Discovery of potential inhibitors against New Delhi metallo-β-lactamase-1 from natural compounds: in silico-based methods

www.nature.com/scientificreports OPEN Discovery of potential inhibitors against New Delhi metallo‑β‑lactamase‑1 from natural compounds: in silico‑based methods Azhar Salari‑jazi1, Karim Mahnam2, Parisa Sadeghi1, Mohamad Sadegh Damavandi1 & Jamshid Faghri1* New Delhi metallo-β-lactamase variants and different types of metallo-β-lactamases have attracted enormous consideration for hydrolyzing almost all β-lactam antibiotics, which leads to multi drug resistance bacteria. Metallo-β-lactamases genes have disseminated in hospitals and all parts of the world and became a public health concern. There is no inhibitor for New Delhi metallo-β-lactamase-1 and other metallo-β-lactamases classes, so metallo-β-lactamases inhibitor drugs became an urgent need. In this study, multi-steps virtual screening was done over the NPASS database with 35,032 natural compounds. At first Captopril was extracted from 4EXS PDB code and use as a template for the first structural screening and 500 compounds obtained as hit compounds by molecular docking. Then the best ligand, i.e. NPC120633 was used as templet and 800 similar compounds were obtained. As a final point, ten compounds i.e. NPC171932, NPC100251, NPC18185, NPC98583, NPC112380, NPC471403, NPC471404, NPC472454, NPC473010 and NPC300657 had proper docking scores, and a 50 ns molecular dynamics simulation was performed for calculation binding free energy of each compound with New Delhi metallo-β-lactamase. Protein sequence alignment, 3D conformational alignment, pharmacophore modeling on all New Delhi metallo-β-lactamase variants and all types of metallo-β-lactamases were done. Quantum chemical perspective based on the fragment molecular orbital (FMO) method was performed to discover conserved and crucial residues in the catalytic activity of metallo-β-lactamases. These residues had similar 3D coordinates of spatial location in the 3D conformational alignment. So it is posibble that all types of metallo-β-lactamases can inhibit by these ten compounds. Therefore, these compounds were proper to mostly inhibit all metallo-βlactamases in experimental studies. Abbreviations NDM-1 New Delhi metallo-beta-lactamase-1 MBL Metallo-β-lactamases MDR Multidrug Resistance RMSD Root mean square deviation RMSF Root mean square fluctuation NP Natural product Multi-drug resistance has become a significant threat to global health, and it appears that discovery of new class antibiotics is in an uttermost need for humankind1. Globally, beta-lactam antibiotics have been extensively prescribed to treat bacterial infections. The considerable rise of antibiotic resistance in bacteria emanates from excessive use of beta-lactam antibiotics2. Beta-lactamases in bacteria are the most common mechanism to hydrolyze beta-lactam antibiotics and their resistance. β-Lactamase enzymes are a bacterial defense mechanism to hydrolyze amide bond in beta-lactam antibiotics that inactivate them. According to the Ambler 1 Department of Microbiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran. 2Biology Department, Faculty of Sciences, Shehrekord University, Shahrekord, Iran. *email: Scientific Reports | (2021) 11:2390 | https://doi.org/10.1038/s41598-021-82009-6 1 Vol.:(0123456789) www.nature.com/scientificreports/ classification, beta-lactamases are divided into four classes (A, B, C, and D) consisting of two major families: serine-β-lactamases (SBLs) and Metallo-β-lactamases (MBLs)3,4. SBLs (A, C, and D Ambler’s class) are serine hydrolases, while MBLs (B class) perform zinc ion in the active site as metallo-enzyme. Metallo-β-lactamases, owing to their broad-spectrum activities in the hydrolase of β-lactam antibiotics, are a considerable danger for human health. MBLs are divided into subclasses B1, B2, and B3, and subclass B1 has the most clinical relevance and most commonly emergence among MBLs enzymes. This class has been found in Enterobacteriaceae members, and the enzyme members of this class have two ion zinc in the active site. Some enzymes of subclass B1 consisting of VIM (Verona integron-borne metallo-β-lactamase), IMP (imipenemase), and NDM (New Delhi metallo-βlactamase-1) have the highest f requency4. First time in 2009, New Delhi metallo-β-lactamase-1 (NDM-1) was identified in Klebsiella pneumonia from a clinical sample isolated from a tourist patient in New Delhi5. Further assessments showed that this enzyme had high resistance to all classes of beta-lactam antibiotics except m onobactams6. After the NDM-1 first report, variants of this enzyme emerged in the world and it became a global concern7. Furthermore, most plasmids carrying the NDM-1 gene often associate to other resistance genes, such as sulfonamides, rifampin, chloramphenicol, quinolones, and macrolides8,9. This property converts NDM-1 carrying bacteria to multi-drug resistant bacteria. Hence, NDM positive strains with these broad resistances to multiple drugs have grown a severe worldwide menace. The worldwide distribution of NDM-1 has a considerable impact on treating different kinds of infections. Currently, there is no potent inhibitor against this enzyme; therefore, finding an inhibitor for it has become indispensable10,11. Natural products (NPs) are a safe resource for human use and are suggested as a valuable source substitute for small molecule drugs. NPs are secondary metabolites derived from natural sources, e.g., micro-organisms, plants and animals, which have valuable and considerable biological activity12–14. These molecules have been selected within thousands of years to improve human health. In this study, the Natural Products Activity and Species Source (NPASSv1.0) database is used to screen natural compounds against NDM-1. Currently, the NPASS database consists of 35,032 NPs from different species sources. Traditional chines medicine (TCM) plants and different kinds of NPs and plants are included in this d atabase15. Every subclass of MBLs has several types of enzymes and every type has several subtypes of enzymes. There are some FDA-approval small molecules (such as Vaborbactam, clavulanic acid, sulbactam, tazobactam) to inhibit the serine β-lactamases, however these small molecules are ineffective to suppress the metallo-β-lactamases16–18. It seems like common pharmacophore, 3D conformational alignment and fragment molecular orbital calculation are essential to recognize worthy small molecules that are potent to inhibit all types of metallo-β-lactamases. Pharmacophore modeling and 3D conformational alignment across all types of the MBL lead to monitor hot spot or vital residues which are common in the spatial location and sequence position. Finally, FMO and pair interaction energy decomposition analyses were the best option to analyze the crucial conserved residues and confirm the other results. Targeting of these residues by small molecules or natural compounds maybe inhibit all forms of MBLs and terminate domination of them. Small molecules w (...truncated)