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1.
J Comput Aided Mol Des ; 32(1): 59-73, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29052792

RESUMO

Advanced molecular docking methods often aim at capturing the flexibility of the protein upon binding to the ligand. In this study, we investigate whether instead a simple rigid docking method can be applied, if combined with multiple target structures to model the backbone flexibility and molecular dynamics simulations to model the sidechain and ligand flexibility. The methods are tested for the binding of 35 ligands to FXR as part of the first stage of the Drug Design Data Resource (D3R) Grand Challenge 2 blind challenge. The results show that the multiple-target docking protocol performs surprisingly well, with correct poses found for 21 of the ligands. MD simulations started on the docked structures are remarkably stable, but show almost no tendency of refining the structure closer to the experimentally found binding pose. Reconnaissance metadynamics enhances the exploration of new binding poses, but additional collective variables involving the protein are needed to exploit the full potential of the method.


Assuntos
Desenho de Fármacos , Simulação de Acoplamento Molecular , Receptores Citoplasmáticos e Nucleares/metabolismo , Sítios de Ligação , Bases de Dados de Proteínas , Descoberta de Drogas , Humanos , Ligantes , Simulação de Dinâmica Molecular , Ligação Proteica , Conformação Proteica , Receptores Citoplasmáticos e Nucleares/agonistas , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Receptores Citoplasmáticos e Nucleares/química
2.
J Comput Aided Mol Des ; 31(1): 119-132, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27573983

RESUMO

The funnel metadynamics method enables rigorous calculation of the potential of mean force along an arbitrary binding path and thereby evaluation of the absolute binding free energy. A problem of such physical paths is that the mechanism characterizing the binding process is not always obvious. In particular, it might involve reorganization of the solvent in the binding site, which is not easily captured with a few geometrically defined collective variables that can be used for biasing. In this paper, we propose and test a simple method to resolve this trapped-water problem by dividing the process into an artificial host-desolvation step and an actual binding step. We show that, under certain circumstances, the contribution from the desolvation step can be calculated without introducing further statistical errors. We apply the method to the problem of predicting host-guest binding free energies in the SAMPL5 blind challenge, using two octa-acid hosts and six guest molecules. For one of the hosts, well-converged results are obtained and the prediction of relative binding free energies is the best among all the SAMPL5 submissions. For the other host, which has a narrower binding pocket, the statistical uncertainties are slightly higher; longer simulations would therefore be needed to obtain conclusive results.


Assuntos
Ligantes , Simulação de Dinâmica Molecular , Proteínas/química , Termodinâmica , Água/química , Sítios de Ligação , Conformação Molecular , Estrutura Molecular , Ligação Proteica , Software , Solventes/química
3.
Cell Biochem Biophys ; 75(1): 49-64, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27981421

RESUMO

Human immunodeficiency virus (HIV)-negative factor (Nef) protein is an accessory pathogenic factor, which plays a significant role in acquired immune deficiency syndrome (AIDS). Nef deficient HIV virus took a longer time to progress into AIDS. Therefore, targeting Nef protein is considered as a key strategy towards HIV/AIDS treatment. Up-to-date, only few compounds were reported as Nef inhibitors. This has prompted us to provide a first account of an integrated computational framework in order to identify more potential Nef inhibitors. Herein, using a hybrid ligand (shape similarity and pharmacophore) and structure-(molecular docking) based virtual screening approaches combined with molecular dynamics as well as post dynamics analysis, potential new hits were identified as HIV-Nef inhibitors. The top ranked compounds of molecular docking from the shape similarity-based library (ZINC04177596, ∆ G bind= -28.7482 kcal/mol) and pharmacophore-based library (ZINC36617540, ∆ G bind= -20.2271 kcal/mol) possess comparatively better binding affinities than the reference molecule, B9 (∆ G bind = -18.0694 kcal/mol). Both these hits (ZINC04177596 and ZINC36617540) showed similar binding mode at the binding site as like the prototype, B9. Hydrophobic and electrostatic interactions seemed to be the prominent binding forces that hold these ligands at the dimer interface of Nef protein. Finally, a set of chemical structural features that can be used as a guide in the design of novel potential Nef inhibitors is also highlighted herein. We believe that the information gained from this study would be of great importance in the discovery and design of potential small molecules targeting HIV-Nef.


Assuntos
Fármacos Anti-HIV/química , Produtos do Gene nef do Vírus da Imunodeficiência Humana/antagonistas & inibidores , Avaliação Pré-Clínica de Medicamentos , Humanos , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ligação Proteica , Domínios Proteicos , Bibliotecas de Moléculas Pequenas , Relação Estrutura-Atividade , Termodinâmica , Produtos do Gene nef do Vírus da Imunodeficiência Humana/química
4.
Cell Biochem Biophys ; 74(1): 35-48, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26972300

RESUMO

Molecular dynamics simulations, binding free energy calculations, principle component analysis (PCA), and residue interaction network analysis were employed in order to investigate the molecular mechanism of M184I single mutation which played pivotal role in making the HIV-1 reverse transcriptase (RT) totally resistant to lamivudine. Results showed that single mutations at residue 184 of RT caused (1) distortion of the orientation of lamivudine in the active site due to the steric conflict between the oxathiolane ring of lamivudine and the side chain of beta-branched amino acids Ile at position 184 which, in turn, perturbs inhibitor binding, (2) decrease in the binding affinity by (~8 kcal/mol) when compared to the wild-type, (3) variation in the overall enzyme motion as evident from the PCA for both systems, and (4) distortion of the hydrogen bonding network and atomic interactions with the inhibitor. The comprehensive analysis presented in this report can provide useful information for understanding the drug resistance mechanism against lamivudine. The results can also provide some potential clues for further design of novel inhibitors that are less susceptible to drug resistance.


Assuntos
Fármacos Anti-HIV/farmacologia , Domínio Catalítico , Transcriptase Reversa do HIV/metabolismo , Lamivudina/farmacologia , Simulação de Dinâmica Molecular , Mutação de Sentido Incorreto , Inibidores da Transcriptase Reversa/farmacologia , Fármacos Anti-HIV/química , Transcriptase Reversa do HIV/química , Transcriptase Reversa do HIV/genética , HIV-1/enzimologia , Lamivudina/química , Ligação Proteica , Inibidores da Transcriptase Reversa/química
5.
Anticancer Agents Med Chem ; 16(8): 961-972, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26863881

RESUMO

In spite of tremendous advancement in the field of cancer therapy, it is still one of the leading causes of death worldwide. One of the newest targets in the field of cancer therapeutics is 5'Adenosine Mono Phosphate activated protein kinase (AMPK). In vitro and in vivo evidences suggest anti-cancer activity of AMPK. AMPK activation may promote catabolism while preventing the anabolic processes of cell. Thus it may modulate cellular protein and lipid metabolism and affect the growth and division of cell. Here we review the mechanisms of action of AMPK modulators as future anti-cancer agents.

6.
Chem Biol Drug Des ; 88(2): 159-77, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-26872937

RESUMO

Recent advances in biochemistry and drug design have placed proteases as one of the critical target groups for developing novel small-molecule inhibitors. Among all proteases, aspartic proteases have gained significant attention due to their role in HIV/AIDS, malaria, Alzheimer's disease, etc. The binding cleft is covered by one or two ß-hairpins (flaps) which need to be opened before a ligand can bind. After binding, the flaps close to retain the ligand in the active site. Development of computational tools has improved our understanding of flap dynamics and its role in ligand recognition. In the past decade, several computational approaches, for example molecular dynamics (MD) simulations, coarse-grained simulations, replica-exchange molecular dynamics (REMD) and metadynamics, have been used to understand flap dynamics and conformational motions associated with flap movements. This review is intended to summarize the computational progress towards understanding the flap dynamics of proteases and to be a reference for future studies in this field.


Assuntos
Ácido Aspártico Proteases/química , Domínio Catalítico , Protease de HIV/química , Simulação de Dinâmica Molecular , Conformação Proteica
7.
J Biomol Struct Dyn ; 34(5): 1008-19, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26208540

RESUMO

Flap motif and its dynamics were extensively reported in aspartate proteases, e.g. HIV proteases and plasmepsins. Herein, we report the first account of flap dynamics amongst different conformations of ß-secretase using molecular dynamics simulation. Various parameters were proposed and a selected few were picked which could appropriately describe the flap motion. Three systems were studied, namely Free (BACEFree) and two ligand-bound conformations, which belonged to space groups P6122 (BACEBound1) and C2221 (BACEBound2), respectively and four parameters (distance between the flaps tip residue, Thr72 and Ser325, d1; dihedral angle, ϕ (Thr72-Asp32-Asp228-Ser325); TriCα angles, θ1 (Thr72-Asp32-Ser325), and θ2 (Thr72-Asp228-Ser325)) were proposed to understand the change in dynamics of flap domain and the extent of flap opening and closing. Analysis of, θ2, d1, θ1 and ϕ confirmed that the BACEFree adopted semi-open, open and closed conformations with slight twisting during flap opening. However, BACEBound1 (P6122) showed an adaptation to open conformation due to lack of hydrogen bond interaction between the ligand and flap tip residue. A slight flap twisting, ϕ (lateral twisting) was observed for BACEBound1 during flap opening which correlates with the opening of BACEFree. Contradictory to the BACEBound1, the BACEBound2 locked the flap in a closed conformation throughout the simulation due to formation of a stable hydrogen bond interaction between the flap tip residue and ligand. Analyses of all three systems highlight that d1, θ2 and ϕ can be precisely used to describe the extent of flap opening and closing concurrently with snapshots along the molecular dynamics trajectory across several conformations of ß-secretase.


Assuntos
Secretases da Proteína Precursora do Amiloide/química , Simulação de Dinâmica Molecular , Conformação Proteica , Relação Quantitativa Estrutura-Atividade
8.
J Biomol Struct Dyn ; 34(1): 135-51, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-25671669

RESUMO

The PR20 HIV-1 protease, a variant with 20 mutations, exhibits high levels of multi-drug resistance; however, to date, there has been no report detailing the impact of these 20 mutations on the conformational and drug binding landscape at a molecular level. In this report, we demonstrate the first account of a comprehensive study designed to elaborate on the impact of these mutations on the dynamic features as well as drug binding and resistance profile, using extensive molecular dynamics analyses. Comparative MD simulations for the wild-type and PR20 HIV proteases, starting from bound and unbound conformations in each case, were performed. Results showed that the apo conformation of the PR20 variant of the HIV protease displayed a tendency to remain in the open conformation for a longer period of time when compared to the wild type. This led to a phenomena in which the inhibitor seated at the active site of PR20 tends to diffuse away from the binding site leading to a significant change in inhibitor-protein association. Calculating the per-residue fluctuation (RMSF) and radius of gyration, further validated these findings. MM/GBSA showed that the occurrence of 20 mutations led to a drop in the calculated binding free energies (ΔGbind) by ~25.17 kcal/mol and ~5 kcal/mol for p2-NC, a natural peptide substrate, and darunavir, respectively, when compared to wild type. Furthermore, the residue interaction network showed a diminished inter-residue hydrogen bond network and changes in inter-residue connections as a result of these mutations. The increased conformational flexibility in PR20 as a result of loss of intra- and inter-molecular hydrogen bond interactions and other prominent binding forces led to a loss of protease grip on ligand. It is interesting to note that the difference in conformational flexibility between PR20 and WT conformations was much higher in the case of substrate-bound conformation as compared to DRV. Thus, developing analogues of DRV by retaining its key pharmacophore features will be the way forward in the search for novel protease inhibitors against multi-drug resistant strains.


Assuntos
Inibidores da Protease de HIV/química , Protease de HIV/química , HIV-1/química , Sulfonamidas/química , Sítios de Ligação , Resistência a Múltiplos Medicamentos/genética , Protease de HIV/genética , Protease de HIV/metabolismo , HIV-1/enzimologia , Humanos , Ligação de Hidrogênio , Simulação de Dinâmica Molecular , Mutação , Conformação Proteica/efeitos dos fármacos , Termodinâmica
9.
J Biomol Struct Dyn ; 34(4): 892-905, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26273990

RESUMO

Methylenetetrahydrofolate reductase (MTHFR) protein catalyzes the only biochemical reaction which produces methyltetrahydrofolate, the active form of folic acid essential for several molecular functions. The Ala222Val polymorphism of human MTHFR encodes a thermolabile protein associated with increased risk of neural tube defects and cardiovascular disease. Experimental studies have shown that the mutation does not affect the kinetic properties of MTHFR, but inactivates the protein by increasing flavin adenine dinucleotide (FAD) loss. The lack of completely solved crystal structure of MTHFR is an impediment in understanding the structural perturbations caused by the Ala222Val mutation; computational modeling provides a suitable alternative. The three-dimensional structure of human MTHFR protein was obtained through homology modeling, by taking the MTHFR structures from Escherichia coli and Thermus thermophilus as templates. Subsequently, the modeled structure was docked with FAD using Glide, which revealed a very good binding affinity, authenticated by a Glide XP score of -10.3983 (kcal mol(-1)). The MTHFR was mutated by changing Alanine 222 to Valine. The wild-type MTHFR-FAD complex and the Ala222Val mutant MTHFR-FAD complex were subjected to molecular dynamics simulation over 50 ns period. The average difference in backbone root mean square deviation (RMSD) between wild and mutant variant was found to be ~.11 Å. The greater degree of fluctuations in the mutant protein translates to increased conformational stability as a result of mutation. The FAD-binding ability of the mutant MTHFR was also found to be significantly lowered as a result of decreased protein grip caused by increased conformational flexibility. The study provides insights into the Ala222Val mutation of human MTHFR that induces major conformational changes in the tertiary structure, causing a significant reduction in the FAD-binding affinity.


Assuntos
Metilenotetra-Hidrofolato Redutase (NADPH2)/química , Simulação de Dinâmica Molecular , Proteínas Mutantes , Conformação Proteica , Sequência de Aminoácidos , Sítios de Ligação , Catálise , Domínio Catalítico , Códon , Flavina-Adenina Dinucleotídeo/química , Humanos , Ligação de Hidrogênio , Cinética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Simulação de Acoplamento Molecular , Mutação , Ligação Proteica , Relação Estrutura-Atividade
10.
J Recept Signal Transduct Res ; 35(4): 346-56, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26355431

RESUMO

The first account on the dynamic features of Nef or negative factor, a small myristoylated protein located in the cytoplasm believes to increase HIV-1 viral titer level, is reported herein. Due to its major role in HIV-1 pathogenicity, Nef protein is considered an emerging target in anti-HIV drug design and discovery process. In this study, comparative long-range all-atom molecular dynamics simulations were employed for apo and bound protein to unveil molecular mechanism of HIV-Nef dimerization and inhibition. Results clearly revealed that B9, a newly discovered Nef inhibitor, binds at the dimeric interface of Nef protein and caused significant separation between orthogonally opposed residues, namely Asp108, Leu112 and Gln104. Large differences in magnitudes were observed in the radius of gyration (∼1.5 Å), per-residue fluctuation (∼2 Å), C-alpha deviations (∼2 Å) which confirm a comparatively more flexible nature of apo conformation due to rapid dimeric association. Compared to the bound conformer, a more globally correlated motion in case of apo structure of HIV-Nef confirms the process of dimeric association. This clearly highlights the process of inhibition as a result of ligand binding. The difference in principal component analysis (PCA) scatter plot and per-residue mobility plot across first two normal modes further justifies the same findings. The in-depth dynamic analyses of Nef protein presented in this report would serve crucial in understanding its function and inhibition mechanisms. Information on inhibitor binding mode would also assist in designing of potential inhibitors against this important HIV target.


Assuntos
Fármacos Anti-HIV/farmacologia , Compostos Azo/farmacologia , HIV-1/efeitos dos fármacos , Pirazóis/farmacologia , Produtos do Gene nef do Vírus da Imunodeficiência Humana/antagonistas & inibidores , Produtos do Gene nef do Vírus da Imunodeficiência Humana/química , Fármacos Anti-HIV/química , Apoproteínas/química , Apoproteínas/efeitos dos fármacos , Apoproteínas/metabolismo , Compostos Azo/química , Sítios de Ligação , Descoberta de Drogas , HIV-1/química , HIV-1/patogenicidade , Humanos , Modelos Moleculares , Simulação de Dinâmica Molecular , Multimerização Proteica/efeitos dos fármacos , Estrutura Secundária de Proteína , Pirazóis/química , Produtos do Gene nef do Vírus da Imunodeficiência Humana/metabolismo
11.
Mol Biosyst ; 11(8): 2303-11, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26077945

RESUMO

3C protease of Coxsackievirus B3 (CVB3) plays an essential role in the viral replication cycle, and therefore, emerged as an attractive therapeutic target for the treatment of human diseases caused by CVB3 infection. In this study, we report the first account of the molecular impact of the T68A/N126Y double mutant (Mutant(Bound)) using an integrated computational approach. Molecular dynamics simulation and post-dynamics binding free energy, principal component analysis (PCA), hydrogen bond occupancy, SASA, R(g) and RMSF confirm that T68A/N126Y instigated an increased conformational flexibility due to the loss of intra- and inter-molecular hydrogen bond interactions and other prominent binding forces, which led to a decreased protease grip on the ligand (3CPI). The double mutations triggered a distortion orientation of 3CPI in the active site and decreases the binding energy, ΔG(bind) (∼3 kcal mol(-1)), compared to the wild type (Wild(Bound)). The van der Waals and electrostatic energy contributions coming from residues 68 and 126 are lower for Mutant(Bound) when compared with Wild(Bound). In addition, variation in the overall enzyme motion as evident from the PCA, distorted hydrogen bonding network and loss of protein-ligand interactions resulted in a loss of inhibitor efficiency. The comprehensive molecular insight gained from this study should be of great importance in understanding the drug resistance against CVB3 3C protease; also, it will assist in the designing of novel Coxsackievirus B3 inhibitors with high ligand efficacy on resistant strains.


Assuntos
Infecções por Coxsackievirus/genética , Cisteína Endopeptidases/química , Enterovirus/genética , Conformação Molecular , Proteínas Virais/química , Antivirais/química , Infecções por Coxsackievirus/tratamento farmacológico , Infecções por Coxsackievirus/virologia , Cisteína Endopeptidases/genética , Cisteína Endopeptidases/metabolismo , Enterovirus/química , Humanos , Ligação de Hidrogênio , Ligantes , Simulação de Dinâmica Molecular , Mutação , Proteínas Virais/genética , Proteínas Virais/metabolismo
12.
Chem Biol Drug Des ; 86(5): 1131-60, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25958815

RESUMO

There are over 100 different types of cancer, and each is classified based on the type of cell that is initially affected. If left untreated, cancer can result in serious health problems and eventually death. Recently, the paradigm of cancer chemotherapy has evolved to use a combination approach, which involves the use of multiple drugs each of which targets an individual protein. Inhibition of heat-shock protein 90 (Hsp90) is one of the novel key cancer targets. Because of its ability to target several signaling pathways, Hsp90 inhibition emerged as a useful strategy to treat a wide variety of cancers. Molecular modeling approaches and methodologies have become 'close counterparts' to experiments in drug design and discovery workflows. A wide range of molecular modeling approaches have been developed, each of which has different objectives and outcomes. In this review, we provide an up-to-date systematic overview on the different computational models implemented toward the design of Hsp90 inhibitors as anticancer agents. Although this is the main emphasis of this review, different topics such as background and current statistics of cancer, different anticancer targets including Hsp90, and the structure and function of Hsp90 from an experimental perspective, for example, X-ray and NMR, are also addressed in this report. To the best of our knowledge, this review is the first account, which comprehensively outlines various molecular modeling efforts directed toward identification of anticancer drugs targeting Hsp90. We believe that the information, methods, and perspectives highlighted in this report would assist researchers in the discovery of potential anticancer agents.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Descoberta de Drogas/métodos , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Animais , Proteínas de Choque Térmico HSP90/química , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Modelos Moleculares , Terapia de Alvo Molecular , Neoplasias/metabolismo
13.
J Nat Med ; 69(4): 451-62, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25921858

RESUMO

Chikungunya virus (CHIKV) is one of the re-emerging "neglected" tropical diseases whose recent outbreak affected not only Africa and South-East Asia but also several parts of America and Europe. To date, despite its serious nature, no antivirals or vaccines were developed in order to counter this resurgent infectious disease. The recent advancement in crystallography and availability of crystal structures of certain domains of CHIKV initiates the development of anti-CHIKV agents using structure-based drug design or synthetic medicinal chemistry approach. Despite the fact that almost 50% of the new chemical entities against several biological targets were either obtained from natural products or natural product analogues, a very humble effort was directed towards identification of novel CHIKV inhibitors from natural products. In this review, besides a brief overview on CHIKV as well as the nature as a source of medicines, we highlight the current progress and future steps towards the discovery of CHIKV inhibitors from natural products. This report could pave the road towards the design of novel semi-synthetic derivatives with enhanced anti-viral activities.


Assuntos
Antivirais/síntese química , Febre de Chikungunya/virologia , Vírus Chikungunya/química , Antivirais/farmacologia , Química Farmacêutica , Vírus Chikungunya/efeitos dos fármacos
14.
Eur J Med Chem ; 95: 324-48, 2015 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-25827401

RESUMO

Malaria is one of the major parasitic disease whose rapid spreading and mortality rate affects all parts of the world especially several parts of Asia as well as Africa. The emergence of multi-drug resistant strains hamper the progress of current antimalarial therapy and displayed an urgent need for new antimalarials by targeting novel drug targets. Until now, several promising targets were explored in order to develop a promising Achilles hill to counter malaria. Plasmepsin, an aspartic protease, which is involved in the hemoglobin breakdown into smaller peptides emerged as a crucial target to develop new chemical entities to counter malaria. Due to early crystallographic evidence, plasmepsin II (Plm II) emerged as well explored target to develop novel antimalarials as well as a starting point to develop inhibitors targeting some other subtypes of plasmepsins i.e. Plm I, II, IV and V. With the advancements in drug discovery, several computational and synthetic approaches were employed in order to develop novel inhibitors targeting Plm II. Strategies such as fragment based drug design, molecular dynamics simulation, double drug approach etc. were employed in order to develop new chemical entities targeting Plm II. But majority of Plm II inhibitors suffered from poor selectivity over cathepsin D as well as other subtypes of plasmepsins. This review highlights an updated account of drug discovery efforts targeting plasmepsin II from a medicinal chemistry perspective.


Assuntos
Ácido Aspártico Endopeptidases , Desenho de Fármacos , Terapia de Alvo Molecular/métodos , Proteínas de Protozoários , Antimaláricos/química , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Ácido Aspártico Endopeptidases/química , Ácido Aspártico Endopeptidases/metabolismo , Humanos , Malária/tratamento farmacológico , Proteínas de Protozoários/antagonistas & inibidores , Proteínas de Protozoários/química , Proteínas de Protozoários/metabolismo
15.
Mol Biosyst ; 11(4): 1061-6, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25630418

RESUMO

Herein, for the first time, we report the flap opening and closing in Plasmepsin proteases - plasmepsin II (PlmII) was used as a prototype model. We proposed different combined parameters to define the asymmetric flap motion; the distance, d1, between the flap tip residues (Val78 and Leu292); the dihedral angle, ϕ; in addition to TriCα angles Val78-Asp34-Leu292, θ1, and Val78-Asp214-Leu292, θ2. Only three combined parameters, the distance, d1, the dihedral angle, ϕ, and the TriCα angle, θ1, were found to appropriately define the observed "twisting' motion during the flap opening and closing. The coordinated motions of the proline-rich loop adjacent to the binding cavity rim appeared to exert steric hindrance on the flap residues, driving the flap away from the active site cavity. This loop may also have increased movements around the catalytic dyad residue, Asp214, making TriCα, θ2, unreliable in describing the flap motion. The full flap opening at d1, 23.6 Å, corresponded to the largest TriCα angle, θ1, at 78.6° on a ∼46 ns time scale. Overall the average θ1 and θ2 for the bound was ∼46° and ∼53°, respectively, compared to ∼50° and ∼59° for the Apo PlmII, indicating a drastic increase in TriCα as the active site cavity opens. Similar trends in the distance, d1, and the dihedral angle, ϕ, were observed during the simulation. The asymmetrical opening of the binding cavity was best described by the large shift in ϕ from -33.91° to +21.00° corresponding to the partial opening of the flap in the range of 22-31 ns. Though, the dihedral angle described the twisting of the flap, the extent of flap opening can appropriately be defined by combining d1 and θ1. The results presented here, on the combined parameters, will certainly augment current efforts in designing potent structure-based inhibitors against plasmepsins.


Assuntos
Ácido Aspártico Endopeptidases/química , Ácido Aspártico Endopeptidases/metabolismo , Proteínas de Protozoários/química , Proteínas de Protozoários/metabolismo , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Benzamidas/química , Benzamidas/metabolismo , Sítios de Ligação , Simulação de Dinâmica Molecular , Ftalimidas/química , Ftalimidas/metabolismo , Ligação Proteica , Conformação Proteica , Proteínas de Protozoários/antagonistas & inibidores
16.
Molecules ; 20(2): 1984-2000, 2015 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-25633330

RESUMO

he present art of drug discovery and design of new drugs is based on suicidal irreversible inhibitors. Covalent inhibition is the strategy that is used to achieve irreversible inhibition. Irreversible inhibitors interact with their targets in a time-dependent fashion, and the reaction proceeds to completion rather than to equilibrium. Covalent inhibitors possessed some significant advantages over non-covalent inhibitors such as covalent warheads can target rare, non-conserved residue of a particular target protein and thus led to development of highly selective inhibitors, covalent inhibitors can be effective in targeting proteins with shallow binding cleavage which will led to development of novel inhibitors with increased potency than non-covalent inhibitors. Several computational approaches have been developed to simulate covalent interactions; however, this is still a challenging area to explore. Covalent molecular docking has been recently implemented in the computer-aided drug design workflows to describe covalent interactions between inhibitors and biological targets. In this review we highlight: (i) covalent interactions in biomolecular systems; (ii) the mathematical framework of covalent molecular docking; (iii) implementation of covalent docking protocol in drug design workflows; (iv) applications covalent docking: case studies and (v) shortcomings and future perspectives of covalent docking. To the best of our knowledge; this review is the first account that highlights different aspects of covalent docking with its merits and pitfalls. We believe that the method and applications highlighted in this study will help future efforts towards the design of irreversible inhibitors.


Assuntos
Descoberta de Drogas , Simulação de Acoplamento Molecular , Humanos , Ligação Proteica , Software , Termodinâmica
17.
Bioorg Chem ; 58: 72-80, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25506816

RESUMO

A series of twenty 2-aryl-4H-chromen-4-one (flavones) derivatives (3a-3s) were synthesized and tested for hMAO inhibitory activity. Fifteen compounds (3a, 3c, 3e-3h, 3j-3p, 3r, 3s) were found to be selective towards MAO-B, while 3d was selective towards MAO-A, and 3b, 3i and 3q were non-selective. Experimental Selectivity Index for MAO-B ranges from 2.0 (3g, 3p) to 30.0 (3j). Compound 3j, which is carrying 3,4-di-OMeC6H3 groups at R position on the molecule, was found to be potent MAO-B inhibitor amongst the fifteen with Ki value for MAO-B of 0.16±0.01 µM comparable to that of standard drug, Selegiline (Ki for MAO-B is 0.16±0.01 µM). Compound 3j also appeared as the most selective MAO-B inhibitor according to its best selectivity index (30.0), which is comparable to that of Selegiline (SIMAO-B=35.0). Molecular docking and molecular dynamics simulation studies were carried out using Autodock-4.0 and Amber12 to understand the molecular level interaction and energy relation of MAO isoforms with selective inhibitors (3d and 3j). Simulation results are in good agreement with the experimental results. Leads identified may further be explored to develop potent isoform specific inhibitors of MAO.


Assuntos
Benzopiranos/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Benzopiranos/química , Cinética , Simulação de Acoplamento Molecular , Inibidores da Monoaminoxidase/química , Espectroscopia de Prótons por Ressonância Magnética , Espectrometria de Massas por Ionização por Electrospray
18.
Eur J Med Chem ; 87: 677-702, 2014 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-25305334

RESUMO

Neglected tropical diseases are major causes of fatality in poverty stricken regions across Africa, Asia and some part of America. The combined potential health risk associated with arthropod-borne viruses (arboviruses); Dengue virus (DENV), West Nile Virus (WNV) and Chikungunya Virus (CHIKV) is immense. These arboviruses are either emerging or re-emerging in many regions with recent documented outbreaks in the United States. Despite several recent evidences of emergence, currently there are no approved drugs or vaccines available to counter these diseases. Non-structural proteins encoded by these RNA viruses are essential for their replication and maturation and thus may offer ideal targets for developing antiviral drugs. In recent years, several protease inhibitors have been sourced from plant extract, synthesis, computer aided drug design and high throughput screening as well as through drug reposition based approaches to target the non-structural proteins. The protease inhibitors have shown different levels of inhibition and may thus provide template to develop selective and potent drugs against these devastating arboviruses. This review seeks to shed light on the design and development of antiviral drugs against DENV, WNV and CHIKV to date. To the best of our knowledge, this review provides the first comprehensive update on the development of protease inhibitors targeting non-structural proteins of three most devastating arboviruses, DENV, WNV and CHIKV.


Assuntos
Febre de Chikungunya/tratamento farmacológico , Dengue/tratamento farmacológico , Proteínas não Estruturais Virais/efeitos dos fármacos , Febre do Nilo Ocidental/tratamento farmacológico , Antivirais/uso terapêutico , Febre de Chikungunya/metabolismo , Febre de Chikungunya/prevenção & controle , Vírus Chikungunya/metabolismo , Dengue/metabolismo , Dengue/prevenção & controle , Vírus da Dengue/metabolismo , Conformação Proteica , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/metabolismo , Vacinas Virais/uso terapêutico , Febre do Nilo Ocidental/metabolismo , Febre do Nilo Ocidental/prevenção & controle , Vírus do Nilo Ocidental/metabolismo
19.
Protein J ; 33(5): 432-46, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25107349

RESUMO

Non-nucleoside reverse transcriptase inhibitors (NNRTI) have emerged as gold standards in current anti-AIDS drug discovery and development by allosterically inhibiting HIV reverse transcriptase (HIV-RT). Connection sub-domain mutation, N348I and the M184V active site mutation decreases HIV-1 RT susceptibility to NNRTI, nevirapine (NVP), whereas concurrence of both mutations improves enzyme susceptibility to NVP. Molecular dynamics simulation and enhanced post-dynamics analyses were applied to gain molecular insight into occurrence of N348I, M184V and N348I/M184V double mutations and their effect on NVP binding landscape. Results showed that the presence of the double mutation (N348I/M184V) ameliorates the drastic effects of connection sub-domain mutation, N348I alone on NVP binding, which correlates with experimental findings. We showed that the binding of NVP to the NNRTI binding pocket (NNIBP) is drastically distorted in the presence of connection sub-domain mutation, N348I and may further explain the impaired motions of mutant RTs compared to the wild type. The residue based fluctuation further suggested that the occurrence of N348I decreased the overall flexibility of NVP-HIV-RT complex whereas concurrence of N348I/M184V double mutation restored the conformational flexibility as compared to single mutant. This phenomenon was further validated by the trends of binding free energy as well as the per-residue footprints which showed an increased ∆Gbind in case of N348I/M184V double mutant as compared to N348I variant. Further, for the first time residue interaction network highlighted the structural changes due to occurrence of M184V and N348I mutations which gives a conclusive evidence of these mutations. This work provides the most comprehensive analysis of NVP resistance and the impact of double (N348I/M184V) mutation to date from a dynamics perspective and provides information that should prove useful for understanding the drug resistance mechanism against NVP. The results also provide preliminary data which might prove useful for the design of novel inhibitors that are less susceptible to drug resistance.


Assuntos
Transcriptase Reversa do HIV , Nevirapina/química , Nevirapina/metabolismo , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/metabolismo , Sítios de Ligação , Transcriptase Reversa do HIV/química , Transcriptase Reversa do HIV/genética , Transcriptase Reversa do HIV/metabolismo , HIV-1/genética , Simulação de Dinâmica Molecular , Mutação , Análise de Componente Principal , Conformação Proteica , Termodinâmica
20.
Mol Biosyst ; 10(8): 2215-28, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24931725

RESUMO

The emergence of different drug resistant strains of HIV-1 reverse transcriptase (HIV RT) remains of prime interest in relation to viral pathogenesis as well as drug development. Amongst those mutations, M184V was found to cause a complete loss of ligand fitness. In this study, we report the first account of the molecular impact of M184V mutation on HIV RT resistance to 3TC (lamivudine) using an integrated computational approach. This involved molecular dynamics simulation, binding free energy analysis, principle component analysis (PCA) and residue interaction networks (RINs). Results clearly confirmed that M184V mutation leads to steric conflict between 3TC and the beta branched side chain of valine, decreases the ligand (3TC) binding affinity by ∼7 kcal mol(-1) when compared to the wild type, changes the overall conformational landscape of the protein and distorts the native enzyme residue-residue interaction network. The comprehensive molecular insight gained from this study should be of great importance in understanding drug resistance against HIV RT as well as assisting in the design of novel reverse transcriptase inhibitors with high ligand efficacy on resistant strains.


Assuntos
Biologia Computacional/métodos , Transcriptase Reversa do HIV/química , Transcriptase Reversa do HIV/genética , Mutação , Substituição de Aminoácidos , Fármacos Anti-HIV/química , Farmacorresistência Viral , Lamivudina/química , Metionina/metabolismo , Simulação de Dinâmica Molecular , Análise de Componente Principal , Estrutura Secundária de Proteína , Relação Quantitativa Estrutura-Atividade , Valina/metabolismo
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