Computational studies to explore inhibitors against the cyclin-dependent kinase 12/13 enzyme: an insilco pharmacophore modeling, molecular docking and dynamics approach.

Cancer is enlisted among the deadliest disease all over the world. The cyclin-dependent kinases 12 and 13 have been identified as cell cycle regulators. They conduct transcription and co-transcriptional processes by phosphorylating the C-terminal of RNA polymerase-II. Inhibition of CDK12 and 13 selectively presents a novel strategy to treat triple-negative breast cancer, but dual inhibitors are still lacking. Here, we report the screening of the natural product compound class against the dual CDK12/13 enzyme by employing various in silico methods. Complexes of CDK12 enzymes are used to form common feature pharmacophore models, whereas we perform receptor-based pharmacophore modelling on CDK13 enzyme owing to the availability of a single PDB. On conducting screening over the representative pharmacophores, the common drug-like screened natural products were shortlisted for conducting molecular docking studies. After molecular docking calculations, the candidates that showed crucial interaction with CDK12 and CDK13 enzymes were shortlisted for simulation studies. Five common docked candidates were selected for molecular dynamics simulations and free energy calculations. Based on the cut-off criteria of free energy calculations, one common hit was selected as the dual CDK12/13 inhibitor. The outcome concluded that the hit with ID CNP0386383 possesses drug-like properties, displays crucial interaction in the binding pocket, and shows stable dynamic behaviour and higher binding energy than the experimentally reported inhibitor of both CDK12 and CDK13 enzymes.Communicated by Ramaswamy H. Sarma.

Targeting allosteric binding site in methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) to identify natural product inhibitors via structure-based computational approach.

Cancer has been viewed as one of the deadliest diseases worldwide. Among various types of cancer, breast cancer is the most common type of cancer in women. Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is a promising druggable target and is overexpressed in cancerous cells, like, breast cancer. We conducted structure-based modeling on the allosteric site of the enzyme. Targeting the allosteric site avoids the problem of drug resistance. Pharmacophore modeling, molecular docking, HYDE assessment, drug-likeness, ADMET predictions, simulations, and free-energy calculations were performed. The RMSD, RMSF, RoG, SASA, and Hydrogen-bonding studies showed that seven candidates displayed stable behaviour. As per the literature, average superimposed simulated structures revealed a similar protein conformational change in the αE'-ßf' loop, causing its displacement away from the allosteric site. The MM-PBSA showed tight binding of six compounds with the allosteric pocket. The effect of inhibitors interacting in the allosteric site causes a decrease in the binding energy of J49 (active-site inhibitor), suggesting the effect of allosteric binding. The PCA and FEL analysis revealed the significance of the docked compounds in the stable behaviour of the complexes. The outcome can contribute to the development of potential natural products with drug-like properties that can inhibit the MTHFD2 enzyme.

Identifying natural product inhibitors against CDK9 enzyme via combined multicomplex-based pharmacophore modeling, interaction studies and molecular dynamics simulations.

In the current work, multicomplex-based pharmacophore modeling was performed on the CDK9 enzyme. The generated models possess five, four, and six features, which were subjected to the validation process. Among them, six feature models were selected as representative models to conduct the virtual screening process. The screened drug-like candidates were chosen to perform molecular docking to study their interaction patterns within the binding cavity of the CDK9 protein. Based on the docking score and presence of crucial interactions, out of 780 filtered candidates, only 205 were docked. These docked candidates were further accessed via HYDE assessment. Based on ligand efficiency and Hyde score, only nine candidates passed the criteria. The stability of these nine complexes, along with the reference, was studied by molecular dynamics simulations. Out of nine, only seven displayed stable behaviour during the simulations, and their stability was further assessed by molecular mechanics-Poisson-Boltzmann surface area (MM-PBSA)-based free binding energy calculations and per residue contribution. From the present contribution, we obtained seven unique scaffolds that can be utilized as the starting lead for the development of CDK9 anticancer compounds.

Glycerol based carbon sulfonic acid catalyzed synthesis, in silico studies and in vitro biological evaluation of isonicotinohydrazide derivatives as potent antimicrobial and anti-tubercular agents.

The present pathway involves synthesis of isonicotinohydrazide derivatives using isoniazid and diversely substituted aldehydes in the presence of EtOH and catalytic amount of glycerol based carbon sulfonic acid catalyst. The developed pathway has so many merits like excellent yields (91-98%), short reaction time (4-10 min), easy reaction set up, no need of column chromatography, large substrate scope, easily recyclable and reusable catalyst. The synthesized compounds were screened for antimicrobial and anti-tubercular activity and it was observed that compounds possessed high biological potency against the Gram positive and Gram negative bacterial and fungal strains. Regarding anti-tubercular activity, compound 3m exhibited high % inhibition against Mycobacterium tuberculosis H37RV strain. Based on the outcome of in vitro studies, all the synthesized compounds were docked against E. coli (1KZN), C. albicans (1IYL), and M. tuberculosis H 37 Rv strain (2NSD). The synthesized derivatives were docked within the binding site of 1KZN, and 1IYL. However, with 2NSD, apart from 3h, all the derivatives displayed interaction within the binding cavity of the protein. All the crucial interactions with Asn46, Asp73, and Arg136 in 1KZN, His227, Leu451 in 1IYL, and Tyr158 in 2NSD were witnessed in the top-scored docked candidates. Molecular docking studies revealed the importance of the substitution at R position on isonicotinohydrazide scaffold. The nitrogen atoms of hydrazide moiety were involved in forming hydrogen bonding with the active site amino acids, and the substitution at the R position occupy the hydrophobic position in the binding pocket. Also, the functional groups present on the substituted R position were involved in forming hydrogen bonding with the crucial active site residues.

Identification of natural products against enoyl-acyl-carrier-protein reductase in malaria via combined pharmacophore modeling, molecular docking and simulations studies.

Plasmodium falciparum is counted as one of the deadly species causing malaria. In that respect, enoyl acyl carrier protein reductase is recognized as one of the attractive druggable targets for the identification of antimalarials. Thus, from the structural proteome of ENR, common feature pharmacophores were constructed. To identify the representative models, all the hypotheses were subjected to validation methods, like, test set, enrichment factor, and Güner-Henry method, and the selected representative hypotheses were used to screen out the drug-like natural products. Further, the screened candidates were advanced to molecular docking calculations. Based on the docking score criteria and presence of essential interaction with Tyr277, seven candidates were shortlisted to conduct the HYDE and QSAR assessment. Further, the stability of these complexes was evaluated by employing molecular dynamics simulations, molecular mechanics-generalized born surface area approach-based free binding energy calculations with the residue-wise contribution of PfENR to the total binding free energy of the complex. On comparing the root mean square deviation, and fluctuation plots of the docked candidates with the reference, all the candidates displayed stable behavior, and the same outcome was depicted from the secondary structure element. However, from the free energy calculations, and residue-wise contribution conducted after dynamics, it was observed that out of seven, only five candidates sustain the binding with Tyr277 and cofactor of PfENR. Therefore, in the current work, the hybrid study of screening and stability lead to the identification of five structurally diverse candidates that can be employed for the design of novel antimalarials.Communicated by Ramaswamy H. Sarma.

Structural differences in 3C-like protease (Mpro) from SARS-CoV and SARS-CoV-2: molecular insights revealed by Molecular Dynamics Simulations.

Novel coronavirus SARS-CoV-2 has infected millions of people with thousands of mortalities globally. The main protease (Mpro) is vital in processing replicase polyproteins. Both the CoV's Mpro shares 97% identity, with 12 mutations, but none are present in the active site. Although many therapeutics and vaccines are available to combat SARS-CoV-2, these treatments may not be practical due to their high mutational rate. On the other hand, Mpro has a high degree of conservation throughout variants, making Mpro a stout drug target. Here, we report a detailed comparison of both the monomeric Mpro and the biologically active dimeric Mpro using MD simulation to understand the impact of the 12 divergent residues (T35V, A46S, S65N, L86V, R88K, S94A, H134F, K180N, L202V, A267S, T285A and I286L) on the molecular microenvironment and the interaction between crucial residues. The present study concluded that the change in the microenvironment of residues at the entrance (T25, T26, M49 and Q189), near the catalytic site (F140, H163, H164, M165 and H172) and in the substrate-binding site (V35, N65, K88 and N180) is due to 12 mutations in the SARS-CoV-2 Mpro. Furthermore, the involvement of F140, E166 and H172 residues in dimerization stabilizes the Mpro dimer, which should be considered. We anticipate that networks and microenvironment changes identified here might guide repurposing attempts and optimization of new Mpro inhibitors. Supplementary Information: The online version contains supplementary material available at 10.1007/s11224-022-02089-6.

Reckoning apigenin and kaempferol as a potential multi-targeted inhibitor of EGFR/HER2-MEK pathway of metastatic colorectal cancer identified using rigorous computational workflow.

In the past two decades, the treatment of metastatic colorectal cancer (mCRC) has been revolutionized as multiple cytotoxic, biological, and targeted drugs are being approved. Unfortunately, tumors treated with single targeted agents or therapeutics usually develop resistance. According to pathway-oriented screens, mCRC cells evade EGFR inhibition by HER2 amplification and/or activating Kras-MEK downstream signaling. Therefore, treating mCRC patients with dual EGFR/HER2 inhibitors, MEK inhibitors, or the combination of the two drugs envisaged to prevent the resistance development which eventually improves the overall survival rate. In the present study, we aimed to screen potential phytochemical lead compounds that could multi-target EGFR, HER2, and MEK1 (Mitogen-activated protein kinase kinase) using a computer-aided drug design approach that includes molecular docking, endpoint binding free energy calculation using MM-GBSA, ADMET, and molecular dynamics (MD) simulations. Docking studies revealed that, unlike all other ligands, apigenin and kaempferol exhibit the highest docking score against all three targets. Details of ADMET analysis, MM/GBSA, and MD simulations helped us to conclusively determine apigenin and kaempferol as potentially an inhibitor of EGFR, HER2, and MEK1 apigenin and kaempferol against mCRC at a systemic level. Additionally, both apigenin and kaempferol elicited antiangiogenic properties in a dose-dependent manner. Collectively, these findings provide the rationale for drug development aimed at preventing CRC rather than intercepting resistance.

Computational studies to identify the common type-I and type-II inhibitors against the CDK8 enzyme.

In this study, multicomplex-based pharmacophore modeling was conducted on the structural proteome of the two states of CDK8 protein, that is, DMG-in and out. Three pharmacophores having six, five, and four features were selected as the representative models to conduct the virtual screening process using the prepared drug-like natural product database. The screened candidates were subjected to molecular docking studies on DMG-in (5XS2) and out (4F6U) conformation of the CDK8 protein. Subsequently, the common four docked candidates of 5XS2 and 4F6U were selected to perform the molecular dynamics simulation studies. Apart from one of the complexes of DMG-in (5XS2-UNPD163102), all other complexes displayed stable dynamic behavior. The interaction and stability studies of the docked complexes were compared with the references selected from the two conformations (DMG-in and out) of the protein. The current work leads to the identification of three common DMG-in and out hits with diverse scaffolds which can be employed as the initial leads for the design of the novel CDK8 inhibitors.

Identification of natural inhibitors against prime targets of SARS-CoV-2 using molecular docking, molecular dynamics simulation and MM-PBSA approaches.

The recently emerged COVID-19 has been declared a pandemic by the World Health Organization as to date; no therapeutic drug/vaccine is available for the treatment. Due to the lack of time and the urgency to contain the pandemic, computational screening appears to be the best tool to find a therapeutic solution. Accumulated evidence suggests that many phyto-compounds possess anti-viral activity. Therefore, we identified possible phyto-compounds that could be developed and used for COVID-19 treatment. In particular, molecular docking was used to prioritize the possible active phyto-compounds against two key targets namely RNA dependent RNA polymerase (RdRp) and main protease (Mpro) of SARS-CoV-2. In this study, an antiviral drug- Remdesivir (RdRp inhibitor) and Darunavir (Mpro inhibitor) are used as reference drugs. This study revealed that phyto-molecules- Mulberroside-A/C/E/F, Emblicanin A, Nimbolide, and Punigluconin showed high binding affinity against RdRp while Andrographolides, Mulberrosides, Anolignans, Chebulic acid, Mimusopic acid, and Punigluconin showed better binding affinity against Mpro as compared with the reference drug. Furthermore, ADME profiles validated the drug-likeness properties of prioritized phyto-compounds. Besides, to assess the stability, MD simulations studies were performed along with reference inhibitors for Mpro (Darunavir) and RdRp (Remdesivir). Binding free energy calculations (MM-PBSA) revealed the estimated value (ΔG) of Mpro_Darunavir; Mpro_Mulberroside E; RdRp_Remdesivir and RdRp_Emblicanin A were -111.62 ± 6.788, -141.443 ± 9.313, 30.782 ± 5.85 and -89.424 ± 3.130 kJmol-1, respectively. Taken together, the study revealed the potential of these phyto-compounds as inhibitors of RdRp and Mpro inhibitor that could be further validated against SARS-CoV-2 for clinical benefits.Communicated by Ramaswamy H. Sarma.

Identification of the natural compound inhibitors against Plasmodium falciparum plasmepsin-II via common feature based screening and molecular dynamics simulations.

Malaria is counted amongst the deadly disease caused by Plasmodium falciparum. Recently, plasmepsin-II enzyme has gained much importance as an attractive drug target for the exploration of antimalarials. Therefore, the common feature pharmacophore models were generated from the crystallized complexes of the plasmepsin-II proteome. These models were subjected to a series of validation procedures, i.e. test set and Güner Henry studies to enlist the representative models. The selected representative hypotheses incorporating the most essential chemical features (common ZHHA) were screened against the natural product database to retrieve the potential candidates. To ensure the selection of the drug-like candidates, prior to screening, filtering steps (Drug-likeness and ADMET filters) were employed on the selected database. To study the interaction pattern of the candidates within the protein, these molecules were advanced to the molecular docking studies. Subsequently, based on the selected cut-off criteria obtained via redocking of the reference (4Z22), 15 compounds showed higher docking score (> -16.05 kcal/mol), and displayed the presence of hydrogen bonding with the crucial amino acids, i.e. Asp34 and Asp214. Further, the stability of the docked molecules was scrutinized via molecular dynamics simulations, and the results were compared with the reference compound 4Z22. All the docked compounds showed stable dynamics behaviour. Thus, in the present contribution, the combination of screening and stability procedures resulted in the identification of 15 hits that can serve as a new chemical space in the designing of the novel antimalarials.Communicated by Ramaswamy H. Sarma.

DFT/TD-DFT study to decipher the fluoride induced ring opening process of spiropyran.

DFT/TD-DFT methods were used to determine the fluoride anion sensing mechanism of 3',6'-Bis(tert-butyldimethylsilyloxy)spiro[benzo[f]chromene3,9'ffuorene], abbreviated as SP. The description of ring opening in the ground state of SP molecule and its isomerization in open form is presented. It was revealed from the study that in the ground state, SP is the most stable form in contrast with the isomer obtained in the open form. To initiate the ring opening, at first, the fluoride ion attacks as a nucleophile to de-silylate the SP molecule. This attack of fluoride ion may induce Cspiro-O bond cleavage leading to the formation of two anionic species, i.e., MC-D1 and MC-D2 respectively (MC is merocyanin). The mono-de-silylation process was endogenic, which was followed by the ring opening process. Furthermore, the orthogonal geometry of probe SP does not show ICT character, whereas, MC-D1 and MC-D2 displayed ICT character owing to the formation of planar geometry along with an increase in conjugation. The fluorescence property of SP, and most stable isomers of open form (CT, MC-D1, and MC-D2) were predicted theoretically. The calculated emission spectra uncovered that SP may show fluorescence, which could be quenched in presence of fluoride anion.

Oral Health Status and Treatment Need in Geriatric Patients with Different Degrees of Cognitive Impairment and Dementia: A Cross-Sectional Study.

BACKGROUND: Health can be defined as more than an absence or lack of disease. It is generally related to personal, physical, social, along with spiritual wellness. However, the importance of good health is comparable with a progressive physical and cognitive limitations due to aging and hence, its clear definition is not possible. Hence, most of the important aims or goals in aging are unrelated to finding a cure but rather toward achieving an optimal function. Thus, a healthy aging process that encompasses physical, mental, psychological, and spiritual well-being is always much desired. AIM AND OBJECTIVES: The aim and objective of this study is to assess the oral health status and degree of cognitive impairment along with dementia, if present. MATERIALS AND METHODS: This is a prospective and cross-sectional analysis comprising of 300 study participants of which 150 are males while 150 are females. Cognitive ability is assessed using the Standardized Mini-Mental State Examination (SMMSE) scoring test. A score value lesser than or equal to 23 is considered as low, whereas a score of 24 and above represents normal cognitive abilities. Subjects with low score are selected for the study. Oral health status is assessed by examining a) total numbers of teeth present; b) presence or absence of denture use; and c) capacity for masticatory or chewing ability (recorded as yes or no). Demographic variables parameters include age, gender, and presence of smoking habit. Clinical parameters or variables are analyzed by employing the independent t-test and Chi-square test. Pearson's correlation analysis is used to test a correlation between impairment of cognitive capacity, oral health status, masticatory capability, and use of dentures, if present. Two-tailed t-test is used to derive a P value for significance. RESULTS: The total numbers of teeth present are significantly correlated with a lower SMMSE score (R = + 0.56; P = 0.03) while a significant association is noted between ability for mastication and lower SMMSE score (P = 0.05). CONCLUSION: This study concluded that loss of cognition or dementia is closely related to a poor oral health status.

New simple molecular fluorescent probes for rapid and highly selective sensing of hydrazine by aggregate-induced emission.

With an aim towards the design of efficient and straightforward fluorescent probes for hydrazine, the synthesis of (2-acetoxyaryl) methylene diacetate derivatives (1-4) was carried out by reacting substituted aromatic α-hydroxy aldehydes with acetyl chloride and sodium acetate in excellent yields. As a preliminary investigation, the ability of probe 1 was examined for the detection of substituted aliphatic and aromatic amines, amino acids, and other ions in Britton-Robinson buffer solution (50 mM, water/ethanol v/v of 99/1 at pH 7.4). Probe 1 selectively exhibited an intense blue fluorescence with hydrazine in less than 2 minutes, whereas light green or no fluorescence was noticed with substituted amines and amino acids. Among all the probes employed (1-4) in the present study, probes 1 and 2 were found efficient towards the rapid detection of hydrazine. Furthermore, the fluorescence sensing ability of probes 1 and 2 was tested not only under varying pH conditions but also by varying water-fraction from 0-99%. Moreover, the detection limits of hydrazine using 1 and 2 were found as 8.4 and 8.7 ppb, respectively, which is less than the acceptable limit as per the standards of the US Environment Protection Agency. In this contribution, the probes 1 and 2 demonstrate rapid, selective, sensitive, and ratiometric detection of highly toxic hydrazine by OFF-ON fluorescence switch in water samples as well as living cells.

Binding Insight of Anti-HIV Phytocompounds with Prime Targets of HIV: A Molecular Dynamics Simulation Analysis.

BACKGROUND: Despite intense efforts, AIDS is difficult to tackle by current anti-retroviral therapy (ART) due to its side effects; therefore, there is an urgent need to discover potential, multitarget and low-cost anti-HIV compounds. OBJECTIVE: We have shown that few phytocompounds can potentially inhibit the prime targets of HIV namely GP120 envelope protein, reverse transcriptase, protease, integrase and ribonulcease. In this study, top ranked prioritized compounds were subjected to Molecular Dynamics (MD) simulation in order to study the conformational dynamics and integrity of crucial interaction in the receptor sites. METHODS: The system was built for selected protein-ligand complex using TIP3P water model and OPLS_2005 force field. Trajectories were recorded up to 20 ns simulation time in Desmond module of Schrödinger software. RESULTS: As a result of a comprehensive analysis of molecular properties and dynamics of the complexes, it has been concluded that Chebulic acid, Curcumin and Mulberroside C could be developed as envelope glycoprotein GP120 inhibitor, reverse transcriptase inhibitor and protease inhibitor respectively. However, the fluctuation of Chebulic acid with respect to integrase and ribonuclease protein was higher during the simulation. CONCLUSION: These findings can aid in the designing of the structural properties for more effective anti-HIV compounds against the given targets.

A profound computational study to prioritize the natural compound inhibitors against the P. falciparum orotidine-5-monophosphate decarboxylase enzyme.

In the current contribution, a multicomplex-based pharmacophore modeling approach was employed on the structural proteome of Plasmodium falciparum orotidine-5-monophosphate decarboxylase enzyme (PfOMPDC). Among the constructed pharmacophore models, the representative hypotheses were selected as the primary filter to screen the molecules with the complementary features responsible for showing inhibition. Thereafter, auxiliary evaluations were performed on the screened candidates via drug-likeness and molecular docking studies. Subsequently, the stability of the docked protein-ligand complexes was scrutinized by employing molecular dynamics simulations and molecular mechanics-Poisson Boltzmann surface area based free binding energy calculations. The stability the docked candidates was compared with the highly active crystallized inhibitor (3S9Y-FNU) to seek more potential candidates. All the docked molecules displayed stable dynamic behavior and high binding free energy in comparison to 3S9Y-FNU. The employed workflow resulted in the retrieval of five drug-like candidates with diverse scaffolds that may show inhibitory activity against PfOMPDC and could be further used as the novel scaffold to develop novel antimalarials.Communicated by Ramaswamy H. Sarma.

Pharmacophore modeling, molecular docking and molecular dynamics simulation for screening and identifying anti-dengue phytocompounds.

Dengue is a fast spreading mosquito borne viral disease that poses a serious threat to human health. Lack of therapeutic drugs and vaccines signify that more resources need to be explored. Accumulated evidence has suggested that plants offer a vast reservoir for antiviral drug discovery which are safe for human consumption. Plant-based drug discovery is a complex and time-consuming process as plants possess rich repository of chemically diverse compounds. Various in silico methods can make this process simple and economic. We, therefore, performed pharmacophore mapping, molecular docking, molecular dynamics (MD) simulations and ADME (absorption, distribution, metabolism, excretion) prediction to screen potential candidates against dengue. In particular, combined pharmacophore mapping and molecular docking were used to prioritize the potentially active ligands from a ligand library. Biological activities of plant based ligands were predicted using 3D-QSAR pharmacophore modeling. Interaction between proteins, namely, envelope G protein, NS2B/NS3 protease, NS5 methyltransferase, NS1, NS5 polymerase and active plant-based ligands (pIC50 > 5.1) were analyzed using molecular docking. Best docked complex, namely, envelope G protein-mulberroside C, NS2B-NS3 protease-curcumin, NS5 methyltransferase-chebulic acid, NS1-mulberroside A, NS5 methyltransferase-punigluconin and NS5 methyltransferase-chebulic acid were further subjected to MD simulations study to assess the fluctuation and conformational changes during protein-ligand interaction. ADME studies were performed to assess their drug-likeness properties. Collectively, these in silico results helped to identify the potential plant-based hits against the various receptors of dengue virus which can be further validated by bioactivity-based experiments.Communicated by Ramaswamy H. Sarma.

Structure-based identification of novel sirtuin inhibitors against triple negative breast cancer: An in silico and in vitro study.

Triple-negative breast cancer (TNBC) is an aggressive disease exemplified by a poor prognosis, greater degrees of relapse, the absence of hormonal receptors for coherent utilization of targeted therapy, poor response to currently available therapeutics and development of chemoresistance. Aberrant activity of sirtuins (SIRTs) has strong implications in the metastatic and oncogenic progression of TNBC. Synthetic SIRT inhibitors are effective, however, they have shown adverse side effects emphasizing the need for plant-derived inhibitors (PDIs). In the current study, we identified potential plant-derived sirtuin inhibitors using in silico approach i.e. molecular docking, ADMET and molecular dynamics simulations (MD). Docking studies revealed that Sulforaphane, Kaempferol and Apigenin exhibits the highest docking scores against SIRT1 & 5, 3 and 6 respectively. ADMET analysis of above hits demonstrated drug-like profile. MD of prioritized SIRTs-PDIs complexes displayed stability with insignificant deviations throughout the trajectory. Furthermore, we determined the effect of our prioritized molecules on cellular viability, global activity as well as protein expression of sirtuins and stemness of TNBC cells utilizing in vitro techniques. Our in vitro findings complements our in silico results. Collectively, these findings provide a better insight into the structural basis of sirtuin inhibition and can facilitate drug design process for TNBC management.

Identification of natural compound inhibitors against PfDXR: A hybrid structure-based molecular modeling approach and molecular dynamics simulation studies.

In the present contribution, multicomplex-based pharmacophore studies were carried out on the structural proteome of Plasmodium falciparum 1-deoxy-D-xylulose-5-phosphate reductoisomerase. Among the constructed models, a representative model with complementary features, accountable for the inhibition was used as a primary filter for the screening of database molecules. Auxiliary evaluations of the screened molecules were performed via drug-likeness and molecular docking studies. Subsequently, the stability of the docked inhibitors was envisioned by molecular dynamics simulations, principle component analysis, and molecular mechanics-Poisson-Boltzmann surface area-based free binding energy calculations. The stability assessment of the hits was done by comparing with the reference (beta-substituted fosmidomycin analog, LC5) to prioritize more potent candidates. All the complexes showed stable dynamic behavior while three of them displayed higher binding free energy compared with the reference. The work resulted in the identification of the compounds with diverse scaffolds, which could be used as initial leads for the design of novel PfDXR inhibitors.

Multicomplex-based pharmacophore modeling in conjunction with multi-target docking and molecular dynamics simulations for the identification of PfDHFR inhibitors.

Plasmodium falciparum dihydrofolate reductase enzyme (PfDHFR) is counted as one of the attractive and validated antimalarial drug targets. However, the point mutations in the active site of wild-type PfDHFR have developed resistance against the well-known antifolates. Therefore, there is a dire need for the development of inhibitors that can inhibit both wild-type and mutant-type DHFR enzyme. In the present contribution, we have constructed the common feature pharmacophore models from the available PfDHFR. A representative hypothesis was prioritized and then employed for the screening of natural product library to search for the molecules with complementary features responsible for the inhibition. The screened candidates were processed via drug-likeness filters and molecular docking studies. The docking was carried out on the wild-type PfDHFR (3QGT); double-mutant PfDHFR (3UM5 and 1J3J) and quadruple-mutant PfDHFR (1J3K) enzymes. A total of eight common hits were obtained from the docking calculations that could be the potential inhibitors for both wild and mutant type DHFR enzymes. Eventually, the stability of these candidates with the selected proteins was evaluated via molecular dynamics simulations. Except for SPECS14, all the prioritized candidates were found to be stable throughout the simulation run. Overall, the strategy employed in the present work resulted in the retrieval of seven candidates that may show inhibitory activity against PfDHFR and could be further exploited as a scaffold to develop novel antimalarials. Communicated by Ramaswamy H. Sarma.

In search of the representative pharmacophore hypotheses of the enzymatic proteome of Plasmodium falciparum: a multicomplex-based approach.

Drug resistance has made malaria an untreatable disease and therefore intensified the need for the development of new drugs and the identification of potential drug targets. In this pursuit, in silico efforts made in the past have not shown significant responses. Therefore, in the present work, the multicomplex-based pharmacophore modeling approach was employed to construct the pharmacophores of the 16 selected Plasmodium falciparum (Pf) targets. All the constructed hypotheses (153) were screened against a focused dataset made up of experimental actives of the chosen targets (3705 inhibitors). The rationale was to check the affinity of the inhibitors for the off-targets. Subsequently, the constructed hypotheses from each target were pooled based on the feature types and the pooled-hypotheses were then clustered to offer an insight about the pharmacophore similarity. Tanimoto similarity index was also calculated to look for the similarity among the inhibitors belonging to different Pf targets. Overall, the work was accomplished to bid healthier perceptive of the pharmacophore-based virtual screening and abet in providing guiding principles for the construction of stringent pharmacophores that can be employed for the screening.