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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.
Insights
Developing new drugs against Leptospira infections is crucial. Researchers identified MurD as a key target and used computational methods to discover 17 novel inhibitors for potential anti-leptospirosis therapies.
Area of Science:
- Microbiology and Drug Discovery
- Computational Chemistry and Structural Biology
Background:
- Leptospira infections pose a significant global health threat, particularly in developing nations.
- Controlling environmental factors for infection prevention is challenging, necessitating the development of effective anti-leptospirosis drugs.
Purpose of the Study:
- To identify and validate a common drug target in pathogenic Leptospira serovars.
- To computationally design and screen potential inhibitors against the identified target for anti-leptospirosis drug development.
Main Methods:
- Subtractive genomic analysis identified ATP-dependent MurD as a drug target.
- 3D models of MurD were generated and refined using molecular modeling software.
- Virtual screening of a large chemical library against MurD was performed, incorporating pharmacokinetic predictions.
Main Results:
- MurD, essential for peptidoglycan biosynthesis, was confirmed as a viable target.
- Structural modeling and refinement provided insights into the active site of MurD.
- Virtual screening yielded 17 novel MurD inhibitor analogs with potential therapeutic value.
Conclusions:
- The study successfully identified MurD as a promising target for anti-leptospirosis drug development.
- Computational approaches facilitated the discovery of novel inhibitor candidates.
- These findings pave the way for developing new treatments targeting bacterial peptidoglycan biosynthesis.
