Characterization of disinfectant susceptibility profiles among clinical isolates of Acinetobacter baumannii in Ardabil, Iran.

Antimicrobial disinfectants have been extensively used to control hospital-acquired infections worldwide. Prolonged exposure to bacteria could promote resistance to antimicrobial disinfectants. This study evaluated the antimicrobial activity of four commonly used disinfectants; triclosan, chlorhexidine digluconate, benzalkonium chloride, and formaldehyde against Acinetobacter baumannii clinical isolates. This study also determined the prevalence and association of efflux pumps encoding genes qacE, qacED1, emrA, and aceI with tolerance to disinfectants. A total of 100 A. baumannii isolates were included in the current study. The antimicrobial disinfectants' minimum inhibitory concentration (MIC) was determined using an agar dilution method. Genes involved in resistance to disinfectants were investigated by PCR method. The benzalkonium chloride MICs ranged between 32 and 128 µg mL-1, chlorhexidine digluconate 8-64 µg mL-1, triclosan 1-32 µg mL-1, and formaldehyde 128 µg mL-1. Overall, the highest MIC90 value was identified for formaldehyde (128 µg mL-1), followed by benzalkonium chloride and chlorhexidine digluconate (64 µg mL-1, each one) and triclosan (4 µg mL-1). In the present study, the qacE, qacED1, emrA, and aceI genes were found in 91%, 55%, 100%, and 88% of isolates, respectively. The qacG gene was not identified in our A. baumannii isolates. The qacED1 gene was associated with higher MICs for all disinfectants tested (P < 0.05), while the qacE and aceI genes were associated with higher MICs for benzalkonium chloride and chlorhexidine. This study indicated that triclosan is the most effective disinfectant against A. baumannii isolates.

Vitamin E as alternative local treatment in genitourinary syndrome of menopause: a randomized controlled trial.

INTRODUCTION AND HYPOTHESIS: Genitourinary syndrome of menopause is a major health concern in postmenopausal women. This study was aimed at comparing the effect of a vitamin E vaginal suppository with that of conjugated estrogen vaginal cream on sexual function in postmenopausal women with genitourinary syndrome of menopause. METHODS: This survey was carried out on 52 postmenopausal women aged 40-65 years who had been referred to gynecology clinics in Mashhad city, during 2013-2014. Keeping ß = 0.1, the power was calculated to be 90%. The patients were randomly divided into two groups: vitamin E vaginal suppository and conjugated estrogen vaginal cream. Participants used the medications for 12 weeks. They were visited at the 4th, 8th, and 12th weeks. Validated Abbreviated Sexual Function Questionnaire (ASFQ), as the primary outcome measure, and a demographic information questionnaire, were used to collect data at each visit. Data were analyzed using SPSS and p < 0.05 was considered statistically significant. RESULTS: Mean overall scores of the ASFQ were increased significantly in both groups during the course of the study, compared with baseline (p < 0.001). However, the mean ASFQ scores of the two treatments did not differ significantly. CONCLUSION: Improved scores of ASFQ after the 12th week showed that the treatment was successful in both groups. Therefore, a vitamin E vaginal suppository may be an alternative to vaginal estrogen in relieving the symptoms of vaginal atrophy in postmenopausal women, especially those not able to use hormone therapy or have low compliance.

Structure-based pharmacophore design and virtual screening for novel potential inhibitors of epidermal growth factor receptor as an approach to breast cancer chemotherapy.

Cancer cells are described with features of uncontrolled growth, invasion and metastasis. The epidermal growth factor receptor subfamily of tyrosine kinases (EGFR-TK) plays a crucial regulatory role in the control of cellular proliferation and progression of various cancers. Therefore, its inhibition might lead to the discovery of a new generation of anticancer drugs. In the present study, structure-based pharmacophore modeling, molecular docking and molecular dynamics simulations were applied to identify potential hits, which exhibited good inhibition on the proliferation of MCF-7 breast cancer cell line and favorable binding interactions on EGFR-TK. Selected compounds were examined for their anticancer activity against the Michigan Cancer Foundation-7 (MCF-7) breast cancer cell line which overexpresses EGFR using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) tetrazolium reduction assay. Compounds 1 and 2, with an isoindoline-1-one core, induced significant inhibition of breast cancer cells proliferation with IC[Formula: see text] values 327 and 370 nM, respectively.

Synthesis, evaluation, and molecular docking studies of aryl urea-triazole-based derivatives as anti-urease agents.

Considering the importance of urease inhibitors in the treatment of ureolytic bacterial infections, in this work, the synthesis of novel, aryl urea-triazole-based derivatives as effective urease inhibitors is described. Dichloro-substituted derivative 4o, with IC50 = 22.81 ± 0.05 µM, is found to be the most potent urease inhibitor, determined by Berthelot colorimetric assay. Docking studies were also carried out for compound 4o to confirm the effective interactions with the urease active site.

Characterization of the DNA mismatch repair proteins MutS and MutL in a hypermutator Acinetobacter baumannii.

Mutations of mutS and mutL genes have been linked with the emergence of hypermutator (HPM) phenotype in several bacteria. Nevertheless, there is scarce evidence that these mutations occurred in HPM Acinetobacter baumannii, therefore, it remains unknown whether the mutations located in domains mediating the functions of MutS and MutL. To address this information gap, the nucleotide sequences of mutS and mutL were characterized and their mutations were identified. Additionally, we proposed in silico models of mutated proteins and analyzed the secondary and tertiary structures, and the interaction interfaces of MutL and MutS. The HPM A. baumannii and a wild-type strain were subjected to PCR amplification of full length mutS and mutL, cloning, and sequencing. Following several reads of both strands of each gene and sequence assembly, the mutations were identified. Thereafter, the three-dimensional (3-D) structure of A. baumannii ATCC 19606 was developed and utilized as a template for homology modeling of the mutated amino acid sequences using the Phyre2 and I-TASSER, VMD 1.9.3, LigPlus v.1.4.5, PyMOL v.0.99 software. Regardless of silent mutations (n = 43), 11 missense mutations were identified in the MutS domains of HPM strain such as A4T, T272S, D278N in N-terminus, connector, and core domains, respectively. Three mutations -I357T, A408S, N447S- and 16 silent mutations were observed in MutL. Secondary structure prediction of MutS revealed that the amount of alpha helices, beta sheets, and coils in HPM were 35, 29, and 63, respectively, while these values were 36, 28, and 63 for A. baumannii ATCC 19606 as non mutator. In the case of MutL, for both HPM and non-mutator, 20, 21, and 39 of complete protein were alpha helices, beta sheets, and coils, respectively. Superimposition of structures of MutS of HPM on non-mutator revealed that T272, D278, G457, S528, A533, Y715, and E747 are closely matched with S272, D278, A457, P528, V533, C715, and K747, respectively in non-mutator strain. When the structure of MutL model in HPM was superimposed on its counterpart in non-mutator, all but residues S447, S408, and T357 were identical. Many mutations along the mutS and mutL were noted, but most of the mutations were observed in the interaction interfaces of MutS and MutL. Other substitutions were predominantly detected in C-terminus of MutS that may lead to reduced ATP binding and hydrolysis. Three substitution mutations were adjacent to C-terminus of MutL and are raising the suggestion of reduction in MutL dimerization. It seems that a combination of these mutations is implicated in increased mutation frequency and accordingly emergence of HPM strain.

Intestinal parasitic infections in different groups of immunocompromised patients in Kashan and Qom cities, central Iran.

INTRODUCTION: Intestinal parasitic infections (IPIs) are important causes of morbidity and mortality in patients with immunocompromising conditions. OBJECTIVE: The aim of this study was to determine the prevalence of IPIs in different groups of immunocompromised patients, including hemodialysis patients (HD), renal transplant recipients (RTR), cancer and HIV/AIDS patients in comparison with healthy individuals in two central cities of Iran (Kashan and Qom). METHODS: In this case-control study, the stool samples of 135 HD, 50 RTR, 60 cancer patients, 20 HIV/AIDS patients and 120 healthy subjects were tested using direct-smear, formol-ether concentration, Ziehl-Neelsen staining and Agar plate method. RESULTS: The overall infection rate was 11.7% (31/265) in patient groups and 0% (0/120) in the control group. The frequency of parasites was 25% in HIV/AIDS patients, 11.9% (16/135) in HD, 12.0% (6/50) in RTR and 6.7% (4/60) in cancer patients. Blastocystis hominis (4.2%) and Giardia lamblia (3.0%) were the most prevalent parasites in patient groups. The infection rate was significantly higher in male (17.6%) than female (5.4%) patients (p = .002), but no statistically significant association was observed according to the age and educational levels. CONCLUSIONS: This study showed a high prevalence of IPIs in immunocompromised patients. The results of this study suggest that periodic stool examinations for screening of IPIs should be included as a part of routine medical care in these patients.

Display of B. pumilus chitinase on the surface of B. subtilis spore as a potential biopesticide.

BACKGROUND: Chitinases can inhibit the growth of many fungal diseases which are a great threat for global agricultural production. Biological control of pathogens like fungi, is believed to be one of the best ways to eliminate the adverse effects of plant pathogens. To this end, we expressed and displayed a chitinase from Bacillus pumilus (ChiS) on the surface of Bacillus subtilis spores, as a biocontrol agent. RESULT: ChiS enzyme from B. pumilus was expressed on the spores of B. subtilis using CotG as a carrier protein. Immunofluorescence microscopy confirmed the expression of ChiS on the surface of the spores. Enzyme activity assay showed that the surface displayed ChiS was active and was also able to inhibit the growth of Rhizoctonia solani and Trichoderma harzianum fungi. Western blot analysis also indicated that CotG-ChiS is partially processed after display. Molecular dynamics simulation showed that the stability of the heterologous protein was decreased after fusion. CONCLUSION: ChiS was successfully displayed on the surface of Bacillus spores by fusion to the CotG, one of the main spore coat proteins. In-vitro experiments showed that the displayed enzyme was effective in growth inhibition of R. solani and T. harzianum fungi.

Serological and molecular survey of toxoplasmosis in renal transplant recipients and hemodialysis patients in Kashan and Qom regions, central Iran.

Toxoplasma gondii is one of the important opportunistic pathogen among solid-organ transplant recipients and hemodialysis patients (HD). This study was aimed to detect toxoplasmosis among 50 renal transplant recipients (RTR), 135 HD and 120 healthy individuals in two cities (Kashan and Qom) that located in the center of Iran, from 2014 to 2015. Serological detection (IgG and IgM antibodies) was performed among all individuals in case and control groups. Molecular detection was performed on all IgM positive individuals or IgG positive with moderate to high (>51 IU/mL) antibody titers in HD (n = 42) and control groups (n = 21). In RTR patients, molecular detection was conducted among all seropositive or seronegative individuals (n = 50). IgG seropositivity was detected in 52% (26/50) of RTR, 63% (85/135) of HD and 33.3% (40/120) of the control group. The rate of anti-T. gondii IgG antibody was significantly elevated in RTR and HD patients than the control group (p = 0.023 and p < 0.001, respectively). IgM seropositivity was only detected in one HD patient. T. gondii DNA was detected in 12% (6/50) of RTR and 7.1% (3/42) of HD patients. The results of this study suggested that the screening of toxoplasmosis should be given greater consideration among RTR and hemodialysis patients.

Sentinel Node Mapping in Ovarian Tumors: A Study Using Lymphoscintigraphy and SPECT/CT.

Purpose: Ovarian cancer in the early stage requires a complete surgical staging, including radical lymphadenectomy, implying subsequent risk of morbidity and complications. Sentinel lymph node (SLN) mapping is a procedure that attempts to reduce radical lymphadenectomy-related complications and morbidities. Our study evaluates the feasibility of SLN mapping in patients with ovarian tumors by the use of intraoperative Technetium-99m-Phytate (Tc-99m-Phytate) and postoperative lymphoscintigraphy using tomographic (single-photon emission computed tomography/computed tomography (SPECT/CT)) acquisition. Materials and Methods: Thirty-two patients with ovarian mass participated in this study. Intraoperative injection of the radiopharmaceutical was performed just after laparotomy and before the removal of tumor in utero-ovarian and suspensory ligaments of the ovary just beneath the peritoneum. Subsequently, pelvic and para-aortic lymphadenectomy was performed for malignant masses, and the presence of tumor in the lymph nodes was assessed through histopathological examination. Conversely, lymphadenectomy was not performed in patients with benign lesions or borderline ovarian tumors. Lymphoscintigraphy was performed within 24 hr using tomographic acquisition (SPECT/CT) of the abdomen and pelvis. Results: Final pathological examination showed 19 patients with benign pathology, 5 with borderline tumors, and 6 with malignant ovarian tumors. SPECT/CT identified SLNs in para-aortic-only areas in 6 (20%), pelvic/para-aortic areas in 14 (47%), and pelvic-only areas in 7 (23%) cases. Notably, additional unusual SLN locations were revealed in perirenal, intergluteal, and posterior to psoas muscle regions in three patients. We were not able to calculate the false negative rate due to the absence of patients with involved lymph nodes. Conclusion: SLN mapping using intraoperative injection of radiotracers is safe and feasible. Larger studies with more malignant cases are needed to better evaluate the sensitivity of this method for lymphatic staging of ovarian malignancies.

Optimization of Ketobenzothiazole-Based Type II Transmembrane Serine Protease Inhibitors to Block H1N1 Influenza Virus Replication.

Human influenza viruses cause acute respiratory symptoms that can lead to death. Due to the emergence of antiviral drug-resistant strains, there is an urgent requirement for novel antiviral agents and innovative therapeutic strategies. Using the peptidomimetic ketobenzothiazole protease inhibitor RQAR-Kbt (IN-1, aka N-0100) as a starting point, we report how substituting P2 and P4 positions with natural and unnatural amino acids can modulate the inhibition potency toward matriptase, a prototypical type II transmembrane serine protease (TTSP) that acts as a priming protease for influenza viruses. We also introduced modifications of the peptidomimetics N-terminal groups, leading to significant improvements (from µM to nM, 60 times more potent than IN-1) in their ability to inhibit the replication of influenza H1N1 virus in the Calu-3 cell line derived from human lungs. The selectivity towards other proteases has been evaluated and explained using molecular modeling with a crystal structure recently obtained by our group. By targeting host cell TTSPs as a therapeutic approach, it may be possible to overcome the high mutational rate of influenza viruses and consequently prevent potential drug resistance.

Epigenetic-based cancer therapeutics: new potential HDAC8 inhibitors.

Designing dual small molecule inhibitors against enzymes associated with cancer has turned into a new strategy in cancer chemotherapy. Targeting DNA methyltransferase (DNMT) and histone deacetylase (HDAC) enzymes, involved in epigenetic modifications, are considered as promising treatments for a wide range of cancers, due to their association with the initiation, proliferation, and survival of cancer cells. In this study, for the first time, the dual inhibitors of the histone deacetylases 8 (HDAC8) and DNA methyltransferase 1 (DNMT1) has introduced as novel potential candidates for epigenetic-based cancer therapeutics. This research has been facilitated by employing pharmacophore-based virtual screening of ZINC and Maybridge databases, as well as performing molecular docking, molecular dynamics simulations and free binding energy calculation on the top derived compound. Results have demonstrated that the suggested compounds not only adopt highly favorable conformations but also possess strong binding interaction with the HDAC8 enzyme. Additionally, the obtained results from the experimental assay confirmed the predicted behavior of inhibitors from virtual screening. These results can be used for further optimization to yield promising more effective candidates for the treatment of cancer.Communicated by Ramaswamy H. Sarma.

Feasibility of sentinel lymph node mapping in ovarian tumors: A systematic review and meta-analysis of the literature.

Purpose of the report: Since the presence of lymph node metastases upstages the disease and to reduce the morbidity of total lymphadenectomy, sentinel lymph node (SLN) mapping in ovarian mass has been the focus of extensive research. This study aims to review all the literature associated with ovarian SLN mapping and assess the feasibility of ovarian SLN mapping. Materials and methods: PubMed and Scopus were searched using the following keywords: (Sentinel lymph node) AND (Ovary OR Ovarian) AND (Tumor OR Neoplasm OR Cancer). All studies with information regarding sentinel node biopsy in ovaries were included. Different information including mapping material, injection sites, etc., was extracted from each study. In total, two indices were calculated for included studies: detection rate and false-negative rate. Meta-analysis was conducted using Meta-MUMS software. Pooled detection rate, sensitivity, heterogeneity, and publication bias were evaluated. Quality of the studies was evaluated using the Oxford center for evidence-based medicine checklist. Results: Overall, the systematic review included 14 studies. Ovarian SLN detection rate can vary depending on the type of tracer, site of injection, etc., which signifies an overall pooled detection rate of 86% [95% CI: 75-93]. The forest plot of detection rate pooling is provided (Cochrane Q-value = 31.57, p = 0.003; I2 = 58.8%). Trim and fill method resulted in trimming of 7 studies, which decreased the pooled detection rate to 79.1% [95% CI: 67.1-87.5]. Overall, pooled sensitivity was 91% [59-100] (Cochrane Q-value = 3.93; p = 0.41; I2 = 0%). The proportion of lymph node positive patients was 0-25% in these studies with overall 14.28%. Conclusion: Sentinel lymph node mapping in ovarian tumors is feasible and seems to have high sensitivity for detection of lymph node involvement in ovarian malignant tumors. Mapping material, injection site, and previous ovarian surgery were associated with successful mapping. Larger studies are needed to better evaluate the sensitivity of this procedure in ovarian malignancies.

The possible effect of microRNA-155 (miR-155) and BACE1 inhibitors in the memory of patients with down syndrome and Alzheimer's disease: Design, synthesis, virtual screening, molecular modeling and biological evaluations.

MiR-155 plays main roles in several physiological and pathological mechanisms, such as Down syndrome (DS), immunity and inflammation and potential anti-AD therapeutic target. The miR-155 is one of the overexpressed miRNAs in DS patients that contribute directly and indirectly to the onset or progression of the DS. Since the miR-155 can simultaneously reduce the translation of several genes at post-transcriptional levels, targeting the miR-155 might set the stage for the treatment of DS. One of the rational strategies in providing therapeutic interventions in this respect is to design and develop novel small molecules inhibiting the miR-155 function or biogenesis or maturation. In the present study, we aim to introduce small molecule compounds with the potential to inhibit the generation of the selectively miR-155 processing by employing computational drug design approaches, as well as in vitro studies. We designed and synthesized a novel series of imidazo[1,2-a]pyridines derivatives as new nonpeptic candidates for the treatment of DS with AD. The designed compounds were investigated for their BACE1 and miR-155 binder inhibitory potential in vitro and in cell. In addition, we present a systematic computational approach that includes 3 D modeling, docking-based virtual screening, and molecular dynamics simulation to identify Small - molecule inhibitors of pre-miR-155 maturation. To confirm the inhibitory potential of compound 8k on miR-155 maturation, qRT- PCR was performed. All our results confirm that compound 8k, in addition to being a good inhibitor of BACE1, can also be a good inhibitor of miR-155.Communicated by Ramaswamy H. Sarma.

Effects of onopordia, a novel isolated compound from Onopordon acanthium, on pentylenetetrazole-induced seizures in mice: Possible involvement of nitric oxide pathway.

Epilepsy is identified as a brain disorder and characterized by unpredictable disruption of normal brain function. Due to adverse side effect associated with antiepileptic drugs and also resistance profile, improvement of antiepileptic medications with more beneficial anticonvulsant activity is essential. Natural products have demonstrated their therapeutic properties such as anxiolytic, antidepressant and anticonvulsant activities and a source for identification of novel lead compounds. Therefore, the purpose of this study was to evaluate the effects of Onopordon acanthium secondary metabolite, onopordia, on pentylenetetrazole (PTZ)-induced seizure in male mice and investigate the possible role of nitric oxide pathway. Different doses of onopordia (0.1, 1 and 10 mg/kg) and phenobarbital (20 mg/kg) were administered intraperitoneally (i.p., 30, 60 and 120 min) prior to induction of epileptic seizure and compared to control groups. Onopordia demonstrated anticonvulsant effects when administrated at dose of 10 mg/kg, i.p. and optimum time 60 min prior to induction of seizure. Anticonvulsant effect of onopordia was blocked by applying a single dose of a non-selective nitric oxide synthase (NOS) inhibitor, Nω-nitro-l-arginine methyl ester hydrochloride (l-NAME; 10 mg/kg, i.p.), and also a single dose of a selective neuronal NOS (nNOS) inhibitor, 7-nitroindazole (7-NI; 30 mg/kg, i.p.). Administration of ketamine as a N-Methyl-d-aspartic acid (NMDA) receptor antagonist (0.5 mg/kg; i.p.) with onopordia did not change the anticonvulsant effect of onopordia. The results of the present study demonstrated the anticonvulsant effect of onopordia as a new lead compound and also contribution of NO/nNOS pathway on PTZ-induced seizure in mice.

Targeting the microRNA binding domain of argonaute 2: rational inhibitor design and study of mutation effects on protein-ligand interaction.

Based on the accumulative evidences during recent decades, miRNAs have been found overexpressed in several human cancer types and also in Down syndrome patients, contributing to the neuropathology of Down syndrome. From this point of view, investigations on the structure and dynamic mechanisms related to the Argonaute 2 miRNAs binding in which silencing of the mRNA occurs, have inspired many clinical researchers to target this complex to inhibit the silencing process. In the current research, we have virtually screened the OTAVA_CNS_library to introduce new inhibitor compounds for the Ago2/miRNA complex. Ten hit compounds were obtained, with just one of them nominated as the best compound. Following the interaction analysis, by utilizing molecular dynamics (MD) simulations, effects of two mutations (Thr526 to isoleucine and Gln545 to alanine) on the dynamic properties of Ago2 in the complex with the best inhibitor compound were investigated. RMSD, RMSF and h-bond number beside other analyses, highlighted the importance of the Thr526 and Gln545 mutations for the stability and flexibility of the (Ago2)/ligand complex.[Formula: see text]Communicated by Ramaswamy H. Sarma.

Hearing impairment in pregnancy toxemia.

OBJECTIVE: Preeclampsia, characterized by widespread endothelial damage and dysfunction, systemic toxicity, coagulation defects, and an increased systemic inflammatory response, poses some risk factors for hearing loss. STUDY DESIGN: A case-control study. SUBJECTS AND METHODS: Two groups with 37 preeclamptic and 38 healthy pregnant women were matched by age. Other factors that could possibly influence hearing were ruled out. Transient otoacoustic emission (TEOAE) was carried out for both groups before delivery and was repeated two weeks after delivery in cases of failure. RESULTS: We could not find any abnormality in the healthy pregnant women who underwent the TEOAE test, but five of the preeclamptic women failed the initial test before delivery. This condition was recovered two weeks later. Statistical analysis showed significant difference (TEOAE disturbances) between the two groups (P = 0.025). CONCLUSIONS: This study showed that pregnancy toxemia might have effects on hearing abilities.

Hearing impairment in the neonate of preeclamptic women.

OBJECTIVE: Preeclampsia is a critical condition that puts both pregnant women and their offspring at risk for multiorgan failure, including inner ear, due to systemic toxemia and vascular events. This study was done to determine the probable prevalence of hearing impairment in children whose mothers had pregnancy-induced hypertension, compared to those born to healthy mothers. METHODS AND MATERIALS: A cohort study was performed on two groups; the first group was made up of the offspring of preeclamptic women (n = 36) and the second was made up of offspring born to healthy mothers (n = 114). They were matched for sex and age. Other confounding variables that could have influenced the hearing were excluded. Transient evoked otoacoustic emission (TEOAE) and auditory brain response (ABR) tests were performed to screen hearing loss in each group. RESULTS: Failure rates in the first step for cases and controls were 33.33 percent and 12.76%, respectively, which showed a significant difference statistically (P = 0.001). However, the final results of the second TEOAE and ABR between the two groups were not statistically significant (P > 0.05). CONCLUSION: Although it does not seem that pregnancy toxemia plays a role in permanent hearing loss in neonates of affected mothers, it might have a transient effect on hearing.

The importance of the non-active site and non-periodical structure located histidine residue respect to the structure and function of exo-inulinase.

Here, we have studied the role of a histidine residue with the lowest solvent accessibility among other histidine residues at the end of a short connecting structure (189AELH192) of the catalytic domain of the exo-inulinase through creation of H192A mutant. Site-directed mutagenesis method was applied to create the mutant enzyme. Molecular dynamics (MD) simulations, spectroscopic, calorimetric and kinetics analysis were used to study the structural and functional consequences of His192 substitution. Accordingly, the thermo-stabilities and catalytic performance were decreased upon H192A mutation. In silico and experimental approaches evidently confirm that His192 residue of exo-inulinase possesses structural and functional importance regardless of the lack of direct interaction with the substrate or involvement in the catalytic activity of exo-inulinase.

A comparative study based on docking and molecular dynamics simulations over HDAC-tubulin dual inhibitors.

Nowadays the ability to prediction of complex behavior rationally based on the computational approaches has been a successful technique in drug discovery. In the present study interactions of a new series of hybrids, which were made by linking colchicine as a tubulin inhibitor and suberoylanilide hydroxamic acid (SAHA) as a HDAC inhibitor, with HDAC8 and HDAC1 were investigated and compared. This research has been facilitated by the availability of experimental information besides employing docking methodology as well as classical molecular dynamics simulations and binding free energy calculation were performed. The obtained findings indicate different modes of interactions and inhibition strengths of the studied inhibitors for HDAC8 and HDAC1. HDAC8 binding free energies (-34.35 to -26.27kcal/mol) revealed higher binding affinity to HDAC8 compared to HDAC1 (-33.17 to -7.99kcal/mol). The binding energy contribution of each residue with the hybrid compounds 4a-4e within the active site of HDAC1 and HDAC8 was analyzed and the results confirmed the rule of key amino acids in interaction with the hybrid compounds.