(3H)-one derivatives.

A series of novel substituted quinazolin-4(3H)-one derivatives were synthesized and screened in vivo for their antihypertensive activities. Out of eighteen synthesized compounds, seven i.e. 2a, 2c, 4a, 4d, 5d, 6a & 6b compounds have shown hypotensive effect and produced bradycardia. These compounds have shown better activity than reference drug Prazosin (which acts as anti-hypertensive agent by α1 blocking action). All the compounds have shown ALD50>1000mg/kg with maximum in 2c & 4d (>1200mg/kg).