In silico strategies for identifying therapeutic candidates against Acinetobacter baumannii: spotlight on the UDP-N-acetylmuramoyl-L-alanine-D-glutamate:meso-diaminopimelate ligase (MurE).

The opportunistic bacterium Acinetobacter baumannii, which belongs to ESKAPE group of pathogenic bacteria, is leading cause of infections associated with gram-negative bacteria. Acinetobacter baumannii causes severe diseases, such as VAP (ventilator-associated pneumonia), meningitis, and UTI (urinary tract infections) among the nosocomial infections contracted in hospitals. The high infection rate and growing resistance to the vast array of antibiotics makes it paramount to look for new therapeutic strategies against this pathogen. The most promising therapeutic targets are the proteins involved in the synthesis of peptidoglycan which is chief component of bacterial cell wall, MurE is one of those enzymes and is responsible for the addition of one unit of meso-diaminopimelic acid (meso-A2pm) to the nucleotide precursor, UDPMurNAc-L-Ala-D-Glu, and aids in the formation of crosslinker pentapeptide chain. The three-dimensional structure of MurE was modelled using homology modelling technique and then vHTS was performed using this model against Approved Drug Library on DrugRep server using AutoDock Vina. Out of 500 drug molecules, two were selected based on estimated binding affinity, interaction pattern, interacting residues, etc. The selected drug molecules are DB12887 (Tazemetostat) and DB13879 (Glecaprevir). Then, MD simulations were performed on native MurE and its complexes with ligands to examine their dynamical behaviour, stability, integrity, compactness, and folding properties. The protein-ligand complexes were then subjected to binding free energy calculations using the MM/PBSA-based binding free energy analysis and the values are -109.788 ± 8.03 and -152.753 ± 11.98 kcal for MurE-DB12887 and MurE-DB13879 complex, respectively. All the analysis performed on MD trajectories for the complexes of these ligands with protein provided plenty of dependable evidences to consider these molecules for inhibition of MurE enzyme from A. baumannii. Communicated by Ramaswamy H. Sarma.

Pathology, target discovery, and the evolution of XO inhibitors from the first discovery to recent advances (2020-2023).

Hyperuricemia, a disease characterized by elevation of serum uric acid level beyond 6 mg/dL. This elevation led to appearance of symptoms from joint pain to gout and from gout to difficulty in mobility of the patient. So, in this review, we have summarized the pathology of hyperuricemia, discovery of target and discovery of first XO inhibitor. At last, this review provides in-sights about the recently discovered as natural XO inhibitors, followed by design, structure activity relationship and biological activity of synthetic compounds as XO inhibitors discovered between 2020 and 2023 years. At last, the pharmacophores generated in this study will guide new researchers to design and modify the structure of novel XO inhibitors.

Molecular dynamics simulations assisted investigation of phytochemicals as potential lead candidates against anti-apoptotic Bcl-B protein.

Due to the multifarious nature of cancer, finding a single definitive cure for this dreadful disease remains an elusive challenge. The dysregulation of the apoptotic pathway or programmed cell death, governed by the Bcl-2 family of proteins plays a crucial role in cancer development and progression. Bcl-B stands out as a unique anti-apoptotic protein from the Bcl-2 family that selectively binds to Bax which inhibits its pro-apoptotic function. Although several inhibitors are reported for Bcl-2 family proteins, no specific inhibitors are available against the anti-apoptotic Bcl-B protein. This study aims to address this research gap by using virtual screening of an in-house library of phytochemicals from seven anti-cancer medicinal plants to identify lead molecules against Bcl-B protein. Through pharmacokinetic analysis and molecular docking studies, we identified three lead candidates (Enterolactone, Piperine, and Protopine) based on appreciable drug-likeliness, ADME properties, and binding affinity values. The identified molecules also exhibited specific interactions with critical amino acid residues of the binding cleft, highlighting their potential as lead candidates. Finally, molecular dynamics simulations and MM/PBSA based binding free energy analysis revealed that Enterolactone (CID_114739) and Piperine (CID_638024) molecules were on par with Obatoclax (CID_11404337), which is a known inhibitor of the Bcl-2 family proteins.Communicated by Ramaswamy H. Sarma.

Non-Steroidal Anti-Inflammatory Drug Effect on the Binding of Plasma Protein with Antibiotic Drug Ceftazidime: Spectroscopic and In Silico Investigation.

The coexistence of ceftazidime, which is a popular third-generation of cephalosporin antibiotic, with ubiquitous paracetamol or acetaminophen, is very likely because the latter is given to the patients to reduce fever due to bacterial infection along with an antibiotic such as the former. Therefore, in this study, we investigated the detailed binding of ceftazidime with plasma protein, human serum albumin (HSA), in the absence and presence of paracetamol using spectroscopic techniques such as fluorescence, UV-visible, and circular dichroism, along with in silico methods such as molecular docking, molecular dynamics simulations, and MM/PBSA-based binding free energy analysis. The basic idea of the interaction was attained by using UV-visible spectroscopy. Further, fluorescence spectroscopy revealed that there was a fair interaction between ceftazidime and HSA, and the mechanism of the quenching was a dynamic one, i.e., the quenching constant increased with increasing temperature. The interaction was, primarily, reinforced by hydrophobic forces, which resulted in the partial unfolding of the protein. Low concentrations of paracetamol were ineffective in affecting the binding of ceftazidime with has; although, a decrease in the quenching and binding constants was observed in the presence of high concentrations of the former. Competitive binding site experiments using warfarin and ibuprofen as site markers revealed that ceftazidime neither binds at drug site 1 or at drug site 2, articulating another binding site, which was confirmed by molecular docking simulations.

Targeting multi-drug-resistant Acinetobacter baumannii: a structure-based approach to identify the promising lead candidates against glutamate racemase.

CONTEXT: Acinetobacter baumannii, one of the critical ESKAPE pathogens, is a highly resilient, multi-drug-resistant, Gramnegative, rod-shaped, highly pathogenic bacteria. It is responsible for almost 1-2% of all hospital-borne infections in immunocompromised patients and causes community outbreaks. Because of its resilience and MDR characteristics, looking for new strategies to check the infections related to this pathogen becomes paramount. The enzymes involved in the peptidoglycan biosynthetic pathway are attractive and the most promising drug targets. They contribute to the formation of the bacterial envelope and help to maintain the rigidity and integrity of the cell. The MurI (glutamate racemase) is one of the crucial enzymes that aid in the formation of the pentapeptide responsible for the interlinkage of peptidoglycan chains. It converts L-glutamate to D-glutamate, which is required to synthesise the pentapeptide chain. METHODS: In this study, the MurI protein of A. baumannii (strain AYE) was modelled and subjected to high-throughput virtual screening against the enamine-HTSC library, taking UDP-MurNAc-Ala binding site as the targeted site. Four ligand molecules, Z1156941329 (N-(1-methyl-2-oxo-3,4-dihydroquinolin-6-yl)-1-phenyl-3,4-dihydro-1H-isoquinoline-2-carboxamide), Z1726360919 (1-[2-[3-(benzimidazol-1-ylmethyl)piperidin-1-yl]-2-oxo-1-phenylethyl]piperidin-2-one), Z1920314754 (N-[[3-(3-methylphenyl)phenyl]methyl]-8-oxo-2,7-diazaspiro[4.4]nonane-2-carboxamide) and Z3240755352 (4R)-4-(2,5-difluorophenyl)-1-(4-fluorophenyl)-1,3a,4,5,7,7a-hexahydro-6H-pyrazolo[3,4-b]pyridin-6-one), were identified to be the lead candidates based on Lipinski's rule of five, toxicity, ADME properties, estimated binding affinity and intermolecular interactions. The complexes of these ligands with the protein molecule were then subjected to MD simulations to scrutinise their dynamic behaviour, structural stability and effects on protein dynamics. The molecular mechanics/Poisson-Boltzmann surface area-based binding free energy analysis was also performed to compute the binding free energy of protein-ligand complexes, which offered the following values -23.32 ± 3.04 kcal/mol, -20.67 ± 2.91kcal/mol, -8.93 ± 2.90 kcal/mol and -26.73 ± 2.95 kcal/mol for MurI-Z1726360919, MurI-Z1156941329, MurI-Z3240755352 and MurI-Z3240755354 complexes respectively. Together, the results from various computational analyses utilised in this study proposed that Z1726360919, Z1920314754 and Z3240755352 could act as potential lead molecules to suppress the function of MurI protein from Acinetobacter baumannii.

Identification and prioritization of potential therapeutic molecules against LpxA from Acinetobacter baumannii - A computational study.

A. baumannii is a ubiquitously found gram-negative, multi-drug resistant bacterial species from the ESKAPE family of pathogens known to be the causative agent for hospital-acquired infections such as pneumonia, meningitis, endocarditis, septicaemia and urinary tract infections. A. baumannii is implicated as a contributor to bloodstream infections in approximately 2% of all worldwide infections. Hence, exploring novel therapeutic agents against the bacterium is essential. LpxA or UDP-N-acetylglucosamine acetyltransferase is an essential enzyme important in Lipid A biosynthesis which catalyses the reversible transfer of an acetyl group on the glucosamine 3-OH of the UDP-GlcNAc which is a crucial step in the biosynthesis of the protective Lipopolysaccharides (LPS) layer of the bacteria which upon disruption can lead to the elimination of the bacterium which delineates LpxA as an appreciable drug target from A. baumannii. The present study performs high throughput virtual screening of LpxA against the enamine-HTSC-large-molecule library and performs toxicity and ADME screening to identify the three promising lead molecules subjected to molecular dynamics simulations. Global and essential dynamics analysis of LpxA and its complexes along with FEL and MM/PBSA based binding free energy delineate Z367461724 and Z219244584 as potential inhibitors against LpxA from A. baumannii.

Structural and functional characterization of 1-deoxy-D-xylulose-5-phosphate synthase (DXS) from Acinetobacter baumannii: identification of promising lead molecules from virtual screening, molecular docking and molecular dynamics simulations.

The advent of multi drug resistance and extensive-drug resistance among various pathogens has caused a rise in nosocomial infections, which in turn has led to rising hospital-acquired infection-related mortality rates. Amongst them, carbapenem-resistant Acinetobacter baumannii is one of the most notorious bacterial species, categorized as a Priority 1: Critical pathogen by the WHO. Therefore, the discovery and development of novel antibiotics, as well as the identification of potential inhibitors, have become the need of the hour. In this study, we have employed computational methods to explore and identify molecules capable of inhibiting enzymes essential in the methylerythritol 4-phosphate (MEP) biosynthetic pathway. The high throughput virtual screening of small molecules (Enamine Advanced Collection (AC) library) against the highly conserved substrate-binding site of the DXS target protein provided us with a total of 1000 molecules. The top four potential candidate molecules, namely-Z3353989070, Z3353989049, Z2295848528, and Z1685501455, alongside fluoropyruvate (control), a known inhibitor of DXS, was chosen for a molecular dynamic simulation study. The molecular dynamic simulation trajectories suggested high structural and thermodynamical stability and strong binding affinity of all the DXS-ligand complexes. Moreover, the MM/PBSA-based binding free energy calculations also exhibited strong interactions of the selected ligand molecules with DXS. In conclusion, we have found that all four molecules displayed better results and stronger binding affinity than the control. In the end, based on all the above-mentioned criteria, we have proposed Z3353989049 to be the promising lead candidate against DXS from A. baumannii.Communicated by Ramaswamy H. Sarma.

Droperidol as a potential inhibitor of acyl-homoserine lactone synthase from A. baumannii: insights from virtual screening, MD simulations and MM/PBSA calculations.

Acinetobacter baumannii belongs to the ESKAPE family of pathogens and is a multi-drug resistant, gram-negative bacteria which follows the anaerobic form of respiration. A. baumannii is known to be the causative agent of hospital-related infections such as pneumonia, meningitis, endocarditis, septicaemia and a plethora of infections such as urinary tract infections found primarily in immunocompromised patients. These attributes of A. baumannii make it a priority pathogen against which potential therapeutic agents need to be developed. A. baumannii employs the formation of a biofilm to insulate its colonies from the outer environment, which allows it to grow under harsh environmental conditions and develop resistance against various drug molecules. Acyl-homoserine lactone synthase (AHLS) is an enzyme involved in the quorum-sensing pathway in A. baumannii, which is responsible for the synthesis of signal molecules known as acyl-homoserine lactones, which trigger the signalling pathway to regulate the factors involved in biofilm formation and regulation. The present study utilised a homology-modelled structure of AHLS to virtually screen it against the ZINC in trial/FDA-approved drug molecule library to find a subset of potential lead candidates. These molecules were then filtered based on Lipinski's, toxicological and ADME properties, binding affinity, and interaction patterns to delineate lead molecules. Finally, three promising molecules were selected, and their estimated binding affinity values were corroborated using AutoDock 4.2. The identified molecules and a control molecule were subsequently subjected to MD simulations to mimic the physiological conditions of protein ligand-binding interaction under the influence of a GROMOS forcefield. The global and essential dynamics analyses and MM/PBSA based binding free energy computations suggested Droperidol and Cipargamin as potential inhibitors against the binding site of AHLS from A. baumannii. The binding free energy calculations based on the MM/PBSA method showed excellent results for Droperidol (- 50.02 ± 4.67 kcal/mol) and Cipargamin (- 42.29 ± 4.05 kcal/mol).

A computational essential dynamics approach to investigate structural influences of ligand binding on Papain like protease from SARS-CoV-2.

Papain like protease (PLpro) is a cysteine protease from the coronaviridae family of viruses. Coronaviruses possess a positive sense, single-strand RNA, leading to the translation of two viral polypeptides containing viral structural, non-structural and accessory proteins. PLpro is responsible for the cleavage of nsp1-3 from the viral polypeptide. PLpro also possesses deubiquitinating and deISGlyating activity, which sequesters the virus from the host's immune system. This indispensable attribute of PLpro makes it a protein of interest as a drug target. The present study aims to analyze the structural influences of ligand binding on PLpro. First, PLpro was screened against the ZINC-in-trials library, from which four lead compounds were identified based on estimated binding affinity and interaction patterns. Next, based on molecular docking results, ZINC000000596945, ZINC000064033452 and VIR251 (control molecule) were subjected to molecular dynamics simulation. The study evaluated global and essential dynamics analyses utilising principal component analyses, dynamic cross-correlation matrix, free energy landscape and time-dependant essential dynamics to predict the structural changes observed in PLpro upon ligand binding in a simulated environment. The MM/PBSA-based binding free energy calculations of the two selected molecules, ZINC000000596945 (-41.23 ± 3.70 kcal/mol) and ZINC000064033452 (-25.10 ± 2.65 kcal/mol), displayed significant values which delineate them as potential inhibitors of PLpro from SARS-CoV-2.

An extensive computational study to identify potential inhibitors of Acyl-homoserine-lactone synthase from Acinetobacter baumannii (strain AYE).

A member of the ESKAPE family of pathogens, A. baumannii, is an opportunistic gram-negative multidrug-resistant bacterium. A. baumannii is a ubiquitous coccobacillus involved in various hospital-related infections such as wound infections, pneumonia, urinary tract infections, septicaemia, endocarditis and ventilator assisted pneumonia and accounts for approximately 1-2% of all nosocomial bloodstream infections; hence it becomes imperative to identify potential therapeutic agents against the dreadful pathogen. The quorum-sensing pathway becomes an attractive drug target due to its role in biofilm regulation and formation, which provides the bacteria insulation from the harsh environment. A crucial protein in biofilm formation and regulation is Acyl-homoserine-lactone synthase (AHLS), responsible for producing signal molecules that trigger the signalling pathway for biofilm formation and regulation. The current study modeled the three-dimensional structure of AHLS in A. baumannii (strain AYE) followed by high-throughput virtual screening of the enamine-AC small-molecule database to identify lead molecules against its acylated-ACP (Acyl Carrier Protein) substrate-binding site. Based on the estimated binding affinity, estimated inhibition constant, ADME analysis and interaction patterns of the screened molecules, three lead candidates (Z815888654, Z2416029019, Z3766992625) were identified along with a control molecule (J8-C8). These molecules were then subjected to molecular dynamics simulations where the physiological effect of ligand binding on the protein was virtually predicted and analysed. The MM/PBSA based binding free energy calculations showed favourable results for Z815888654 (-22.77 ± 2.94 kcal/mol), Z2416029019 (-33.68 ± 2.63 kcal/mol), Z3766992625 (-21.44 ± 3.40 kcal/mol). The study employed global and essential dynamics analyses, MM/PBSA based binding free energy, free energy landscape and dynamic cross-correlation matrix to suggest Z815888654, Z2416029019 and Z3766992625 as potential inhibitors against the acylated-ACP substrate-binding site in AHLS from A. baumannii.

Identification of promising antiviral drug candidates against non-structural protein 15 (NSP15) from SARS-CoV-2: an in silico assisted drug-repurposing study.

The recent COVID-19 pandemic caused by SARS-CoV-2 has recorded a high number of infected people across the globe. The virulent nature of the virus makes it necessary for us to identify promising therapeutic agents in a time-sensitive manner. The current study utilises an in silico based drug repurposing approach to identify potential anti-viral drug candidates targeting non-structural protein 15 (NSP15), i.e. a uridylate specific endoribonuclease of SARS-CoV-2 which plays an indispensable role in RNA processing and viral immune evasion from the host immune system. The NSP15 protein was screened against an in-house library of 123 antiviral drugs obtained from the DrugBank database from which three promising drug candidates were identified based on their estimated binding affinities (ΔG), estimated inhibition constants (Ki), the orientation of drug molecules in the active site and the key interacting residues of NSP15. Molecular dynamics (MD) simulations were performed for the screened drug candidates in complex with NSP15 as well as the apo form of NSP15 to mimic their physiological states. Based on the stable MD simulation trajectories, the binding free energies of the screened NSP15-drug complexes were calculated using the MM/PBSA approach. Two candidate drugs, Simeprevir and Paritaprevir, achieved the lowest binding free energies for NSP15, with a value of -259.522 ± 17.579 and -154.051 ± 33.628 kJ/mol, respectively. In addition, their complexes with NSP15 also exhibited the strongest structural stabilities. Taken together, we propose that Simeprevir and Paritaprevir are promising drug candidates to inhibit NSP15 and may act as potential therapeutic agents against SARS-CoV-2.Communicated by Ramaswamy H. Sarma.

Identifying the natural compound Catechin from tropical mangrove plants as a potential lead candidate against 3CLpro from SARS-CoV-2: An integrated in silico approach.

SARS-CoV-2, a member of beta coronaviruses, is a single-stranded, positive-sense RNA virus responsible for the COVID-19 pandemic. With global fatalities of the pandemic exceeding 4.57 million, it becomes crucial to identify effective therapeutics against the virus. A protease, 3CLpro, is responsible for the proteolysis of viral polypeptides into functional proteins, which is essential for viral pathogenesis. This indispensable activity of 3CLpro makes it an attractive target for inhibition studies. The current study aimed to identify potential lead molecules against 3CLpro of SARS-CoV-2 using a manually curated in-house library of antiviral compounds from mangrove plants. This study employed the structure-based virtual screening technique to evaluate an in-house library of antiviral compounds against 3CLpro of SARS-CoV-2. The library was comprised of thirty-three experimentally proven antiviral molecules extracted from different species of tropical mangrove plants. The molecules in the library were virtually screened using AutoDock Vina, and subsequently, the top five promising 3CLpro-ligand complexes along with 3CLpro-N3 (control molecule) complex were subjected to MD simulations to comprehend their dynamic behaviour and structural stabilities. Finally, the MM/PBSA approach was used to calculate the binding free energies of 3CLpro complexes. Among all the studied compounds, Catechin achieved the most significant binding free energy (-40.3 ± 3.1 kcal/mol), and was closest to the control molecule (-42.8 ± 5.1 kcal/mol), and its complex with 3CLpro exhibited the highest structural stability. Through extensive computational investigations, we propose Catechin as a potential therapeutic agent against SARS-CoV-2. Communicated by Ramaswamy H. Sarma.

Targeting SARS-CoV-2: a systematic drug repurposing approach to identify promising inhibitors against 3C-like proteinase and 2'-O-ribose methyltransferase.

The recent pandemic associated with SARS-CoV-2, a virus of the Coronaviridae family, has resulted in an unprecedented number of infected people. The highly contagious nature of this virus makes it imperative for us to identify promising inhibitors from pre-existing antiviral drugs. Two druggable targets, namely 3C-like proteinase (3CLpro) and 2'-O-ribose methyltransferase (2'-O-MTase) were selected in this study due to their indispensable nature in the viral life cycle. 3CLpro is a cysteine protease responsible for the proteolysis of replicase polyproteins resulting in the formation of various functional proteins, whereas 2'-O-MTase methylates the ribose 2'-O position of the first and second nucleotide of viral mRNA, which sequesters it from the host immune system. The selected drug target proteins were screened against an in-house library of 123 antiviral drugs. Two promising drug molecules were identified for each protein based on their estimated free energy of binding (ΔG), the orientation of drug molecules in the active site and the interacting residues. The selected protein-drug complexes were then subjected to MD simulation, which consists of various structural parameters to equivalently reflect their physiological state. From the virtual screening results, two drug molecules were selected for each drug target protein [Paritaprevir (ΔG = -9.8 kcal/mol) & Raltegravir (ΔG = -7.8 kcal/mol) for 3CLpro and Dolutegravir (ΔG = -9.4 kcal/mol) and Bictegravir (ΔG = -8.4 kcal/mol) for 2'-OMTase]. After the extensive computational analysis, we proposed that Raltegravir, Paritaprevir, Bictegravir and Dolutegravir are excellent lead candidates for these crucial proteins and they could become potential therapeutic drugs against SARS-CoV-2. Communicated by Ramaswamy H. Sarma.

A comprehensive review on promising anti-viral therapeutic candidates identified against main protease from SARS-CoV-2 through various computational methods.

BACKGROUND: The COVID-19 pandemic caused by SARS-CoV-2 has shown an exponential trend of infected people across the planet. Crediting its virulent nature, it becomes imperative to identify potential therapeutic agents against the deadly virus. The 3-chymotrypsin-like protease (3CLpro) is a cysteine protease which causes the proteolysis of the replicase polyproteins to generate functional proteins, which is a crucial step for viral replication and infection. Computational methods have been applied in recent studies to identify promising inhibitors against 3CLpro to inhibit the viral activity. This review provides an overview of promising drug/lead candidates identified so far against 3CLpro through various in silico approaches such as structure-based virtual screening (SBVS), ligand-based virtual screening (LBVS) and drug-repurposing/drug-reprofiling/drug-retasking. Further, the drugs have been classified according to their chemical structures or biological activity into flavonoids, peptides, terpenes, quinolines, nucleoside and nucleotide analogues, protease inhibitors, phenalene and antibiotic derivatives. These are then individually discussed based on the various structural parameters namely estimated free energy of binding (ΔG), key interacting residues, types of intermolecular interactions and structural stability of 3CLpro-ligand complexes obtained from the results of molecular dynamics (MD) simulations. CONCLUSION: The review provides comprehensive information of potential inhibitors identified through several computational methods thus far against 3CLpro from SARS-CoV-2 and provides a better understanding of their interaction patterns and dynamic states of free and ligand-bound 3CLpro structures.

Identification of promising molecules against MurD ligase from Acinetobacter baumannii: insights from comparative protein modelling, virtual screening, molecular dynamics simulations and MM/PBSA analysis.

Acinetobacter baumannii, an opportunistic bacterium of the multidrug-resistant (MDR) ESKAPE family of pathogens, is responsible for 2-10% infections associated with all gram-negative bacteria. The hospital-acquired nosocomial infections caused by A.baumannii include deadly diseases like ventilator-associated pneumonia, bacteremia, septicemia and urinary tract infections (UTI). Over the last 3 years, it has evolved into multiple strains demonstrating high antibiotic resistance against a wide array of antibiotics. Hence, it becomes imperative to identify novel drug-like molecules to treat such infections effectively. UDP-N-acetylmuramoyl-L-alanine-D-glutamate ligase (MurD) is an essential enzyme of the Mur family which is responsible for peptidoglycan biosynthesis, making it a unique and ideal drug target. Initially, a homology modelling approach was employed to predict the three-dimensional model of MurD from A. baumannii using MurD from Escherichia coli (PDB ID: 4UAG) as a suitable structural template. Subsequently, an optimised model of MurD was subjected to virtual high-throughput screening (vHTS) against a ZINC library of ~ 642,759 commercially available molecules to identify promising lead compounds demonstrating high binding affinities towards it. From the screening process, four promising molecules were identified based on the estimated binding affinities (ΔG), estimated inhibition constants (Ki), catalytic residue interactions and drug-like properties, which were then subjected to molecular dynamics (MD) simulation studies to reflect the physiological state of protein molecules in vivo equivalently. The binding free energies of the selected MurD-ligand complexes were also calculated using MM/PBSA (molecular mechanics with Poisson-Boltzmann and surface area solvation) approach. Finally, the global dynamics along with binding free energy analysis suggested that ZINC19221101 (ΔG = - 62.6 ± 5.6 kcal/mol) and ZINC12454357 (ΔG = - 46.1 ± 2.6 kcal/mol) could act as most promising candidates for inhibiting the function of MurD ligase and aid in drug discovery and development against A.baumannii. Graphical abstract.