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Molecular docking studies of gyrase inhibitors: weighing earlier screening bedrock.

ABSTRACT: For any antimicrobial assay, a standard drug is used to compare the bactericidal efficiency of the bioactive compound under screening. The standard drugs have different targets that may be intracellular or membrane located. The location of the target is believed to be determining the bioactivity of the drug depending on the drug's access to its target. Therefore, different drugs must have a different magnitude in exhibiting the biological effect. However, in most of the published literature about the screening of bioactive compounds on antimicrobial activity, generally, the standard drug is randomly chosen while comparing against the bioactive compound of interest. Further, the antimicrobial activity is inferred by comparing the randomly chosen standard drugs without knowing the physicochemical parameters of the standard drug and the test molecule. It is just like an unfair comparison of the impact of a bullet with the impact of an explosive in a combat scene. Computer-based strategies for structure-based drug discovery presents a valuable alternative to the costly and time-consuming process of random screening. The docking studies provide better insights into the binding mechanism of substrate and inhibitor at the molecular level. The evaluation of such a comparison of bioactive compounds against randomly selected standard drugs through a customized virtual screening pipeline showed 57% false positives, 18% true positive, 17% true negative, 8% false-negative results. This study directs for mandatory cheminformatics-based assessment of the bioactive compounds before choosing the standard drug to compare with.

Supplementary information

The online version contains supplementary material available at 10.1007/s40203-020-00064-9.

SUBMITTER: Kumar HSS

PROVIDER: S-EPMC7775855 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background:In experimental therapy of cancer, survivin is considered to be one of the well-established targets. Studies have found that it is overexpression in most of the human tumors, but it is rarely found in normal tissues. It is having varied structural and functional role. It controls cell division and cellular stress response and also regulates metastasis and migration of cancerous cells. It has also been recognized as a biomarker which makes it unconventional drug target. In spite of being one of the centrally active components in metastasis and invasion, their clinical use is minimal. To increase the therapeutic efficiency of cancer and its various stages, it is important to survey novel reagents targeting the pathways and mechanism involving survivin. Objective:The aim of this study was to identify novel survivin inhibitor candidates using in silico screening. Materials and Methods:In this course of work, virtual screening on a dataset of natural compounds retrieved from ZINC and other libraries were performed. Comparative analysis of the protein was done by studying the binding affinity of inhibitors that are already available. The best interacting complex was set for molecular dynamics simulation for 25 ns to validate the stability of system. These molecules were checked for their toxicity and absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties using OSIRIS and pre-ADMET tools. Results:We discovered ten such candidates with better binding efficiency with survivin in comparison to marketed chemical against the same. Furthermore, these inhibitor candidates did not induce cell toxicity. Binding affinity of reference molecules was varied from -6.8 to -8.5 kcal/mol while that of top scoring compound ZINC00689728 is -9.3 kcal/mol binding energy. Good placement and strong bond formation of selected molecule was observed during course of work. It is also having permissible ADMET property. Conclusion:Considering all the parameters, the screened molecule can be considered as a potential lead compound for designing new drug against survivin. Further investigation and testing will be required to make it to the final stage. SUMMARY:Survivin is one of the important protein of metastasis. Inhibiting survivin might led to the increased therapeutic efficiency of cancer. In this work we are screening library of natural compounds in view of finding some potent inhibitor against survivin. Abbreviations used: MD: Molecular dynamics, LogS: Aqueous solubility, Acceptor HB: Hydrogen bond acceptor, Donor HB: Donor hydrogen bond donor, ADMET: Absorption, distribution, metabolism, excretion, and toxicity, RCSB: Research Collaboratory for Structural Bioinformatics, OPLS: Optimized potentials for liquid simulations, RMSD: Root-mean-square deviation.

Dataset Information

Molecular docking studies of gyrase inhibitors: weighing earlier screening bedrock.

Supplementary information

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