Surgical Site Infection (SSI) is the common consequence of hernia surgery. This study aimed to develop an artificial intelligence (AI)-driven predictive model for SSI following open ventral hernia repair using pre- and intra-operative parameters for early detection. A prospective analysis of ventral hernia patients was conducted. Demographic, pre-operative and intra-operative parameters were collected. Feature selection using Recursive Feature Elimination (RFE) identified key predictors. Five models, eXtreme Gradient Boosting (XGBoost), logistic regression, support vector machine (SVM), Adaptive Boosting and random forest (RF), were trained and validated. Among 253 patients, 22 were SSI-positive. RF demonstrated the highest predictive power (area under receiver operating characteristic curve = 0.82) and diagnostic odds ratio (DOR = 55). Seven key predictors were identified: defect size area, HbA1c, lymphocytes, neutrophil-to-lymphocyte ratio, blood loss (ml), platelet count and serum albumin. Decision curve analysis showed an estimated risk stratification at an 8.3 https://surgicut-ai.netlify.app/ ”. The model’s high accuracy supports its potential for clinical decision-making. External validation is required for real-world application. Integrating this AI model into bedside tools may enhance SSI prevention, especially in resource-limited settings.

Acinetobacter baumannii is an opportunistic pathogen known for its extensive antibiotic resistance, posing a significant concern in healthcare settings. Given global concern over broad-spectrum antibiotic use and its impact on the human microbiome, targeting the bacterial cell-division protein Filamenting temperature-sensitive Z (FtsZ) is a promising strategy for developing new antibiotics, as this protein is essential for bacterial cell division. FtsZ polymerizes into filaments to form the Z-ring at the cell division site. This Z-ring orchestrates the recruitment of other crucial proteins in cytokinesis and cell wall synthesis, making it critical for bacterial viability. To target FtsZ from Acinetobacter baumannii (abFtsZ), we have elucidated the first crystal structures in the apo and GDP-bound state. The structural analysis revealed that the abFtsZ-GDP complex exists in a relaxed state conformation with weak inter-subunit interactions. The GTPase activity of abFtsZ showed a Vmax of 3.3 ± 0.4 nmolP/nmolFtsZ/min, and a Km of 2.3 mM. By virtual screening using the crystal structure of abFtsZ, we identified six potential inhibitors: Gossypin, Stafib-1, Tryphostin A51, Sangivamycin, Scutellarin, and Ellagic acid that target the GTP-binding pocket. These inhibitors exhibited high docking scores ranging from -10.2 to -8.4 kcal/mol and remained stable throughout the 500 ns MD simulation. These inhibitors can serve as lead molecules for the development of a new antibacterial agent.

BACKGROUND Cancer remains a major cause of mortality globally, and EGFR overexpression is implicated in ~30% of epithelial malignancies with poor prognosis. While two classes of drugs are clinically approved for their treatment, these drugs suffer from drawbacks, including acquired resistance, bypassed signalling, limited solid tumor penetration, on-target toxicity, and higher production costs. To overcome these limitations, we require alternative therapeutics against the EGFR altered cancers. METHODS In this study, we identified Apt64, a novel G-quadruplex-forming DNA aptamer, using Protein-SELEX against a baculovirus-expressed EGFR ectodomain. Biophysical and biochemical analysis of Apt64 revealed the formation of a stable parallel G-quadruplex conformation, exceptional thermal and serum stability. Functional assays were performed with different cancer cell lines to evaluate target specificity, cytotoxicity, cell cycle analysis, apoptosis assay, and inhibition of EGFR signalling RESULTS The selected aptamer exhibited high-affinity binding for sEGFR ( Kd = 25.77 nM), comparable to Cetuximab ( Kd = 8.98 nM). Functional evaluation in different cell lines suggested its target specificity and superior efficacy compared to Cetuximab. Apt64 induced 83% G0/G1 cell cycle arrest at 250 nM, whereas Cetuximab caused only 67% arrest even at 500 nM and triggered more than two-fold higher apoptosis than Cetuximab. Further, Apt64 effectively inhibited EGFR phosphorylation at Tyr1068, thereby stalling downstream signalling required for cancer cell survival and proliferation. CONCLUSIONS Collectively, these findings highlight Apt64 as a potent, structurally stable, and cost-effective therapeutic candidate against EGFR-driven cancers compared with existing therapies, warranting further preclinical and clinical evaluation.

RdRp is a critical component of an RNA virus life cycle. Among coronaviruses, NSP12, along with one copy of NSP7 and two copies of NSP8, forms the RdRp holoenzyme and exhibits polymerase activity. While coronavirus RNA replication is sufficiently understood, the interplay among these NSPs and its influence on RNA binding and nascent strand synthesis remains poorly understood. Here, we reconstituted a functional RdRp holoenzyme using recombinant SARS-CoV-2 NSP12, NSP7, and NSP8 in vitro. Molecular interactions among NSPs and their effect on the polymerase activity were investigated, wherein NSP12 alone exhibited notable activity, which was further enhanced by the presence of both NSP7 and NSP8. The presence of only one cofactor, either NSP7 or NSP8, completely inhibited NSP12 activity and led to RNA template detachment. Computational analyses of different NSP12 complexes suggested that binding of NSP7 or NSP8 alone to NSP12 constricts the RNA entry channel, which was higher in the presence of NSP8, making it inappropriate for RNA entry/binding. We conclude that NSP7 and NSP8 together synergize to enhance the NSP12 activity, but antagonize when alone. These findings have implications for novel drug development, and compounds inhibiting NSP7 or NSP8 interactions with NSP12 can be lethal to coronavirus replication.

Background: Heavy metals, such as Cadmium (Cd), Arsenic (As), Mercury (Hg) and Lead (Pb) might potentially induce reproductive toxicity in male infertility patients, regardless of the varying concentrations of these heavy metals in the blood. Genetic polymorphism is one of the least studied internal contributing factors in male infertility cases associated with high level of heavy metal in blood. Therefore, this study aims at identifying the difference in the serum levels of heavy metals in non-obstructive azoospermia (NOA) patients associated with genetic variants. Methods: It’s a hospital based observational study where patients reporting with azoospermia due to hypospermatogenesis (HS) were recruited prospectively. Comprehensive clinical history, and blood samples were collected. Whole exome sequencing (WES) and was performed for 50 HS patients to identify variants. Inductively coupled plasma mass spectrometry (ICP-MS) was performed to assess levels of Cd, As, Hg and Pb levels in serum samples of 50 HS patients. Statistical analysis was performed to determine difference in heavy metal concentration of HS patients with and without the presence of metallothionein gene associated single nucleotide polymorphism (SNP). Results: Genomic analysis for SNPs identified deleterious candidate variants in MT1A (rs11640851 and rs8052394) associated with 18/50, MT1E (rs138690474) associated with 4/50 and MT4 (rs11643815) associated with 5/50 HS patients. A statistically significant difference in the blood concentration of Cd and Hg was observed in HS patients associated with metallothionein gene SNPs. Conclusions: This exploratory genomic analysis conducted on HS patients shows prevalence of deleterious candidate SNPs in metallothionein gene. The HS patients with candidate SNPs showed higher levels of Cd and Hg which indicate the genomic susceptibly towards heavy metal-induced reproductive toxicity.

To evaluate the effects of a very-low-calorie diet (VLCD) on insulin resistance (IR), metabolic gene expression, and fatty acid profiles in obese patients (body mass index [BMI] ≥ 30 kg/m2) undergoing bariatric surgery compared to age- and sex-matched nonobese controls (BMI ≤ 25 kg/m2) undergoing elective abdominal surgery. A total of 38 participants (21 obese and 17 nonobese controls) were recruited for this study. Obese patients underwent VLCD (800 kcal/day) for four weeks before surgery. Fasting blood samples and tissue biopsies were collected during surgery. Key parameters included IR (measured using HOMA-IR), metabolic gene expression (quantified via RT-PCR), and fatty acid composition (analyzed by gas chromatography). Data were compared between pre- and post-VLCD groups in the obese cohort. GLUT4 expression was reduced (1.57-fold, p = 0.025), whereas PDK4 (3.9-fold, p = 0.002), CPT1 (2.5-fold, p = 0.013), and AMPK (twofold, p = 0.004) expression were Correlation analysis revealed that GLUT4 was negatively correlated with BMI (r = -0.85), glucose (r = -0.94), and IR (r = -0.79), CPT1 was positively correlated with these parameters (BMI: r = 0.84, glucose: r = 0.92, IR: r = 0.82). VLCD significantly reduced monounsaturated fatty acids, including alpha-linolenic acid (p = 0.03) and erucic acid (p = 0.019). Postsurgical improvements included reductions in BMI (Δ = 6.21, p < 0.0001), glucose level (Δ = 6.94, p = 0.0007), and IR (Δ = 10.19, p = 0.0039). VLCD modulated metabolic gene expression and fatty acid profiles, enhancing IR and metabolic health both pre- and post-surgery. This represents a critical strategy for optimizing the outcomes of obese patients undergoing bariatric surgery.

Histological grade holds great clinical significance in the management and prognosis of bladder cancer; therefore, timely and accurate prediction through non-invasive techniques such as MRI may improve health outcomes. Our objective was to create an MRI-based radiomics model that can predict the histological grade of cancer pre-operatively. In a prospective study, we gathered data from 45 bladder cancer patients who had an mpMRI scan from December 2018 to December 2022 prior to their operative procedure. Radiomics features were extracted from T2-weighted (T2W), diffusion-weighted imaging (DWI), and dynamic DCE-MRI-enhanced (DCE) MR images obtained from a 1.5 T MRI scanner. A standard 5-point VI-RADS scoring system was also assessed for each scan. The variable clustering algorithm was applied to these features, and all cluster features were univariably assessed using receiver operating characteristic (ROC) curves. Multiple predictive models were created and cross-validated based on multivariable analysis to minimize overfitting and predict the grade of the tumor. Among 45 eligible patients, 28 (62.2

IntroductionHypospermatogenesis is a common histopathological subtype of non-obstructive azoospermia and is characterized by a decrease in the total number of germ cells within the seminiferous tubule as a result of spermatogenic failure. Determination of genetic factors before intracytoplasmic sperm injection can prevent the inheritance of these factors, as hypospermatogenesis patients gives high successful sperm retrieval rate. This study aimed to identify the structural variants associated with idiopathic hypospermatogenesis (iHS) by analyzing patient cohorts diagnosed with azoospermia using whole exome sequencing.MethodsIt is a hospital-based observational study in which patients reporting with azoospermia due to spermatogenic failure were recruited prospectively. Comprehensive clinical history, blood samples, semen analysis parameters, and reproductive endocrine evaluation reports of 51 hypospermatogenesis patients were collected. The known genetic causes were investigated using XY fluorescent in situ hybridization and Yq microdeletion for exclusion. Whole exome sequencing was performed, and the data of 42 iHS patients was analyzed to identify single nucleotide variants associated with diagnostically important male infertility genes.ResultsGenomic analysis of SNVs identified rare deleterious candidate variants in CFTR (c.1265C>T; p.Ser422Phe), CYP21A2 (c.955C>T; p.Gln319Glu), SRD5A2 (c.737G>A; p.Arg245Gln), LHCGR (c.378A>C; p.Lys126Asn) and AR (c.2179C>A; p.Arg727Ser) genes associated with 7/42 idiopathic hypospermatogenesis patients. In silico analysis of variants shows deleterious and probably damaging effects on canonical transcripts of the genes.DiscussionThis exploratory genomic analysis conducted on idiopathic hypospermatogenesis patients shows prevalence of rare deleterious candidate variants in genes associated with human male infertility. The candidate variants in idiopathic hypospermatogenesis patients are heterozygous and genotypically associated with syndromic male infertility. The symptomatic heterozygosity leading to mild spermatogenic failure resulting in hypospermatogenesis points towards a multifactorial etiology of the disease. This study justifies the importance of genetic screening of idiopathic hypospermatogenesis patients for the presence of structural variants in known human male infertility genes.

Background: Infertility has emerged as one of the most challenging reproductive health issues of modern times affecting approximately 10–15% of couples globally. Infertility is a multidimensional issue requiring psychosocial interventions. To explore perceptions regarding individual, psychosocial and cultural influences on infertility among women of reproductive age in Chandigarh. To interrelate individual, psychosocial and cultural influences of infertility with demographic characteristics of women. Methods: Cross-sectional study conducted during January 2025 to June 2025, using mixed-method approach included 256 women aged 18–49 years in Chandigarh selected by stratified two-stage random sampling technique. They were interviewed in depth for their opinions concerning individual and socio-cultural contexts of infertility. Quantitative analysis included descriptive statistics and Chi-square tests. Results: Most participants were aged 26–35 years (42.6%), followed by 36–49 years (41.8%), Blaming women for infertility was reported by 83 (32.4%) respondents. Infertility was perceived influencing adversely women’s self-esteem strongly agreed by 58 (22.7%) respondents, Societal attitudes included banning from social functions (22.3%), lack of respect from family (149.2%), extramarital affairs (16.4%). Cultural beliefs included emotional breakdown (33.6%) followed by old age support (8.8%). No significant associations between socio-cultural contexts and demographic characteristics were found, indicating that stigma and negative perceptions surrounding infertility cut across all socio-demographic groups. Conclusions: Infertility was mostly attributed to women with significant emotional, social and cultural linkages such as guilt, reduced self-esteem, lack of family support and exclusion from social functions. Individual and socio-cultural contexts were found irrespective of demographic characteristics. Psycho-social interventions along with medical infertility management strategies should be adopted addressing stigma and cultural misconceptions.

Hypoxia emerges as the major barrier at high altitude for military troops and mountaineers. Prophylaxis with carbonic anhydrase inhibitors like acetazolamide (ACZ) has been suggested for better adaptation and survival at altitude above 2500 m. The study present here compares the prophylactic efficacies of quercetin and acetazolamide in preventing Acute Mountain Sickness (AMS). We further aim to identify the potential pathway quercetin follows to exert its effects through binding studies with carbonic anhydrase (CA-II). Male SD rats (total number rats used=36) were supplemented orally with quercetin (50 mg/Kg BW) and acetazolamide (50 mg/Kg BW) and then subjected to hypobaric hypoxia (25,000 ft. for 12 h). Hypoxia induced oxidative imbalance, antioxidant inactivity and carbonic anhydrase activity were assessed in plasma of rats. The results obtained suggested that hypoxia induced oxidative imbalance (protein carbonylation) and antioxidant inactivity (glutathione reductase) was significantly restored by supplementation of quercetin in plasma of rats (p < 0.001). However, ACZ supplemented normoxia rats showed, enhanced levels of protein carbonylation in plasma of these rats in comparison with the normoxia control group. Prophylactic potential of both the drugs were further evaluated with hematological and blood gas parameters as well. Western blotting studies determined the differential expressions of EPO, Nrf-2 and HO-1 in rat kidney homogenates. Later, binding affinity of quercetin with CA-II was evaluated with Surface Plasmon Resonance (SPR). Quercetin considerably restored the expression of EPO, Nrf-2 and HO-1 to optimum levels by attenuating the oxidative stress and promoting the antioxidant milieu in the hypoxia exposed rats. SPR and molecular data does not support such inhibition of CA-II with quercetin. Thus, quercetin might have explored some other mechanism to attain the acclimatization in rats under hypoxia. These results indicate that, quercetin is a safe and potent drug for high altitude adjustments for better adaptability.

Introduction: Infertility is recognized as a global public health concern with life time prevalence of 17.5%. Infertility affects 60–80 million couples worldwide and about one fourth living in India. Knowledge about awareness, stigma, and socio-cultural beliefs attached with infertility in community set-up is very limited. Objectives: To investigate perceptions and challenges of women regarding awareness of infertility and fertility treatment. To identify their perceived needs facilitators and barriers in seeking treatment for infertility. To investigate socio-demographic characteristics of women influencing their awareness and perceptions concerning infertility. Methodology: Community-based, cross-sectional mixed-methods study conducted in Chandigarh during January to May 2025. Stratified two-stage random sampling was adopted. A total of 256 women aged 18–49 years were interviewed using semi-structured schedules. Quantitative data were analyzed using descriptive statistics and Chi-square test. Qualitative data were thematically analyzed.Results: Among 256 respondents, 55.9% were aware of infertility treatment; however, only 32.8% knew it is treatable. Education and socioeconomic status were significantly associated with awareness (P<0.05). Private hospitals were the preferred facility (53.1%). High treatment cost (41.4%), lack of family support (34.0%), and fear of side effects (37.5%) were major barriers. Income showed significant association with cost as a barrier (P=0.028). Conclusion: Awareness of infertility treatment among women in Chandigarh remains suboptimal, with misconceptions and stigma prevalent. Barriers include affordability, limited public facilities, and family-related pressures. Affordable and accessible infertility services in public health settings and psychosocial interventions are urgently required.

Background: Hormonal imbalance, mitochondrial dysfunctions, and oxidative stress (OS) have been implicated in the pathogenesis of polycystic ovarian syndrome (PCOS) and its associated clinical features. A sedentary lifestyle, exposure to air pollutants, prenatal exposure to endocrine-disrupting chemicals, processed and nutritionally depleted food, rich in trans fats, salts, and sugars, and high BMI specifically in visceral adiposity induce OS. OS damages the mitochondrial DNA, lipids, and proteins that impair mitochondrial function. Sequentially, dysfunctional mitochondria produce more reactive oxygen species that aggravate the OS. Mitochondria is pivotal for ovarian cell functioning for instance steroidogenesis, ovarian follicle development, and energy metabolism. Dysfunctional mitochondria can alter the ovarian follicle functioning leading to ovulatory dysfunction and infertility in PCOS. Aims and Objectives: This study is designed to investigate the effect of 12-week yoga practice on endocrine parameters, OS, and mitochondrial health, comparing outcomes in yoga and non-yoga groups. Material and Methods: A total of 75 participants, 32 PCOS females who completed yoga intervention in the yoga group and 29 in the nonyoga group. Hormonal levels were assessed through an immunoassay, while mitochondrial health markers, such as mtDNA copy number (mtDNA CN), reactive oxygen species, and lipid peroxidation were measured through quantitative polymerase chain reaction (qPCR), chemiluminescence, and ELISA respectively. Gene expression related to mitochondrial integrity, respiratory chain, and inflammation was analyzed via reverse transcription qPCR. Additionally, depression severity was also assessed using beck depression inventory II. Result: The Yoga group showed a significant increase in mtDNA-CN and upregulation of transcripts responsible for maintaining mitochondrial integrity and the mitochondrial respiratory chain. In addition, the post-yoga group shows a reduction in, lipid peroxidation, inflammatory, OS markers, and an improvement in telomere length. Conclusion: Yoga positively affects hormonal balance, mitochondrial health, OS, and inflammation in women with PCOS. It also alleviates depression symptoms, highlighting yoga as an effective adjunct therapy for managing PCOS. Regular yoga practice could prevent, delay, and help in managing PCOS symptoms.

The translation machinery of bacteria plays a crucial role in their survival, making it an attractive target for the development of antibiotics. The translation process may be halted due to various factors, leading to ribosome stalling and the release of lethal peptidyl-tRNA. Peptidyl tRNA hydrolase (PtH) cleaves the ester bond between the peptide and the tRNA in peptidyl-tRNA to rescue the cell. Therefore, targeting this enzyme holds significant potential for combating drug-resistant bacteria, as it represents a novel target and plays an indispensable role in bacterial survival. In this study, we virtually screened three different databases: DrugBank, Maybridge, and ZINC natural products to identify potential inhibitors of PtH from Mycobacterium tuberculosis. We evaluated the stability of the PtH-inhibitor complexes obtained from screening through Molecular Dynamics (MD) simulations. Furthermore, we estimated their binding energy and performed per-residue decomposition to understand the contributions of individual amino acids. We also assessed the top ten potential inhibitors for their ADMET properties and drug-likeness. Although experimental validation is currently pending, this study represents a significant step toward the development of potent and specific inhibitors of PtH.

The present prospective cohort study evaluated the prevalence of FSH-R receptor Asn680Ser and Ala307Thr among infertile Indian women and the correlation of these polymorphisms with ART outcomes. Total 804 infertile and 209 fertile controls were enrolled for FSH-R analysis. Correlation of different genotypes with ovarian reserve markers, IVF parameters, and cumulative live birth rates (CLBR) was done among women undergoing IVF. In fertile controls, at 680 position GG (Ser/Ser) was the most common genotype; but among infertile women, all the genotypes were equally distributed. There was no significant difference in ovarian response parameters, oocyte yield, and CLBR among the three genotype groups. Empty follicle syndrome (EFS) was highest in women with AA or AG type at both positions. On categorisation of unexpected poor responders according to POSEIDON stratification; GG genotype at both positions had the lowest risk ratio of low-oocyte yield in ART cycles, but these differences were not statistically significant. This is the largest study from Indian ethnicity showing GG (Ser/Ser) genotype is most common among fertile women. The effect of FSH-R genotypes is very marginal on IVF parameters and is not reflected in CLBR. More prospective data may be required on the correlation of these genotypes with genuine EFS, thus stratifying the next cycles with self or donor oocytes. Routine genetic testing of FSH-R polymorphism should not be done except in a research setting. As both 680 and 307 positions are in linkage disequilibrium, only 680 position analysis may be done in a research setting.

The study presented here aims at assessing the effects of hypobaric hypoxia on RAAS pathway and its components along with mitigation of anomalies with quercetin prophylaxis. One hour prior to hypobaric hypoxia exposure, male SD rats were orally supplemented with quercetin (50 mg/kg BW) and acetazolamide (50 mg/kg BW) and exposed them to 25,000 ft. (7,620 m) in a simulated environmental chamber for 12 h at 25 ± 2 °C. Different biochemical parameters like renin activity, aldosterone, angiotensin I, ACE 2 were determined in plasma. As a conventional response to low oxygen conditions, oxidative stress parameters (ROS and MDA) were elevated along with suppressed antioxidant system (GPx and catalase) in plasma of rats. Quercetin prophylaxis significantly down regulated the hypoxia induced oxidative stress by reducing plasma ROS & MDA levels with efficient enhancement of antioxidants (GPx and Catalase). Further, hypoxia mediated regulation of renin and ACE 2 proves the outstanding efficacy of quercetin in repudiating altercations in RAAS cascade due to hypobaric hypoxia. Furthermore, differential protein expression of HIF-1α, NFκB, IL-18 and endothelin-1 analyzed by western blotting approves the biochemical outcomes and showed that quercetin significantly aids in the reduction of inflammation under hypoxia. Studies conducted with Surface Plasmon Resonance demonstrated a binding among quercetin and ACE 2 that indicates that this flavonoid might regulate RAAS pathway via ACE 2. Henceforth, the study promotes the prophylaxis of quercetin for the better adaptability under hypobaric hypoxic conditions via modulating the RAAS pathway.

Acinetobacter baumannii is one of the multi-drug-resistant pathogens responsible for hospital-acquired infections reported worldwide. Clinically it is challenging to treat these pathogens as they have developed resistance against the existing class of antibiotics. Hence, there is an urgent need to develop a new class of antibiotics against these pathogens to prevent the spread of infections and mortality. In Acinetobacter baumannii, the filamentous temperature-sensitive mutant Z protein polymerizes at the imminent division site to form a Z-ring at the mid-point of the cell and act as a scaffold to recruit other cell division proteins involved in orchestrating septum synthesis in bacteria. Perturbation in the assembly of FtsZ affects bacterial cell dynamics and survival. Hence, FtsZ has emerged as a new drug target in antibiotic discovery to identify compounds that inhibit bacterial cell division. In this study, we have performed a virtual screening of 30,000 compounds from the ZINC Biogenic natural compound library targeting the nucleotide-binding site of FtsZ from Acinetobacter baumannii. We have identified 8 new natural compounds with binding energy in the range of -8.66 to -6.953 kcal/mol and analyzed them by 200 ns molecular dynamics simulations. Out of these eight compounds, ZINC14708526 showed the best binding with relatively optimal drug-likeness and medicinal chemistry as a potent inhibitor of abFtsZ. Thus, the identified FtsZ inhibitor ZINC14708526 is a promising lead compound to develop potent antimicrobial agents against Acinetobacter baumannii infections.

Background: Leishmaniasis is a vector borne neglected tropical disease infection caused by the protozoa Leishmania infantum. One million people are affected annually and one billion people in endemic areas are at risk. High fatality rate, risk of relapse, toxic chemotherapy and lack of effective vaccines has necessitated prophylactic drug development to prevent the infection. P1 nuclease enzyme in promastigote form is involved in purine salvage pathway in which nucleotides are synthesized from human host material for its own survival, growth and multiplication, and therefore makes it an attractive drug target. Methods: Protein sequence of P1 nuclease from Leishmania infantum (A4I5I0) was taken from uniport for sequence analysis. Homology modeling of the P1 nuclease was done based on the crystal structure of nuclease from E. coli (PDB ID: 1AKO) using SWISS MODEL. Conformational correctness and reliability were carried out using PROCHECK. Zinc ions were fitted into the best validated model and this complex was used as a receptor for structure based In-silico studies. Binding pocket prediction was done using program Sitemap in Maestro suit and resultant pockets with the best Dscore>0.9. Aurintricarboxylic acid (ATA), a general inhibitor of nuclease, was docked to the enzyme at the binding pocket using Glide, followed by Molecular Dynamics simulations for 100ns using Desmond simulation program. A library of molecules similar to scaffold of ATA was made from COCONUT, a natural product database using substructure search based on Ullmann algorithm. Screening was performed in virtual high throughput, standard precision, and extra precision docking modes using Glide. Complexes of molecules compliant for Lipinski rule were subjected to Molecular Dynamics simulations, and their binding parameters were delineated. Results: Structure of P1 nuclease shows a 268 residue globular protein with all its residues in core and allowed regions of Ramachandran plot. Fold comprises of secondary structural elements composed of nine helices, three short helices, and a single β-hairpin. Substrate binding cleft is nestled deep within the protein and comprises of an active site comprising of five histidine residues, three aspartate residues, one tryptophan and one bridging water molecule that together coordinate three zinc ions, a feature that is essential for structural stability. Met 92, Leu 86, and Ilu 195 provide hydrophobic moieties for bases. 2-[(4-hydroxyphenyl)-(4-methoxyphenyl) methyl]benzoic acid (244MBA) is the only screened natural molecule that fulfills all the applied screening criteria. Both ATA and 244MBA induces subtle conformational changes on binding to the enzyme. They make an array of hydrogen bonded and hydrophobic interactions with residues, and coordinate bonds with zinc ions at active site. 244MBA has an association constant of 0.13μM, and total binding energy of -85X103 kcal/mol. Conclusions: Structural modeling of P1 nuclease from Leishmania infantum reveals the three dimensional fold of enzyme. Analysis of enzyme molecule complexes establishes the binding modalities of respective molecules to P1 enzyme. 244MBA with a better potency than ATA has the potential to be developed as a prophylactic agent against leishmaniasis. Funding from Indian Council of Medical Research, New Delhi, India (ICMR/2020-4975) is acknowledged