Identification of promising DNA GyrB inhibitors for Tuberculosis using pharmacophore-based virtual screening, molecular docking and molecular dynamics studies

In the current study, we searched for potential DNA GyrB inhibitors using pharmacophorebased virtual screening followed by molecular docking and molecular dynamics simulation approaches. For this purpose, a set of 248 DNA GyrB inhibitors were collected from the literature and a well-validated pharmacophore model was generated. The best pharmacophore model explained that two each of hydrogen bond acceptor and hydrophobicity were critical for inhibition of DNA GyrB. Good statistical results of the pharmacophore model indicated that the model was robust in nature. Virtual screening of molecular databases revealed three molecules as potential antimycobacterial agents. The final screened promising compounds were evaluated in molecular docking and molecular dynamics simulation studies. In the molecular dynamics studies, RMSD and RMSF values undoubtedly explained that the screened compounds formed stable complexes with DNA GyrB. Therefore it can be concluded that the compounds identified may have potential for the treatment of TB.National Research Foundation (NRF), South Africa.http://onlinelibrary.wiley.com/journal/10.1111/(ISSN)1747-02852018-08-30hb2017Chemical Patholog

Molecular Modeling on Structure-Function Analysis of Human Progesterone Receptor Modulators

Considering the significance of progesterone receptor (PR) modulators, the present study is explored to envisage the biophoric signals for binding to selective PR subtype-A using ligand-based quantitative structure activity relationship (QSAR) and pharmacophore space modeling studies on nonsteroidal substituted quinoline and cyclocymopol monomethyl ether derivatives. Consensus QSAR models (Training set (Tr): nTr=100, R2pred=0.702; test set (Ts): nTs=30, R2pred=0.705, R2m=0.635; validation set (Vs): nVs=40, R2pred=0.715, R2m=0.680) suggest that molecular topology, atomic polarizability and electronegativity, atomic mass and van der Waals volume of the ligands have influence on the presence of functional atoms (F, Cl, N and O) and consequently contribute significant relations on ligand binding affinity. Receptor independent space modeling study (Tr: nTr=26, Q2=0.927; Ts: nTs=60, R2pred=0.613, R2m=0.545; Vs: nVs=84, R2pred=0.611, R2m=0.507) indicates the importance of aromatic ring, hydrogen bond donor, molecular hydrophobicity and steric influence for receptor binding. The structure-function characterization is adjudged with the receptor-based docking study, explaining the significance of the mapped molecular attributes for ligand-receptor interaction in the catalytic cleft of PR-A

Structural requirements for potential HIV-integrase inhibitors identified using pharmacophore-based virtual screening and molecular dynamics studies

Acquired immunodeficiency syndrome (AIDS) is a life-threatening disease which is a collection of symptoms and infections caused by a retrovirus, human immunodeficiency virus (HIV). There is currently no curative treatment and therapy is reliant on the use of existing anti-retroviral drugs. Pharmacoinformatics approaches have already proven their pivotal role in the pharmaceutical industry for lead identification and optimization. In the current study, we analysed the binding preferences and inhibitory activity of HIV-integrase inhibitors using pharmacoinformatics. A set of 30 compounds were selected as the training set of a total 540 molecules for pharmacophore model generation. The final model was validated by statistical parameters and further used for virtual screening. The best mapped model (R = 0.940, rmsd = 2.847, Q2 = 0.912, se = 0.498, R2 pred = 0.847 and r2 m (test) = 0.636) explained that two hydrogen bond acceptor and one aromatic ring features were crucial for the inhibition of HIV-integrase. From virtual screening, initial hits were sorted using a number of parameters and finally two compounds were proposed as promising HIV-integrase inhibitors. Drug-likeness properties of the final screened compounds were compared to FDA approved HIV-integrase inhibitors. HIV-integrase structure in complex with the most active and final screened compounds were subjected to 50ns molecular dynamics (MD) simulation studies to check comparative stability of the complexes. The study suggested that the screened compounds might be promising HIV-integrase inhibitors. The new chemical entities obtained from the NCI database will be subjected to experimental studies to confirm potential inhibition of HIV integrase.University of Pretoria Vice Chancellor’s post-doctoral fellowship and National Research Foundation (NRF), South Africa.http://www.rsc.orgmolecularbiosystems2017-01-31hb2016Chemical Patholog

Simplified molecular input line entry system-based descriptors in QSAR modeling for HIV-protease inhibitors

Simplified molecular input line entry system (SMILES) descriptor based quantitative structure–activity relationship (QSAR) study was performed on a set of HIV-protease inhibitors to explore the structural functionalities for inhibition of the HIV-protease. For this purpose a set of HIV-inhibitors was collected from the literature along with their inhibitory constants. Monte Carlo optimization-based CORAL software was used for QSAR model development. Firstly, the dataset was divided into three random splits and secondly each split was divided into training, calibration, test and validation sets. A training set was used for model development whereas the rest of the sets were used to assess the quality of the developed models. QSAR models were developed with and without considering the influence of cyclic rings toward the inhibitory activity. Statistical quality of QSAR models developed from all splits was very good and fulfilled the criteria. The values of R2, Q2, s, R2 pred and r2 m explained that selected models are robust in nature and efficient enough to predict the inhibitory activity of the molecules outside of the training set. Statistical parameters also suggested that the presence of cyclic rings have a crucial impact on inhibitory activity. The molecular fragmentswere found to be important for the increase or decrease of the inhibitory activity which explained that models have mechanistic interpretation. This ligandbased QSAR study can provide clear directions to design and modulate potential HIV-protease inhibitors.The University of Pretoria Vice Chancellor's post-doctoral fellowship and the National Research Foundation (NRF), South Africa Innovation post-doctoral fellowship schemes.http://www.elsevier.com/locate/chemolab2017-04-30hb2016Chemical Patholog

Exploration of the structural requirements of HIV-protease inhibitors using pharmacophore, virtual screening and molecular docking approaches for lead identification

Please abstract in the article.The University of Pretoria Vice Chancellor's post-doctoral fellowship scheme.http://www.elsevier.com/locate/JMGMhj201

Diabetes mellitus caused by mutations in human insulin : analysis of impaired receptor binding of insulins Wakayama, Los Angeles and Chicago using pharmacoinformatics

Several naturally occuring mutations in the human insulin gene are associated with diabetes mellitus. The three known mutant molecules, Wakayama, Los Angeles and Chicago were evaluated using molecular docking and molecular dynamics (MD) to analyse mechanisms of deprived binding affinity for insulin receptor (IR). Insulin Wakayama, is a variant in which valine at position A3 is substituted by leucine, while in insulin Los Angeles and Chicago, phenylalanine at position B24 and B25 are replaced by serine and leucine respectively. These mutations show radical changes in binding affinity for insulin receptor. The ZDOCK server was used for molecular docking while AMBER 14 was used for the molecular dynamics study. The published crystal structure of insulin receptor bound to natural insulin was also used for molecular dynamics. The binding interactions and molecular dynamics trajectories clearly explained the critical factors for deprived binding to the insulin receptor. The surface area around position A3 was increased when valine was substituted by leucine, while at position B24 and B25 aromatic amino acid phenylalanine replaced by non-aromatic serine and leucine might be responsible for fewer binding interactions at the binding site of insulin receptor that leads to instability of the complex. In the MD simulation the normal mode analysis (NMA), rmsd trajectories and prediction of fluctuation indicated instability of complexes with mutant insulin in order of insulin native insulin < insulin Chicago < insulin Los Angeles < insulin Wakayama molecules which corresponds to the biological evidence of the differing affinities of the mutant insulins for the IR.The University of Pretoria Vice Chancellor’s postdoctoral fellowship and National Research Foundation (NRF), South Africa Innovation postdoctoral fellowship schemes.http://www.tandfonline.com/loi/tbsd202018-03-31hb2017Chemical Patholog

Identification of structural requirements of estrogen receptor modulators using pharmacoinformatics techniques for application to estrogen therapy

An attempt was made in the present study to explore the structural requirements of known estrogen receptor (ER) modulators for biological activity using pharmacoinformatics approaches to elucidate critical functionalities for new, potent and less toxic chemical agents for successful application in estrogen therapy. For this purpose a group of non-steroidal ligands, 7-thiabicyclo[2.2.1]hept-2-ene-7- oxide derivatives were collected from the literature to perform quantitative structure-activity relationship (QSAR), pharmacophore and molecular docking studies. The 2D QSAR models (R2 α = 0.857, seα = 0.370, Q2 α = 0.848, R2 pred-α = 0.675, spα = 0.537; R2 β = 0.874, seβ = 0.261, Q2 β = 0.859, R2 pred-β = 0.659, spβ = 0.408) explained that hydrophobicity and molar refractivity were crucial for binding affinity in both α- and β-subtypes. The space modeling study (R2 α = 0.955, seα = 1.311, Q2 α = 0.932, R2 pred-α = 0.737, spα = 0.497; R2 β = 0.885, seβ = 1.328, Q2 β = 0.878, R2 pred-β = 0.769, spβ = 0.336) revealed the importance of HB donor and hydrophobic features for both subtypes, whereas, HB acceptor and aromatic ring were critical for α- and β-subtypes respectively. The functionalities developed in the QSAR and pharmacophore studies were substantiated by molecular docking which provided the preferred orientation of ligands for effective interaction at the active site cavity.MA Islam and TS Pillay were funded by the University of Pretoria Vice Chancellor’s post-doctoral fellowship and National Research Foundation (NRF), South Africa Innovation Post-doctoral fellowship schemes.http://link.springer.com/journal/442017-03-31hb2016Chemical Patholog

Structure‑based identification of SARS‑CoV‑2 main protease inhibitors from anti‑viral specific chemical libraries : an exhaustive computational screening approach

Worldwide coronavirus disease 2019 (COVID-19) outbreak is still threatening global health since its outbreak first reported in the late 2019. The causative novel virus has been designated as severe acute respiratory syndrome coronavirus 2 (SARSCoV- 2). Although COVID-19 emergent with significant mortality, there is no availability of definite treatment measures. It is now extremely desirable to identify potential chemical entities against SARS-CoV-2 for the treatment of COVID-19. In the present study, a state-of-art virtual screening protocol was implemented on three anti-viral specific chemical libraries against SARS-CoV-2 main protease ( Mpro). Particularly, viewing the large-scale biological role of Mpro in the viral replication process it has been considered as a prospective anti-viral drug target. Herein, on collected 79,892 compounds, hierarchical multistep docking followed by relative binding free energy estimation has been performed. Thereafter, implying a user-defined XP-dock and MM-GBSA cut-off scores as −8.00 and −45.00 kcal/mol, chemical space has been further reduced. Exhaustive molecular binding interactions analyses and various pharmacokinetics profiles assessment suggested four compounds (ChemDiv_D658-0159, ChemDiv_F431-0433, Enamine_Z3019991843 and Asinex_LAS_51389260) as potent inhibitors/modulators of SARS-CoV-2 Mpro. In-depth protein–ligand interactions stability in the dynamic state has been evaluated by 100 ns molecular dynamics (MD) simulation studies along with MM-GBSA-based binding free energy estimations of entire simulation trajectories that have revealed strong binding affinity of all identified compounds towards Mpro. Hence, all four identified compounds might be considered as promising candidates for future drug development specifically targeting the SARS-CoV-2 Mpro; however, they also need experimental assessment for a better understanding of molecular interaction mechanisms.The Deanship of Scientific Research at King Saud University.http://link.springer.com/journal/11030am2022Chemical Patholog

De novo design based identification of potential HIV-1 integrase inhibitors: A pharmacoinformatics study

In the present study, pharmacoinformatics paradigms include receptor-based de novo design, virtual screening through molecular docking and molecular dynamics (MD) simulation are implemented to identify novel and promising HIV-1 integrase inhibitors. The de novodrug/ligand/molecule design is a powerful and effective approach to design a large number of novel and structurally diverse compounds with the required pharmacological profiles. A crystal structure of HIV-1 integrase bound with standard inhibitor BI-224436 is used and a set of 80000 compounds through the de novo approach in LigBuilder is designed. Initially, a number of criteria including molecular docking, in-silico toxicity and pharmacokinetics profile assessments are implied to reduce the chemical space. Finally, four de novo designed molecules are proposed as potential HIV-1 integrase inhibitors based on comparative analyses. Notably, strong binding interactions have been identified between a few newly identified catalytic amino acid residues and proposed HIV-1 integrase inhibitors. For evaluation of the dynamic stability of the protein-ligand complexes, a number of parameters are explored from the 100 ns MD simulation study. The MD simulation study suggested that proposed molecules efficiently retained their molecular interaction and structural integrity inside the HIV-1 integrase. The binding free energy is calculated through the Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) approach for all complexes and it also explains their thermodynamic stability. Hence, proposed molecules through de novo design might be critical to inhibiting the HIV-1 integrase

Identification of selective Lyn inhibitors from the chemical databases through integrated molecular modelling approaches

In the current study, the Asinex and ChEBI databases were virtually screened for the identification of potential Lyn protein inhibitors. Therefore, a multi-steps molecular docking study was carried out using the VSW utility tool embedded in Maestro user interface of the Schrödinger suite. On initial screening, molecules having a higher XP-docking score and binding free energy compared to Staurosporin were considered for further assessment. Based on in silico pharmacokinetic analysis and a common-feature pharmacophore mapping model developed from the Staurosporin, four molecules were proposed as promising Lyn inhibitors. The binding interactions of all proposed Lyn inhibitors revealed strong ligand efficiency in terms of energy score obtained in molecular modelling analyses. Furthermore, the dynamic behaviour of each molecule in association with the Lyn protein-bound state was assessed through an all-atoms molecular dynamics (MD) simulation study. MD simulation analyses were confirmed with notable intermolecular interactions and consistent stability for the Lyn protein-ligand complexes throughout the simulation. High negative binding free energy of identified four compounds calculated through MM-PBSA approach demonstrated a strong binding affinity towards the Lyn protein. Hence, the proposed compounds might be taken forward as potential next-generation Lyn kinase inhibitors for managing numerous Lyn associated diseases or health complications after experimental validation.The Deanship of Scientific Research at Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia through the Fast-track Research Funding Program.https://www.tandfonline.com/loi/gsar20hj2022Chemical Patholog