Multi-cavity molecular descriptor interconnections: Enhanced protocol for prediction of serum albumin drug binding.

The role of human serum albumin (HSA) in the transport of molecules predicates its involvement in the determination of drug distribution and metabolism. Optimization of ADME properties are analogous to HSA binding thus this is imperative to the drug discovery process. Currently, various in silico predictive tools exist to complement the drug discovery process, however, the prediction of possible ligand-binding sites on HSA has posed several challenges. Herein, we present a strong and deeper-than-surface case for the prediction of HSA-ligand binding sites using multi-cavity molecular descriptors by exploiting all experimentally available and crystallized HSA-bound drugs. Unlike previously proposed models found in literature, we established an in-depth correlation between the physicochemical properties of available crystallized HSA-bound drugs and different HSA binding site characteristics to precisely predict the binding sites of investigational molecules. Molecular descriptors such as the number of hydrogen bond donors (nHD), number of heteroatoms (nHet), topological polar surface area (TPSA), molecular weight (MW), and distribution coefficient (LogD) were correlated against HSA binding site characteristics, including hydrophobicity, hydrophilicity, enclosure, exposure, contact, site volume, and donor/acceptor ratio. Molecular descriptors nHD, TPSA, LogD, nHet, and MW were found to possess the most inherent capacities providing baseline information for the prediction of serum albumin binding site. We believe that these associations may form the bedrock for establishing a solid correlation between the physicochemical properties and Albumin binding site architecture. Information presented in this report would serve as critical in provisions of rational drug designing as well as drug delivery, bioavailability, and pharmacokinetics.

Density functional theory study of the corrosion inhibition performance of 6-mercaptopurine and 6-thioguanine expired drugs toward the aluminium (111) surface.

The potentiality of the 6-mercaptopurine (MP) and 6-thioguanine (TG) expired drugs toward the corrosion inhibition of the aluminium (Al) (111) surface was widely investigated using a series of density functional theory (DFT) calculations. A competition between the anti-corrosive features of the studied drugs in the gas and aqueous phases was conducted on both neutral and protonated forms by means of quantum mechanical descriptors. The results of the electrostatic potential analysis demonstrated the prominent nucleophilic nature of the sulfur and nitrogen atoms over the structures of the examined drugs. The frontier molecular orbital theory findings outlined the higher preferability of TG over MP as a corrosion inhibitor. Upon determining the most beneficial configurations of the MP/TG⋯Al (111) complexes, first-principles molecular dynamics simulations were executed. Interestingly, the competence of the TG drug in the corrosion inhibition process of Al (111) was more extensive than that of the MP one, which was confirmed by the interaction energy values of -1.79 and -1.64 eV, respectively. Upon obtaining the relaxed complexes, the effect of the presence of water solvent on the adsorption process was studied. These findings provide a foundation for developing green anti-corrosive inhibitors for the aluminium surface.

Inherent efficacies of pyrazole-based derivatives for cancer therapy: the interface between experiment and in silico.

There has been an increasing trend in the design of novel pyrazole derivatives for desired biological applications. For a cost-effective strategy, scientists have implemented various computational drug design tools to go hand in hand with experiments for the design and discovery of potentially effective pyrazole-based therapeutics. This review highlights the milestones of pyrazole-containing inhibitors and the use of molecular modeling techniques in conjunction with experimental studies to provide a view of the binding mechanism of these compounds. The review focuses on the established targets that play a key role in cancer therapy, including proteins involved in tubulin polymerization, carbonic anhydrase and tyrosine kinase. Overall, using both experimental and computational methods in drug design represents a promising approach to cancer therapy.

Preferability of Molnupiravir, an Anti-COVID-19 Drug, toward Purine Nucleosides: A Quantum Mechanical Study.

Structural aspects of molnupiravir complexed with the RNA of the SARS-CoV-2 virus have been recently resolved inside the RNA-dependent RNA polymerase (RdRp), demonstrating the interactions of molnupiravir with purine nucleosides. However, the preference of molnupiravir to interact with one purine nucleoside over another has not been clearly investigated. Herein, the complexation of molnupiravir in its active form with guanosine and adenosine was compared, using sundry density functional theory calculations. The plausible tautomeric structures of the molnupiravir drug in complex with guanosine/adenosine were minutely scrutinized. The relative energy findings outlined the favorability of amino-molnupiravir···keto-amino-guanosine and imino-molnupiravir···amino-adenosine optimized complexes. According to the interaction (Eint) and binding (Ebind) energy values, higher preferential base-pairing of molnupiravir with guanosine over the adenosine one was recognized with Eint/Ebind values of -31.16/-21.81 and -13.93/-12.83 kcal/mol, respectively. This could be interpreted by the presence of three and two hydrogen bonds within the former and latter complexes, respectively. Observable changes in the electronic properties and global indices of reactivity of the studied complexes also confirmed the preferential binding within the studied complexes. The findings from the quantum theory of atoms in molecules and the noncovalent interaction index also support the partially covalent nature of the investigated interactions. For both complexes, changes in thermodynamic parameters outlined the spontaneous, exothermic, and nonrandom states of the inspected interactions. Inspecting the solvent effect on the studied interactions outlined more observable amelioration within the water medium compared with the gas one. These results would be a durable ground for the forthcoming studies concerned with the interactions of the molnupiravir drug with purine nucleosides.

Therapeutic Path to Triple Knockout: Investigating the Pan-inhibitory Mechanisms of AKT, CDK9, and TNKS2 by a novel 2-Phenylquinazolinone derivative in Cancer Therapy- An In-Silico Investigation.

BACKGROUND: Blocking the oncogenic Wnt//ß-catenin pathway has of late been investigated as a viable therapeutic approach in the treatment of cancer. This involves the multi-targeting of certain members of the tankyrase-kinase family; tankyrase 2 (TNKS2), protein kinase B (AKT), and cyclin-dependent kinase 9 (CDK9), which propagate the oncogenic Wnt/ß-catenin signalling pathway. METHODS: During a recent investigation, the pharmacological activity of 2-(4-aminophenyl)-7-chloro-3H-quinazolin-4-one was repurposed to serve as a 'triple-target' inhibitor of TNKS2, AKT and CDK9. Yet, the molecular mechanism that surrounds its multi-targeting activity remains unanswered. As such, this study aims to explore the pan-inhibitory mechanism of 2-(4-aminophenyl)-7-chloro-3H-quinazolin-4-one towards AKT, CDK9, and TNKS2, using in silico techniques. RESULTS: Results revealed favourable binding affinities of -34.17 kcal/mol, -28.74 kcal/mol, and -27.30 kcal/mol for 2-(4-aminophenyl)-7-chloro-3H-quinazolin-4-one towards TNKS2, CDK9, and AKT, respectively. Pan-inhibitory binding of 2-(4-aminophenyl)-7-chloro-3H-quinazolin-4-one is illustrated by close interaction with specific residues on tankyrase-kinase. Structurally, 2-(4-aminophenyl)-7-chloro-3H-quinazolin-4-one had an impact on the flexibility, solvent-accessible surface area, and stability of all three proteins, which was illustrated by numerous modifications observed in the unbound as well as the bound states of the structures, which evidenced the disruption of their biological function. Prediction of the pharmacokinetics and physicochemical properties of 2-(4-aminophenyl)-7-chloro-3H-quinazolin-4-one further established its inhibitory potential, evidenced by the favourable absorption, metabolism, excretion, and minimal toxicity properties. CONCLUSION: The following structural insights provide a starting point for understanding the pan-inhibitory activity of 2-(4-aminophenyl)-7-chloro-3H-quinazolin-4-one. Determining the criticality of the interactions that exist between the pyrimidine ring and catalytic residues could offer insight into the structure-based design of innovative tankyrase-kinase inhibitors with enhanced therapeutic effects.

Elucidating the adsorption of 2-Mercaptopyridine drug on the aluminum phosphide (Al12P12) nanocage: A DFT study.

Adsorption amplitude of the aluminum phosphide (Al12P12) nanocage toward the 2-Mercaptopyridine (MCP) drug was herein monitored based on density functional theory (DFT) calculations. The adsorption process through MCP⋅⋅⋅Al12P12 complex in various configurations was elucidated by means of adsorption (Eads) energies. According to the energetic affirmations, the Al12P12 nanocage demonstrated potential versatility toward adsorbing the MCP drug within the investigated configurations and exhibited significant negative adsorption energies up to -27.71 kcal/mol. Upon the results of SAPT analysis, the electrostatic forces showed the highest contributions to the overall adsorption process with energetic values up to -74.36 kcal/mol. Concurrently, variations of molecular orbitals distribution along with alterations in the energy gap (Egap) and Fermi level (EFL) of the studied nanocage were denoted after adsorbing the MCP drug. The favorable impact of water solvent within the MCP⋅⋅⋅Al12P12 complexes was unveiled and confirmed by negative solvation energy (ΔEsolv) values up to -17.75 kcal/mol. According to thermodynamic parameters, the spontaneous and exothermic natures of the considered adsorption process were proclaimed by negative values of ΔG and ΔH parameters. Significant changes in the IR and Raman peaks, along with the appearance of new peaks, were noticed, confirming the occurrence of the targeted adsorption process. Furthermore, the adsorption features of the MCP drug on the Al12N12 nanocage were elucidated and compared to the Al12P12 analog. The obtained results demonstrated the higher preferability of Al12P12 nanocage than the Al12N12 candidate towards adsorbing the MCP drug without structural distortion.

Pyronaridine as a Bromodomain-Containing Protein 4-N-Terminal Bromodomain (BRD4-BD1) Inhibitor: In Silico Database Mining, Molecular Docking, and Molecular Dynamics Simulation.

BRD4 (bromodomain-containing protein 4) is an epigenetic reader that realizes histone proteins and promotes the transcription of genes linked to cancer progression and non-cancer diseases such as acute heart failure and severe inflammation. The highly conserved N-terminal bromodomain (BD1) recognizes acylated lysine residues to organize the expression of genes. As such, BD1 is essential for disrupting BRD4 interactions and is a promising target for cancer treatment. To identify new BD1 inhibitors, a SuperDRUG2 database that contains more than 4600 pharmaceutical compounds was screened using in silico techniques. The efficiency of the AutoDock Vina1.1.2 software to anticipate inhibitor-BRD4-BD1 binding poses was first evaluated based on the co-crystallized R6S ligand in complex with BRD4-BD1. From database screening, the most promising BRD4-BD1 inhibitors were subsequently submitted to molecular dynamics (MD) simulations integrated with an MM-GBSA approach. MM-GBSA computations indicated promising BD1 binding with a benzonaphthyridine derivative, pyronaridine (SD003509), with an energy prediction (ΔGbinding) of -42.7 kcal/mol in comparison with -41.5 kcal/mol for a positive control inhibitor (R6S). Pharmacokinetic properties predicted oral bioavailability for both ligands, while post-dynamic analyses of the BRD4-BD1 binding pocket demonstrated greater stability for pyronaridine. These results confirm that in silico studies can provide insight into novel protein-ligand regulators, specifically that pyronaridine is a potential cancer drug candidate.

In-Silico Mining of the Toxins Database (T3DB) towards Hunting Prospective Candidates as ABCB1 Inhibitors: Integrated Molecular Docking and Lipid Bilayer-Enhanced Molecular Dynamics Study.

Multidrug resistance (MDR) is one of the most problematic issues in chemotherapeutic carcinoma therapy. The ABCB1 transporter, a drug efflux pump overexpressed in cancer cells, has been thoroughly investigated for its association with MDR. Thus, discovering ABCB1 inhibitors can reverse the MDR in cancer cells. In the current work, a molecular docking technique was utilized for hunting the most prospective ABCB1 inhibitors from the Toxin and Toxin-Target Database (T3DB). Based on the docking computations, the most promising T3DB compounds complexed with the ABCB1 transporter were subjected to molecular dynamics (MD) simulations over 100 ns. Utilizing the MM-GBSA approach, the corresponding binding affinities were computed. Compared to ZQU (calc. -49.8 kcal/mol), Emamectin B1a (T3D1043), Emamectin B1b (T3D1044), Vincristine (T3D4016), Vinblastine (T3D4017), and Vindesine (T3D2479) complexed with ABCB1 transporter demonstrated outstanding binding affinities with ΔGbinding values of -93.0, -92.6, -93.8, -92.2, and -90.8 kcal/mol, respectively. The structural and energetic investigations confirmed the constancy of the identified T3DB compounds complexed with the ABCB1 transporter during the 100 ns MD course. To mimic the physiological conditions, MD simulations were conducted for those identified inhibitors complexed with ABCB1 transporter in the presence of a POPC membrane. These findings revealed that Emamectin B1a, Emamectin B1b, Vincristine, Vinblastine, and Vindesine are promising ABCB1 inhibitors that can reverse the MDR. Therefore, subjecting those compounds to further in-vitro and in-vivo investigations is worthwhile.

The mystery of titan hunter: Rationalized striking of the MAPK pathway via Newly synthesized 6-Indolylpyridone-3-Carbonitrile derivatives.

MAPK pathway sparkles with RTK activation, passes through subsequent downstream RAS-RAF-MEK-ERK signaling cascades, with consequent direct and indirect CDK4/6 signaling activation, and ends with cell survival, division, and proliferation. However, the emergence of anomalies such as mutations or overexpression in one or more points of the pathway could lead to cancer development and drug resistance. Therefore, designing small inhibitors to strike multitudinous MAPK pathway steps could be a promising synergistic strategy to confine cancer. In this study, twelve 6-indolylpyridone-3-carbonitrile candidates were synthesized and assessed in vitro for antineoplastic activity using four cancer cell lines. The initial antiproliferative screening revealed that compounds 3g, 3h, and 3i were the most potent candidates (GI% Avg = 70.10, 73.94, 74.33%, respectively) compared to staurosporine (GI% Avg = 70.99%). The subsequent safety and selectivity assessment showed that 3h exhibited sub-micromolar inhibition against lung cancer cells (HOP-92 GI50 = 0.75 µM) and 13.7 times selectivity toward cancerous cells over normal cells. As a result, 3h was nominated for deep mechanistic studies which evidenced that compound 3h impressively blocks multiple keystones of the MAPK pathway with nanomolar potency (EGFRWT IC50 = 281 nM, c-MET IC50 = 205 nM, B-RAFWT IC50 = 112 nM, and CDK4/6 IC50 = 95 and 184 nM, respectively). Surprisingly, 3h showed a remarkable potency against mutated EGFR and B-RAF, being 4 and 1.3 more selective to the mutated enzymes over the wild-type forms (EGFRT790M IC50 = 69 nM and B-RAFV600E IC50 = 83 nM). Ultimately, combined molecular docking and molecular dynamics (MD) calculations were executed to inspect the mode of binding and the complex stability of 3h towards the keystones of the MAPK pathway.

SuperNatural inhibitors to reverse multidrug resistance emerged by ABCB1 transporter: Database mining, lipid-mediated molecular dynamics, and pharmacokinetics study.

An effective approach to reverse multidrug resistance (MDR) is P-glycoprotein (P-gp, ABCB1) transport inhibition. To identify such molecular regulators, the SuperNatural II database, which comprises > 326,000 compounds, was virtually screened for ABCB1 transporter inhibitors. The Lipinski rule was utilized to initially screen the SuperNatural II database, identifying 128,126 compounds. Those natural compounds were docked against the ABCB1 transporter, and those with docking scores less than zosuquidar (ZQU) inhibitor were subjected to molecular dynamics (MD) simulations. Based on MM-GBA binding energy (ΔGbinding) estimations, UMHSN00009999 and UMHSN00097206 demonstrated ΔGbinding values of -68.3 and -64.1 kcal/mol, respectively, compared to ZQU with a ΔGbinding value of -49.8 kcal/mol. For an investigation of stability, structural and energetic analyses for UMHSN00009999- and UMHSN00097206-ABCB1 complexes were performed and proved the high steadiness of these complexes throughout 100 ns MD simulations. Pharmacokinetic properties of the identified compounds were also predicted. To mimic the physiological conditions, MD simulations in POPC membrane surroundings were applied to the UMHSN00009999- and UMHSN00097206-ABCB1 complexes. These results demonstrated that UMHSN00009999 and UMHSN00097206 are promising ABCB1 inhibitors for reversing MDR in cancer and warrant additional in-vitro/in-vivo studies.

Adsorption of Favipiravir on pristine graphene nanosheets as a drug delivery system: a DFT study.

The efficiency of pristine graphene (GN) in the delivery process of the Favipiravir (FPV) anti-COVID-19 drug was herein revealed within the FPV⋯GN complexes in perpendicular and parallel configurations in terms of the density functional theory (DFT) method. Adsorption energy findings unveiled that the parallel configuration of FPV⋯GN complexes showed higher desirability than the perpendicular one, giving adsorption energy up to -15.95 kcal mol-1. This favorability could be interpreted as a consequence of the contribution of π-π stacking to the overall strength of the adsorption process in the parallel configuration. Frontier molecular orbitals (FMO) findings demonstrated the ability of the GN nanosheet to adsorb the FPV drug by the alteration in the EHOMO, ELUMO, and Egap values before and after the adsorption process. Based on Bader charge results, the FPV drug and GN sheet exhibited electron-donating and -accepting characters, respectively, which was confirmed by the negative sign of the computed charge transfer (Qt) values. The FPV(R)⋯T@GN complex showed the most desirable Qt value of -0.0377e, which was in synoptic with the adsorption energy pattern. Electronic properties of GN were also altered after the adsorption of the FPV drug in both configurations, with more observable changes in the parallel one. Interestingly, the Dirac point of the GN sheet coincided with the Fermi level after the adsorption process, indicating that the adsorption process unaffected the presence of the Dirac point. The occurrence of the adsorption process was also noticed by the existence of new bands and peaks in the band structure and DOS plots, respectively. Short recovery time rendered the GN nanosheet an efficient FPV drug delivery system. The obtained findings provide new insight into the biomedical applications of the GN sheet as a promising drug delivery system.

On the Use of Graphene Nanosheets for Drug Delivery: A Case Study of Cisplatin and Some of Its Analogs.

Graphene (GN) nanosheets have been widely exploited in biomedical applications as potential nanocarriers for various drugs due to their distinct physical and chemical properties. In this regard, the adsorption behavior of cisplatin (cisPtCl2) and some of its analogs on a GN nanosheet was investigated in perpendicular and parallel configurations by using density functional theory (DFT). According to the findings, the most significant negative adsorption energies (Eads) within the cisPtX2⋯GN complexes (where X = Cl, Br, and I) were observed for the parallel configuration, with values up to -25.67 kcal/mol at the H@GN site. Within the perpendicular configuration of the cisPtX2⋯GN complexes, three orientations were investigated for the adsorption process, namely, X/X, X/NH3, and NH3/NH3. The negative Eads values of the cisPtX2⋯GN complexes increased with the increasing atomic weight of the halogen atom. The Br@GN site showed the largest negative Eads values for the cisPtX2⋯GN complexes in the perpendicular configuration. The Bader charge transfer outcomes highlighted the electron-accepting properties of cisPtI2 within the cisPtI2⋯GN complexes in both configurations. The electron-donating character of the GN nanosheet increased as the electronegativity of the halogen atom increased. The band structure and density of state plots revealed the occurrence of the physical adsorption of the cisPtX2 on the GN nanosheet, which was indicated by the appearance of new bands and peaks. Based on the solvent effect outlines, the negative Eads values generally decreased after the adsorption process in a water medium. The recovery time results were in line with the Eads findings, where the cisPtI2 in the parallel configuration took the longest time to be desorbed from the GN nanosheet with values of 61.6 × 108 ms at 298.15 K. The findings of this study provide better insights into the utilization of GN nanosheets in drug delivery applications.

Terminators or Guardians? Design, Synthesis, and Cytotoxicity Profiling of Chalcone-Sulfonamide Hybrids.

With a "less is more" philosophy, a series of 15 chalcone-sulfonamide hybrids were designed anticipating synergistic anticancer activity. The aromatic sulfonamide moiety was included as a known direct inhibitor of carbonic anhydrase IX activity through its zinc chelating property. The chalcone moiety was incorporated as an electrophilic stressor to indirectly inhibit carbonic anhydrase IX cellular activity. Screening by the Developmental Therapeutics Program of the National Cancer Institute, NCI-60, revealed that 12 derivatives were potent inhibitors of cancer cell growth in multiple cell lines and were promoted to the five-dose screen. The cancer cell growth inhibition profile indicated sub- to two-digit micromolar potency (GI50 down to 0.3 µM and LC50 as low as 4 µM) against colorectal carcinoma cells, in particular. Unexpectedly, most compounds demonstrated low to moderate potency as direct inhibitors of carbonic anhydrase catalytic activity in vitro, with 4d being the most potent, having an average Ki value of 4 µM. Compound 4j showed ca. six-fold selectivity to carbonic anhydrase IX over the other tested isoforms in vitro. Cytotoxicity of both 4d and 4j in live HCT116, U251, and LOX IMVI cells under hypoxic conditions confirmed their targeting of carbonic anhydrase activity. Elevation of oxidative cellular stress was stipulated from the increase in Nrf2 and ROS levels in 4j-treated colorectal carcinoma, HCT116, cells compared to the control. Compound 4j arrested the cell cycle of HCT116 cells at the G1/S phase. In addition, both 4d and 4j showed up to 50-fold cancer cell selectivity compared to the non-cancerous HEK293T cells. Accordingly, this study presents 4d and 4j being new, synthetically accessible, simplistically designed derivatives as potential candidates to be further developed as anticancer therapeutics.

Multi-dimensional structural footprint identification for the design of potential scaffolds targeting METTL3 in cancer treatment from natural compounds.

CONTEXT: [Formula: see text]-adenosine-methyltransferase (METTL3) is the catalytic domain of the 'writer' proteins which is involved in the post modifications of [Formula: see text]-methyladinosine ([Formula: see text]). Though its activities are essential in many biological processes, it has been implicated in several types of cancer. Thus, drug developers and researchers are relentlessly in search of small molecule inhibitors that can ameliorate the oncogenic activities of METTL3. Currently, STM2457 is a potent, highly selective inhibitor of METTL3 but is yet to be approved. METHODS: In this study, we employed structure-based virtual screening through consensus docking by using AutoDock Vina in PyRx interface and Glide virtual screening workflow of Schrodinger Glide. Thermodynamics via MM-PBSA calculations was further used to rank the compounds based on their total free binding energies. All atom molecular dynamics simulations were performed using AMBER 18 package. FF14SB force fields and Antechamber were used to parameterize the protein and compounds respectively. Post analysis of generated trajectories was analyzed with CPPTRAJ and PTRAJ modules incorporated in the AMBER package while Discovery studio and UCSF Chimera were used for visualization, and origin data tool used to plot all graphs. RESULTS: Three compounds with total free binding energies higher than STM2457 were selected for extended molecular dynamics simulations. The compounds, SANCDB0370, SANCDB0867, and SANCDB1033, exhibited stability and deeper penetration into the hydrophobic core of the protein. They engaged in relatively stronger intermolecular interactions involving hydrogen bonds with resultant increase in stability, reduced flexibility, and decrease in the surface area of the protein available for solvent interactions suggesting an induced folding of the catalytic domain. Furthermore, in silico pharmacokinetics and physicochemical analysis of the compounds revealed good properties suggesting these compounds could serve as promising MEETL3 entry inhibitors upon modifications and optimizations as presented by natural compounds. Further biochemical testing and experimentations would aid in the discovery of effective inhibitors against the berserk activities of METTL3.

Exploring Probenecid Derived 1,3,4-Oxadiazole-Phthalimide Hybrid as α-Amylase Inhibitor: Synthesis, Structural Investigation, and Molecular Modeling.

1,3,4-Oxadiazole moiety is a crucial pharmacophore in many biologically active compounds. In a typical synthesis, probenecid was subjected to a sequence of reactions to obtain a 1,3,4-oxadiazole-phthalimide hybrid (PESMP) in high yields. The NMR (1H and 13C) spectroscopic analysis initially confirmed the structure of PESMP. Further spectral aspects were validated based on a single-crystal XRD analysis. Experimental findings were confirmed afterwards by executing a Hirshfeld surface (HS) analysis and quantum mechanical computations. The HS analysis showed the role of the π⋯π stacking interactions in PESMP. PESMP was found to have a high stability and lower reactivity in terms of global reactivity parameters. α-Amylase inhibition studies revealed that the PESMP was a good inhibitor of α-amylase with an s value of 10.60 ± 0.16 µg/mL compared with that of standard acarbose (IC50 = 8.80 ± 0.21 µg/mL). Molecular docking was also utilized to reveal the binding pose and features of PESMP against the α-amylase enzyme. Via docking computations, the high potency of PESMP and acarbose towards the α-amylase enzyme was unveiled and confirmed by docking scores of -7.4 and -9.4 kcal/mol, respectively. These findings shine a new light on the potential of PESMP compounds as α-amylase inhibitors.

Potential drug candidates as P-glycoprotein inhibitors to reverse multidrug resistance in cancer: an in silico drug discovery study.

The failure of chemotherapy in the treatment of carcinoma is mainly due to the development of multidrug resistance (MDR), which is largely caused by the overexpression of P-glycoprotein (P-gp/ABCB1/MDR1). Until recently, the 3D structure of the P-gp transporter has not been experimentally resolved, which restricted the discovery of prospective P-gp inhibitors utilizing in silico techniques. In this study, the binding energies of 512 drug candidates in clinical or investigational stages were assessed as potential P-gp inhibitors employing in silico methods. On the basis of the available experimental data, the performance of the AutoDock4.2.6 software to predict the drug-P-gp binding mode was initially validated. Molecular docking and molecular dynamics (MD) simulations combined with molecular mechanics-generalized Born surface area (MM-GBSA) binding energy computations were subsequently conducted to screen the investigated drug candidates. Based on the current results, five promising drug candidates, namely valspodar, dactinomycin, elbasvir, temsirolimus, and sirolimus, showed promising binding energies against P-gp transporter with ΔGbinding values of -126.7, -112.1, -111.9, -102.9, and -101.4 kcal/mol, respectively. The post-MD analyses revealed the energetical and structural stabilities of the identified drug candidates in complex with the P-gp transporter. Furthermore, in order to mimic the physiological conditions, the potent drugs complexed with the P-gp were subjected to 100 ns MD simulations in an explicit membrane-water environment. The pharmacokinetic properties of the identified drugs were predicted and demonstrated good ADMET characteristics. Overall, these results indicated that valspodar, dactinomycin, elbasvir, temsirolimus, and sirolimus hold promise as prospective P-gp inhibitors and warrant further invitro/invivo investigations.

In silico drug discovery of SIRT2 inhibitors from natural source as anticancer agents.

Sirtuin 2 (SIRT2) is a member of the sirtuin protein family, which includes lysine deacylases that are NAD+-dependent and organize several biological processes. Different forms of cancer have been associated with dysregulation of SIRT2 activity. Hence, identifying potent inhibitors for SIRT2 has piqued considerable attention in the drug discovery community. In the current study, the Natural Products Atlas (NPAtlas) database was mined to hunt potential SIRT2 inhibitors utilizing in silico techniques. Initially, the performance of the employed docking protocol to anticipate ligand-SIRT2 binding mode was assessed according to the accessible experimental data. Based on the predicted docking scores, the most promising NPAtlas molecules were selected and submitted to molecular dynamics (MD) simulations, followed by binding energy computations. Based on the MM-GBSA binding energy estimations over a 200 ns MD course, three NPAtlas compounds, namely NPA009578, NPA006805, and NPA001884, were identified with better ΔGbinding towards SIRT2 protein than the native ligand (SirReal2) with values of - 59.9, - 57.4, - 53.5, and - 49.7 kcal/mol, respectively. On the basis of structural and energetic assessments, the identified NPAtlas compounds were confirmed to be steady over a 200 ns MD course. The drug-likeness and pharmacokinetic characteristics of the identified NPAtlas molecules were anticipated, and robust bioavailability was predicted. Conclusively, the current results propose potent inhibitors for SIRT2 deserving more in vitro/in vivo investigation.

Adsorption of Molnupiravir anti-COVID-19 drug over B12N12 and Al12N12 nanocarriers: a DFT study.

The potentiality of B12N12 and Al12N12 nanocarriers to adsorb Molnupiravir anti-COVID-19 drug, for the first time, was herein elucidated using a series of quantum mechanical calculations. Density function theory (DFT) was systematically utilized. Interaction (Eint) and adsorption (Eads) energies showed higher negative values for Molnupiravir···Al12N12 complexes compared with Molnupiravir···B12N12 analogs. Symmetry-adapted perturbation theory (SAPT) results proclaimed that the adsorption process was predominated by electrostatic forces. Notably, the alterations in the distributions of the molecular orbitals ensured that the B12N12 and Al12N12 nanocarriers were efficient candidates for delivering the Molnupiravir drug. From the thermodynamic perspective, the adsorption process of Molnupiravir drug over B12N12 and Al12N12 nanocarriers had spontaneous and exothermic nature. The ESP, QTAIM, NCI, and DOS observations exposed the tendency of BN and Al12N12 to adsorb the Molnupiravir drug. Overall, these findings proposed that the B12N12 and Al12N12 nanocarriers are efficient aspirants for the development of the Molnupiravir anti-COVID-19 drug delivery process.Communicated by Ramaswamy H. Sarma.

Chetomin, a SARS-CoV-2 3C-like Protease (3CLpro) Inhibitor: In Silico Screening, Enzyme Docking, Molecular Dynamics and Pharmacokinetics Analysis.

The emergence of the Coronavirus Disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has led to over 6 million deaths. The 3C-like protease (3CLpro) enzyme of the SARS-CoV-2 virus is an attractive druggable target for exploring therapeutic drug candidates to combat COVID-19 due to its key function in viral replication. Marine natural products (MNPs) have attracted considerable attention as alternative sources of antiviral drug candidates. In looking for potential 3CLpro inhibitors, the MNP database (>14,000 molecules) was virtually screened against 3CLpro with the assistance of molecular docking computations. The performance of AutoDock and OEDocking software in anticipating the ligand-3CLpro binding mode was first validated according to the available experimental data. Based on the docking scores, the most potent MNPs were further subjected to molecular dynamics (MD) simulations, and the binding affinities of those molecules were computed using the MM-GBSA approach. According to MM-GBSA//200 ns MD simulations, chetomin (UMHMNP1403367) exhibited a higher binding affinity against 3CLpro than XF7, with ΔGbinding values of −55.5 and −43.7 kcal/mol, respectively. The steadiness and tightness of chetomin with 3CLpro were evaluated, revealing the high stabilization of chetomin (UMHMNP1403367) inside the binding pocket of 3CLpro throughout 200 ns MD simulations. The physicochemical and pharmacokinetic features of chetomin were also predicted, and the oral bioavailability of chetomin was demonstrated. Furthermore, the potentiality of chetomin analogues −namely, chetomin A-D− as 3CLpro inhibitors was investigated. These results warrant further in vivo and in vitro assays of chetomin (UMHMNP1403367) as a promising anti-COVID-19 drug candidate.

Mechanistic Insight of Synthesized 1,4-Dihydropyridines as an Antidiabetic Sword against Reactive Oxygen Species.

The pharmacologically privileged DHP derivatives were synthesized using the pragmatic multicomponent Hantzsch synthesis to screen the antidiabetic activity. Initially, the candidates were screened using an in vivo blood glucose test, where compound 8b showed the most prominent antidiabetic effect (% potency = 218%) compared to glimepiride. Then, a propositioned structure-activity relationship study was executed to reveal that longer side chains decreased the DHP's antidiabetic action. Mechanistically, compound 8b diminished ROS in ß-cells and muscle cells simultaneously, which was proved by enhanced serum biochemical markers. Also, compound 8b decreased blood glucose by α-glucosidase inhibition (IC50 = 4.48 ± 0.32 µM), compared to acarbose (7.40 ± 0.41 µM), based selectively on the plasma window of 8b. Acarbose demonstrated auspicious inhibitor activity according to the binding affinity (ΔGbinding), which was slightly lower than that of compound 8b (-54.7 and -46.8 kcal/mol, respectively). During the 100 ns molecular dynamics simulations, the structural and energetic assessments exposed the high consistency of compound 8b to bind to the α-glucosidase.