1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 DOI: 10.1002/minf.201800048 Computational Approaches to Develop Isoquinoline Based Antibiotics through DNA Gyrase Inhibition Mechanisms Unveiled through Antibacterial Evaluation and Molecular Docking Manikandan Alagumuthu, [a] Vivek Panyam Muralidharan, [b] Monic Andrew, [a] Mohammed Habeeb Ahmed, [a] Sathiyanarayanan Kulathu Iyer, [b] and Sivakumar Arumugam* [a] Abstract: Developing a new antibacterial drug by using (Z/ E)-4-(4-substituted-benzylidene)-2-isoquinoline-1,3(2H,4H)- diones (5a–h) via DNA gyrase inhibition mechanism is the main aim of this study. DNA gyrase inhibition assay was executed to confirm the DNA gyrase inhibition potentials of 5a–h. DNA gyrase inhibitory potentials were further vali- dated through molecular docking. Docking study was also intended to get more insight into the binding mode of 5a– h into the active site of DNA gyrase A. Agar well diffusion method antimicrobial activity on Gram Àve bacteria Escher- ichia coli (MTCC 443), Pseudomonas aeruginosa (MTCC 424), and Gram +ve bacteria (Staphylococcus aureus (MTCC 96) and Streptococcus pyogenes (MTCC 442) was evaluated. Excellent DNA gyrase inhibition was exhibited by the compound 5c, IC 50 0.55 Æ 0.12 mM; 5d, IC 50 0.65 Æ 0.075 mg/ mL; 5e, IC 50 0.45 Æ 0.035 mM; 5f, IC 50 0.58 Æ 0.025 mM; 5h, IC 50 0.25 Æ 0.015 mM while Clorobiocin (standard) showed IC 50 0.5 Æ 0.05 mM. Apart from all the in vitro studies, a plausible mechanism of DNA gyrase inhibition was also proposed through the in silico validations that are including molecular docking, predicted SAR, functional group availability, phar- macokinetic, and ADMET properties. These predictions are well supported to confirm the druggability possibility of the most potent compounds among (Z/E)-4-(4-substituted- benzylidene)-2-isoquinoline-1,3(2H,4H) -diones (5a–h). Keywords: Antibacterial · DNA gyrase · Drug designing · Molecular docking · Computational predictions 1 Introduction In recent decades, the bacterial resistance to antibiotics is gradually increasing due to the uneven and prolonged use of antimicrobial/antibiotics. [1] Rapidly increasing microbial invulnerability to the conservative anti-infectious agents clearly indicating the necessity of a sustained search for capable and potent drug compounds by using novel natural product extraction, chemical synthetic techniques that are dependably equipped with bioinformatics. [2–4] Several naturally obtained and synthetically achieved iso- quinoline derivatives are well reported or being reported for their antibacterial effects even today. [5–8] For example, Berberine is one of the known natural isoquinoline alkaloids that is readily been established as an antimicrobial agent. [9] In the present study, we have used computational tools to estimate the drug efficacy of the isoquinoline based drug candidates. Obviously, computer-aided drug discovery (structure-based/ligand-based methods) being the econom- ical method for more than two decades. Significantly, computational tools are taking an important part in the identification of therapeutically important small mole- cules. [10,11] Most importantly, the need for the effective computer-aided antibiotic screening is much awaited/ needed all through the years, because, pathogenic bacteria are one of the main causative agents that are also taking a vital role in global human mortality (WHO). In our earlier report, we have established a few isoquino- line derivatives as the antioxidant agents, [12] anti-inflamma- tory [13] and anticancer agents. [14] Isoquinolines are also known for the potential of tumor necrosis factor-a apart from the anti-inflammatory properties. [15] Other than the above discussed biological activities, isoquinolines are also been assessed for their antimalarial, cytotoxic, and anti-HIV agents. [5] In the present study, (Z/E)-4-(4-substituted- benzylidene)-2-isoquinoline1,3(2H, 4H)-diones (5a–h) are proposed as DNA gyrase inhibitors. Noticeably, the atten- tion on DNA gyrase inhibition validation against small molecule chemical entities is growing well in search of DNA [a] M. Alagumuthu, M. Andrew, M. H. Ahmed, S. Arumugam Dept. of Biotechnology, School of Bio-Sciences and Technology, Vellore Institute of Technology, Vellore-632014, India Mobile: + 91-9791817704 E-mail: mailtomicromani@gmail.com [b] V. P. Muralidharan, S. K. Iyer Dept. of Chemistry, School of Advanced Sciences, Vellore Institute of Technology, Vellore-632014, India Supporting information for this article is available on the WWW under https://doi.org/10.1002/minf.201800048 Full Paper www.molinf.com © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Mol. Inf. 2018, 37, 1800048 (1 of 10) 1800048