Impact of Process Parameters on Particle Size Involved in Media Milling Technique Used for Preparing Clotrimazole Nanocrystals for the Management of Cutaneous Candidiasis.

Clotrimazole is widely used for the management of cutaneous candidiasis infection. The low solubility of clotrimazole and excipient-related topical side effects (of currently available marketed products) cause the compromised efficacy of the therapy with poor patient compliance. In the present investigation, a clotrimazole nanocrystal-based nanogel was developed. Clotrimazole nanocrystals were optimized with studying the impact of individual process parameters of the media milling technique. The optimum level of individual process parameters was considered in the development of optimized batches. A promising result was obtained with a non-ionic stabilizer, polysorbate 80, at a concentration of 1.5%w/v, showing a distinct reduction in the particle size from above 31 µm to 264 nm and a polydispersity index of 0.211 with media milling at 1500 rpm for 6 h. This result was found to be in concordance with the TEM images, revealing a sharp diminution in particle morphology. Powder X-ray diffraction and differential scanning calorimetry results revealed crystallinity of clotrimazole (CTZ) in nanocrystal form. The optimized nanocrystal suspension was formulated into nanogel with carbopol 934, having a viscosity of 86.43 ± 2.06 Pa s at 25°C, which enhanced the ease of application of CTZ nanocrystals topically. A diffusion study showed around 82% of CTZ is transported across the membrane with the flux of 110.07 µg cm-2 h-1. In vivo results of the nanogel revealed improvement in CTZ release with 52% CTZ retention in different strata of the skin. The developed nanogel showed a significant improvement in the eradication of fungal infection within 10 days of application over Candida albicans-induced Wistar rat model. In a nutshell, the CTZ nanocrystal-loaded nanogel could achieve the goal of retaining CTZ in skin layers providing a prolonged effect and was able to treat cutaneous candidiasis in a short span with improved compliance for the candidiasis patients.

Genomic and physiological analyses of an indigenous strain, Enterococcus faecium 17OM39.

The human gut microbiome plays a crucial role in human health and efforts need to be done for cultivation and characterisation of bacteria with potential health benefits. Here, we isolated a bacterium from a healthy Indian adult faeces and investigated its potential as probiotic. The cultured bacterial strain 17OM39 was identified as Enterococcus faecium by 16S rRNA gene sequencing. The strain 17OM39 exhibited tolerance to acidic pH, showed antimicrobial activity and displayed strong cell surface traits such as hydrophobicity and autoaggregation capacity. The strain was able to tolerate bile salts and showed bile salt hydrolytic (BSH) activity, exopolysaccharide production and adherence to human HT-29 cell line. Importantly, partial haemolytic activity was detected and the strain was susceptible to the human serum. Genomics investigation of strain 17OM39 revealed the presence of diverse genes encoding for proteolytic enzymes, stress response systems and the ability to produce essential amino acids, vitamins and antimicrobial compound Bacteriocin-A. No virulence factors and plasmids were found in this genome of the strain 17OM39. Collectively, these physiological and genomic features of 17OM39 confirm the potential of this strain as a candidate probiotic.

Design of experiment approach for formulating multi-unit colon-targeted drug delivery system: in vitro and in vivo studies.

OBJECTIVE: The objective of the present investigation was to develop systematically optimized multiunit formulation for colon targeted delivery of metronidazole (MTZ) by employing design of experiment (DoE) and evaluate it for in vitro as well as in vivo drug release study. METHODS: Core of mini-tablets of MTZ was prepared using drug along with suitable swelling agents to provide pH sensitive pulsatile drug delivery. Eudragit® S 100 (ES) and ethyl cellulose (EC) were used as coating polymers to prevent initial drug release in gastric region. The coating composition was systematically optimized using 3(2)-full factorial design and optimized formulation was evaluated in vitro and then in vivo, to confirm colon targeting ability of the developed system. Stability study of optimized formulation was performed for 6 months as per ICH guidelines. RESULTS: The optimized coating composition was selected from the results of design batches. The optimized formulation showed 6.99 ± 1.5% drug release up to 5 h and 100% drug release within 7.2 ± 0.2 h indicating pH sensitive pulsatile behavior of formulation. Similar drug release profile was observed while performing in vivo study in rabbits with a lag time of 4 h and Cmax of 190 ± 4.9 ng/ml being achieved after 7 h. Stability study indicated insignificant difference in properties of tablets and their drug release patterns. CONCLUSION: Optimization of coating composition (EC and ES) and thickness could offer pH sensitive pulsatile release of drugs at colon. Furthermore, in vivo results confirmed the successful development of colon targeted formulation of MTZ.

Ethyl trans-12-(pyridin-4-yl)-9,10-ethano-anthracene-11-carboxyl-ate.

In the title compound, C24H21NO2, the residues at the central ethyl-ene bridge are trans to each other. The dihedral angles between the pyridine and benzene rings are 67.09 (6) and 61.41 (5)°. In the crystal, centrosymmetrically related mol-ecules are linked into dimers by pairs of C-H⋯O hydrogen bonds.

Drug targets for lymphatic filariasis: a bioinformatics approach.

This review article discusses the current scenario of the national and international burden due to lymphatic filariasis (LF) and describes the active elimination programmes for LF and their achievements to eradicate this most debilitating disease from the earth. Since, bioinformatics is a rapidly growing field of biological study, and it has an increasingly significant role in various fields of biology. We have reviewed its leading involvement in the filarial research using different approaches of bioinformatics and have summarized available existing drugs and their targets to re-examine and to keep away from the resisting conditions. Moreover, some of the novel drug targets have been assembled for further study to design fresh and better pharmacological therapeutics. Various bioinformatics-based web resources, and databases have been discussed, which may enrich the filarial research.

Subclavian artery- internal jugular vein fistula and heart failure: complication of internal jugular vein catheterization.

Hemodialysis in patients with end-stage renal disease (ESRD) requires vascular access which can be either temporary or permanent. However, these procedures are not without complications. Arterial puncture is the most common immediate complication and pseudoaneurysm formation is the most common late sequel of internal jugular venous catheterization (IJVC). However, arterio-venous fistula (AVF) formatiorn following IJVC is rare. We are reporting a case of AVF formation between subclavian artery (SCA) and internal jugular vein (IJV) following IJVC which later on leads to the development of cardiac failure.

Significance of antibody numbering systems in the development of antibody engineering.

Immunotherapy has become increasingly popular in recent years for treating a variety of diseases including inflammatory, neurological, oncological, and auto-immune disorders. The significant interest in antibody development is due to the high binding affinity and specificity of an antibody against a specific antigen. Recent advances in antibody engineering have provided a different view on how to engineer antibodies in silico for therapeutic and diagnostic applications. In order to improve the clinical utility of therapeutic antibodies, it is of paramount importance to understand the various molecular properties which impact antigen targeting and its potency. In antibody engineering, antibody numbering (AbN) systems play an important role to identify the complementarity determining regions (CDRs) and the framework regions (FR). Hence, it is crucial to accurately define and understand the CDR, FR and the crucial residues of heavy and light chains that aid in the binding of the antibody to the antigenic site. Detailed understanding of amino acids positions are useful for modifying the binding affinity, specificity, physicochemical features, and half-life of an antibody. In this review, we have summarized the different antibody numbering systems that are widely used in antibody engineering and highlighted their significance. Here, we have systematically explored and mentioned the various tools and servers that harness different AbN systems.

In-silico identification and prioritization of therapeutic targets of asthma.

Asthma is a "common chronic disorder that affects the lungs causing variable and recurring symptoms like repeated episodes of wheezing, breathlessness, chest tightness and underlying inflammation. The interaction of these features of asthma determines the clinical manifestations and severity of asthma and the response to treatment" [cited from: National Heart, Lung, and Blood Institute. Expert Panel 3 Report. Guidelines for the Diagnosis and Management of Asthma 2007 (EPR-3). Available at: https://www.ncbi.nlm.nih.gov/books/NBK7232/ (accessed on January 3, 2023)]. As per the WHO, 262 million people were affected by asthma in 2019 that leads to 455,000 deaths ( https://www.who.int/news-room/fact-sheets/detail/asthma ). In this current study, our aim was to evaluate thousands of scientific documents and asthma associated omics datasets to identify the most crucial therapeutic target for experimental validation. We leveraged the proprietary tool Ontosight® Discover to annotate asthma associated genes and proteins. Additionally, we also collected and evaluated asthma related patient datasets through bioinformatics and machine learning based approaches to identify most suitable targets. Identified targets were further evaluated based on the various biological parameters to scrutinize their candidature for the ideal therapeutic target. We identified 7237 molecular targets from published scientific documents, 2932 targets from genomic structured databases and 7690 dysregulated genes from the transcriptomics and 560 targets from genomics mutational analysis. In total, 18,419 targets from all the desperate sources were analyzed and evaluated though our approach to identify most promising targets in asthma. Our study revealed IL-13 as one of the most important targets for asthma with approved drugs on the market currently. TNF, VEGFA and IL-18 were the other top targets identified to be explored for therapeutic benefit in asthma but need further clinical testing. HMOX1, ITGAM, DDX58, SFTPD and ADAM17 were the top novel targets identified for asthma which needs to be validated experimentally.

Unexpected positive intraoperative cultures (UPIC) in revision Hip and knee arthroplasty- A review of the literature.

Unexpected positive intraoperative culture (UPIC) in revision hip and knee arthroplasty has a prevalence of 10.5%, there is no consensus in the literature on how to interpret them and how to treat them. Our literature review showed that most authors would consider two or more positive cultures as significant and usually treat them with culture specific antibiotics for 4-6 weeks. A single positive intraoperative culture can or cannot be significant depending on the virulence of the organism, hence taking multiple tissue samples in and around the joint is recommended. All failed arthroplasty cases must be evaluated preoperatively according to musculoskeletal infection society criteria (MSIS) to rule out the possibility of infection as an etiology for failure of the arthroplasty. Most authors reported that large majority of these UPIC were from a low virulence organism. Our review showed that the implant survival is more than 85% with 4-6 weeks of antibiotic treatment.

Clinical outcome, functional outcome and patient satisfaction after cruciate retaining total knee arthroplasty for stiff arthritic knee - A short term outcome study.

BACKGROUND: Various authors have shown that Cruciate Retaining (CR) Total Knee Arthroplasty (TKA) has better long-term survivorship compared to Posterior Stabilized (PS), however most arthroplasty surgeons tend to use PS knees in patients with severe deformity and stiffness. There is limited data correlating stiffness and CR versus PS design. The aim of our study was to assess the outcome of CR TKA for patients with stiff arthritic knee. MATERIALS & METHODS: We evaluated the results of 30 knees with osteoarthritis and inflammatory arthritis and preoperative stiffness (ROM 15-90°), who had been treated with CR TKA with a mean follow up of 2 years. The primary outcome variable measures were improvement in the flexion, flexion deformity (FFD) and overall improvement in the arc of motion. Patients were also evaluated by Knee Society Score (KSS), WOMAC score and 5-point Likert scale for patient satisfaction. RESULT: At the time of final follow-up, the mean arc of motion improved from 75° preoperatively to 108° postoperatively and it was statistically significant (p < 0.001). Similar improvement was noted for FFD (15.43° to 0.83° (p < 0.001)), maximum flexion from 90.9° to 109.1° (p < 0.001), KSS clinical from 37.67 to 87.47 (p < 0.001), KSS functional from 58.5 to 93.83 (p < 0.001), WOMAC from 76.73 to 7.63 (p < 0.001). Further, the Likert Scale for patient satisfaction was excellent for 90% of the patients. CONCLUSION: This study clearly shows that the routine use of PS design for complex stiff knees has questionable scientific intent and standard CR TKA design in stiff knees can produce excellent outcome. Since there is slight preponderance of data pointing towards improved longevity with CR design, it would be a better option for the patients with longer life expectancy.

Nanocrystal: a novel approach to overcome skin barriers for improved topical drug delivery.

INTRODUCTION: Skin is an important route of drug delivery for the treatment of various dermatological conditions. The advent of nanotechnology is paving the roadmaps for topical drug delivery by providing sustained release as well as maintaining a localized effect, outweighing the toxicity concern. AREAS COVERED: This review highlighted the morphology of skin, its barrier nature as well as drug penetration pathways after topical application of formulations. The existing methods to improve topical drug delivery, by infringing or permeating the skin barriers, are discussed. This context concretes the foundation to accentuate the need for the development of nanocrystal-based topical formulation. The mechanism of drug release, immediate as well as sustained release, after topical administration of drug nanocrystals is also elaborated. The special emphasis is given on the breakthrough achieved, in topical drug delivery using drug nanocrystals, so far in the plethora of literature, patents, and products, under clinical trial as well as in the market. EXPERT OPINION: The current research on nanocrystals for topical drug delivery is highlighting the breakthroughs achieved so far. The output of these research envisages that topical nanocrystals based formulations can be a novel strategy for the drugs which are facing solubility, bioavailability and toxicity concerns.

Insight into the intermolecular recognition mechanism involved in complement component 4 activation through serine protease-trypsin.

Serine protease cleaved-complement component 4 (C4) at sessile loop, which is significant for completion of lectin and classical complement pathways at the time of infections. The co-crystalized structure of C4 with Mannose-binding protein-associated serine protease 2 (MASP2) provided the structural and functional aspects of its interaction and underlined the C4 activation by MASP2. The same study also revealed the significance of complement control protein (CCP) domain through mutational study, where mutated CCP domain led to the inhibition of C4 activation. However, the interaction of trypsin serine domain with C4α sessile loop revealed another aspect of C4 activation. The human C4 cleavage by Trypsin (Tryp) in a control manner was explored but not yet revealed the identification of cleaved fragments. Hence, the present study investigated the Tryp mediated C4 activation using computational approach (protein-protein docking and molecular dynamics simulation) by comparing with the co-crystalized structure of C4-MASP2. Docking result identified the crucial interacting residues Gly219, Gln178, and Asn102 of Tryp catalytic pocket which were interacting with Arg756 and Glu759 (sessile loop) of α-Chain (C4) in a similar manner to C4-MASP2 co-crystallized complex. Moreover, MD simulation results and mutational study underlined the conformational rearrangements in the C4 due to the Tryp interaction. Comparative analysis of C4 alone, C4-Tryp, and C4-MASP2 revealed the impact of Tryp on C4 was similar as MASP2. These studies designate the role of sessile loop in the interaction with serine domain, which could be useful to understand the various interactions of C4 with other complement components.

Assessing the feasibility of integrating ecosystem-based with engineered water resource governance and management for water security in semi-arid landscapes: A case study in the Banas catchment, Rajasthan, India.

Much of the developing world and areas of the developed world suffer water vulnerability. Engineering solutions enable technically efficient extraction and diversion of water towards areas of demand but, without rebalancing resource regeneration, can generate multiple adverse ecological and human consequences. The Banas River, Rajasthan (India), has been extensively developed for water diversion, particularly from the Bisalpur Dam from which water is appropriated by powerful urban constituencies dispossessing local people. Coincidentally, abandonment of traditional management, including groundwater recharge practices, is leading to increasingly receding and contaminated groundwater. This creates linked vulnerabilities for rural communities, irrigation schemes, urban users, dependent ecosystems and the multiple ecosystem services that they provide, compounded by climate change and population growth. This paper addresses vulnerabilities created by fragmented policy measures between rural development, urban and irrigation water supply and downstream consequences for people and wildlife. Perpetuating narrowly technocentric approaches to resource exploitation is likely only to compound emerging problems. Alternatively, restoration or innovation of groundwater recharge practices, particularly in the upper catchment, can represent a proven, ecosystem-based approach to resource regeneration with linked beneficial socio-ecological benefits. Hybridising an ecosystem-based approach with engineered methods can simultaneously increase the security of rural livelihoods, piped urban and irrigation supplies, and the vitality of river ecosystems and their services to beneficiaries. A renewed policy focus on local-scale water recharge practices balancing water extraction technologies is consistent with emerging Rajasthani policies, particularly Jal Swavlamban Abhiyan ('water self-reliance mission'). Policy reform emphasising recharge can contribute to water security and yield socio-economic outcomes through a systemic understanding of how the water system functions, and by connecting goals and budgets across multiple, currently fragmented policy areas. The underpinning principles of this necessary paradigm shift are proven and have wider geographic relevance, though context-specific research is required to underpin robust policy and practical implementation.

Total Knee Arthroplasty In Patients With Parkinson's Disease- A Critical Analysis of Available Evidence.

BACKGROUND: In this era of modern medicine, there is an increase in life expectancy and thereby an ageing population. Among this group one of the most common neurological disorder is Parkinson disease and one of the most common operation done in elderly population is a total joint arthroplasty. But total joint arthroplasty in Parkinson disease is a relatively uncommon entity. There is sparse literature available with regards to total knee arthroplasty (TKA) in Parkinson disease. This review focusses on the necessity, complications and previous experiences on TKA in PD based on the literature available. METHOD: The review was conducted after a series of advanced search in the following medical databases; Pub med, Biomed central, Cochrane and Google scholar for articles related to total knee replacement in patients with Parkinson's disease. The following keywords were used; Total knee arthroplasty, Parkinson's disease, Hoehn and Yahr, Flexion Contracture. RESULTS: The review indicates that the functional outcome is comparable to that of controls in immediate post-operative phase, one year and three-year phase, but the long term functional outcome seems to deteriorate significantly. CONCLUSION: Total knee arthroplasty can serve as an effective tool in alleviating pain in short term as well as long term periods, whereas the functional outcome seems to deteriorate post operatively on a long-term basis. Nevertheless, TKA in PD is a challenging situation, thereby necessitating a holistic approach with the efforts from various specialists needed at each stage to ensure a successful operation.

Rationale of Cruciate Retaining Design in Rheumatoid Arthritis: A Review of Clinical Analysis and its Role in Rheumatoid Arthritis.

BACKGROUND: Over the years, proponents of total knee designs (cruciate retaining and posterior stabilised) have conducted several long-term studies to claim the potential of these designs in several subsets of patients. Total knee arthroplasty (TKA) in patients with rheumatoid arthritis has also been one such domain where numerous studies were conducted in the past. A general perception among majority of arthroplasty surgeons is that, posterior stabilised (PS) is the implanted design of choice among patients with Rheumatoid arthritis (RA). However, with the available literature there is a significant disparity related to the selection of implants in patients with rheumatoid RA. In this review of literature, an attempt is made to identify the clinical performance and role of one such implant design, the cruciate retaining (CR) prosthesis in rheumatoid arthritis. METHOD: The review was conducted after a series of advanced search in the following medical databases; Pub med, Biomed central, Cochrane and Google scholar for articles related to long term follow up studies of cruciate retaining total knee arthroplasty in rheumatoid arthritis using the keywords cruciate retaining prosthesis, total knee arthroplasty, rheumatoid arthritis. RESULTS: The available data demonstrate that the CR design is attributed with an excellent long term survivorship and functional outcome even in follow up studies up to twenty-five years. CONCLUSION: The advantages of using a CR design are long term survivorship, controlled femoral roll back and preservation of bone stock. Thus, the data gathered in this review lead to a consideration that the CR design is an implant design on par with PS design in patients with RA.

Essential proteins and possible therapeutic targets of Wolbachia endosymbiont and development of FiloBase--a comprehensive drug target database for Lymphatic filariasis.

Lymphatic filariasis (Lf) is one of the oldest and most debilitating tropical diseases. Millions of people are suffering from this prevalent disease. It is estimated to infect over 120 million people in at least 80 nations of the world through the tropical and subtropical regions. More than one billion people are in danger of getting affected with this life-threatening disease. Several studies were suggested its emerging limitations and resistance towards the available drugs and therapeutic targets for Lf. Therefore, better medicine and drug targets are in demand. We took an initiative to identify the essential proteins of Wolbachia endosymbiont of Brugia malayi, which are indispensable for their survival and non-homologous to human host proteins. In this current study, we have used proteome subtractive approach to screen the possible therapeutic targets for wBm. In addition, numerous literatures were mined in the hunt for potential drug targets, drugs, epitopes, crystal structures, and expressed sequence tag (EST) sequences for filarial causing nematodes. Data obtained from our study were presented in a user friendly database named FiloBase. We hope that information stored in this database may be used for further research and drug development process against filariasis. URL: http://filobase.bicpu.edu.in.

Nanocrystal for ocular drug delivery: hope or hype.

The complexity of the structure and nature of the eye emanates a challenge for drug delivery to formulation scientists. Lower bioavailability concern of conventional ocular formulation provokes the interest of researchers in the development of novel drug delivery system. Nanotechnology-based formulations have been extensively investigated and found propitious in improving bioavailability of drugs by overcoming ocular barriers prevailing in the eye. The advent of nanocrystals helped in combating the problem of poorly soluble drugs specifically for oral and parenteral drug delivery and led to development of various marketed products. Nanocrystal-based formulations explored for ocular drug delivery have been found successful in achieving increase in retention time, bioavailability, and permeability of drugs across the corneal and conjunctival epithelium. In this review, we have highlighted the ocular physiology and barriers in drug delivery. A comparative analysis of various nanotechnology-based ocular formulations is done with their pros and cons. Consideration is also given to various methods of preparation of nanocrystals with their patented technology. This article highlights the success achieved in conquering various challenges of ocular delivery by the use of nanocrystals while emphasizing on its advantages and application for ocular formulation. The perspectives of nanocrystals as an emerging flipside to explore the frontiers of ocular drug delivery are discussed.

Current approaches for in vitro drug release study of long acting parenteral formulations.

Long acting parenteral formulations are preferred over conventional formulations for the treatment of chronic diseases. Prevalence of such diseases provoked the interest of researchers and pharmaceutical industries in the development of long acting parenteral formulations. The regulatory guidelines and pharmacopoeia have remained silent on dissolution methods for long acting parenteral formulations due to their diverse nature. The lack of compendial method for dissolution testing increases the duration of approval process for long acting parenteral formulations. This article reviews various dissolution methods used to study in vitro drug release profile of long acting parenteral formulations. Compendial as well as noncompendial methods, such as- rotating dialysis cell, dialysis tube, rotating bottle, shaking flask, single drop, inverted cup and incubation, are used by researchers for drug release profile of long acting parenteral formulations. This review article also highlights the advantages and disadvantages of reported dissolution methods along with the suitability of these methods for particular type of long acting formulation. The compiled work will help the researchers in designing the biorelevant dissolution method and expedite the development of long acting parenteral formulations.

Formulation optimization of gastroretentive drug delivery system for allopurinol using experimental design.

OBJECTIVES: The objective of the study was to develop gastroretentive dosage form (GRDF) for allopurinol (ALP) using combined approaches of mucoadhesion and floating systems. GRDF was systematically optimized using 3(2)-full factorial design. METHODS: Concentrations of sodium carboxymethyl cellulose (X1) and concentration of polyoxyethylene oxide WSR 303 (X2) were selected as independent variables, whereas gastroretentive parameters like total floating time (TFT) (Y1), mucoadhesive force (MF) (Y2), time required for 10% drug release (Y3) and time required for 80% drug release (Y4) were selected as dependent variables in development of robust GRDF of ALP. GRDF was evaluated for gastroretentive parameters such as floating lag time (FLT) and TFT, MF using texture analyzer and ex vivo residence time using modified disintegration test apparatus. Roentgenography study of optimized formulation was conducted to evaluate in vivo gastro retentive behavior using albino rabbits. RESULTS: Developed tablets showed immediate in situ gas generation and exhibited FLT of 1.68 s after placing into simulated gastric fluid, which lead to buoyancy as well as controlled drug release for 24 h with zero-order drug release kinetics. The optimized formulation was selected based on in vitro drug release characteristics. In vivo retention of optimized formulation was corroborated using roentgenography studies. CONCLUSION: The study concluded that the combination of mucoadhesive and floating approaches for GRDF aids to achieve desired gastroretentive performance and drug release properties for ALP. The formulation scientists may adopt these formulation strategies for drugs suitable for the development of GRDF.

Identification of novel tyrosine kinase inhibitors for drug resistant T315I mutant BCR-ABL: a virtual screening and molecular dynamics simulations study.

BCR-ABL tyrosine kinase plays a major role in the pathogenesis of chronic myeloid leukemia (CML) and is a proven target for drug development. Currently available drugs in the market are effective against CML; however, side-effects and drug-resistant mutations in BCR-ABL limit their full potential. Using high throughput virtual screening approach, we have screened several small molecule databases and docked against wild-type and drug resistant T315I mutant BCR-ABL. Drugs that are currently available, such as imatinib and ponatinib, were also docked against BCR-ABL protein to set a cutoff value for our screening. Selected lead compounds were further evaluated for chemical reactivity employing density functional theory approach, all selected ligands shows HLG value > 0.09900 and the binding free energy between protein-ligand complex interactions obtained was rescored using MM-GBSA. The selected compounds showed least ΔG score -71.53 KJ/mol to maximum -126.71 KJ/mol in both wild type and drug resistant T315I mutant BCR-ABL. Following which, the stability of the docking complexes were evaluated by molecular dynamics simulation (MD) using GROMACS4.5.5. Results uncovered seven lead molecules, designated with Drug-Bank and PubChem ids as DB07107, DB06977, ST013616, DB04200, ST007180 ST019342, and DB01172, which shows docking scores higher than imatinib and ponatinib.