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Albany 2019: 20th Conversation - Abstracts

category image Albany 2019
Conversation 20
June 11-15 2019
Adenine Press (2019)

Integration of binding potency estimations and stability assessments for therapeutic design against MurG of H. pylori

The adverse effects and widespread emergence of resistant Helicobacter pylori strains to the existing drugs is becoming a serious public health concern. As a result there is a real and pressing demand to develop new therapeutics; however, it remains one of the major challenges to science and unmet needs in the clinics. We have therefore selected UDP-N-acetylglucosamine--N-acetylmuramyl-(pentapeptide) pyrophosphoryl-undecaprenol N-acetylglucosamine transferase (MurG), one of the promiscuous common targets for multiple H. pylori strains identified in our previous study (Pasala et al., 2018). Cell wall-related MurG is of special interest, since, it is involved in peptidoglycan biosynthesis with the potential interaction between other proteins, unique to the bacteria, has no mammalian counterpart, and agents inhibiting its synthesis have the potential to become broad-spectrum therapeutics. In the study, the selected target was allowed to Modeller9v20 to generate 100 models with incorporating substrate Uridine-Diphosphate-N-Acetylglucosamine (UD1) using a template (PDB: 3S2U). After validations, the third model was deposited at Protein Model DataBase (PM0081627). The reviewed previous ligands of MurG were allowed to hierarchical-clustering. Subsequently, the obtained five diverse ligands from five clusters with clustering strain 1.261and DU1 were subjected to SwissSimilarity web-tool to perform ligand-based virtual screening of several libraries of ̴ 3 billion small molecules. The retrieved 4177 similar contours were further assigned to lead-optimization campaign includes, rigid receptor docking (Glide parameters), quantum-polarized ligand docking (quantum mechanics) and induced-fit docking (80 replications with charge calculations) coupled with Molecular Mechanics/Generalized Born Surface Area methods to estimate relative binding affinity (∆Gbind) of the previous, screened compounds and DU1. As a result, seven compounds were observed with better ∆Gbind free energies than top diverse ligand BMS-190134 (-63.12 kcal/mol) and DU1 (-49.33 kcal/mol). Moreover, interaction stability of DU1 and the best lead1 (-67.85 kcal/mol) with MurG was dynamically assessed for 50ns and 150ns chemical time respectively (Katari et al., 2016, Pasala et al., 2018b). Consequently, the consistency of lead1-MurG was found with lower deviations, fluctuations and fair compactness than DU1-MurG. The stable interactions with lead1 have been maintained throughout the simulations period and correlated with docking analysis thereby that contacts might be vital hotspots for catalytic activity of MurG. Therefore, as the proposed 7 leads fulfilling all the criteria from different aspects of drug design study, these could be promiscuous therapeutic agents against H. pylori.

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PC acknowledges to ICMR, New Delhi, for supporting with the Senior Research Fellowship (3/1/3/JRF-2014/HRD-8). Authors are highly thankful to DBT, Ministry of Science and Technology, Govt. of India for providing Bioinformatics infrastructure facility to SVIMS Bioinformatics Centre (BT/BI/25/037/2012 (BIF-SVIMST)).

References
    C. Pasala, C.S.R. Chilamakuri, S. K. Katari, R. M. Nalamolu, A.R. Bitla, Umamaheswari A. (2018a). An in silico study: Novel targets for potential drug and vaccine design against drug resistant H. pylori. Microb Pathog122, 156-161.

    S. K. Katari, P. Natarajan, S. Swargam, H. Kanipakam, C. Pasala, Umamaheswari, A. (2016). Inhibitor design against JNK1 through e-pharmacophore modeling docking and molecular dynamics simulations. J Recept Signal Transduct Res. 36(6), 558-571.

    C. Pasala, C. S. R. Chilamakuri, S. K. Katari, R. M. Nalamolu, A. R. Bitla, Umamaheswari, A. (2018b). Epitope-driven common subunit vaccine design against H. pylori strains. Journal of Biomolecular Structure and Dynamics. doi: 10.1080/07391102.2018.1526714. (In press)

Pasala Chiranjeevi*
Katari Sudheer Kumar
Nalamolu Ravina Madhulitha,
Sharon Priya Alexander
Amineni Umamaheswari**

Bioinformatics Centre
Department of Bioinformatics
SVIMS University
Tirupati-517507, AP, India

*Email: chiranjeevipasala09@gmail.com
**Email: svims.btisnet@nic.in