CONFORMATIONAL STUDY OF MOLECULES IN A BIOLOGICAL ENVIRONMENT, DESIGN OF INHIBITORS OF HUMAN AMINOPEPTIDASE M1 IMPLICATED IN CANCER THERAPY

Objective: A novel subnanomolar anticancer hydroxamic acid containing drug candidates, inhibitors of human M1 aminopeptidase (APN) a recent validated target and has reached the predicted subnanomolar range of inhibitory potency. Methods: A quantitative structure activity relationships (QSAR) complexation model has been developed from a compounds of 37 hydroxamic acid derivatives (AHD1-37 as training set, TS) to establish a linear correlation between the calculated relative Gibbs free energies (GFE: ΔΔGcom) of APN-AHDx complex formation and the experimental inhibition potency (Kiexp). The predictive power of the QSAR model was then validated first with 9 other AHDs not included in the TS and thereafter with the generation of a 3D-QSAR-PH4 pharmacophore (PH4) model to screen the AHD chemical subspace built as a virtual combinatorial library of more than 58,644 AHD analogs). Finally the best PH4 hits were evaluated with the initial QSAR model for predicted potency (Kipre) and pharmacokinetic profile. Results: The QSAR model linear correlation equation: pKiexp=-0.1901×∆∆Gcom + 8.2886 , R2=0.94, the subsequent PH4 model linear correlation between experiment and PH4-estimated Ki: pKiexp=1.0006× pKipre + 0.0028, R2=0.79 documents the high predictive power of this approach. Finally the screening of the virtual library of AHD analogs yielded 95 orally bioavailable candidates the best reaching a predicted potency (Kipre) of 50 pM and displaying favorable pharmacokinetic profile. Conclusion: The combined use of molecular modeling (QSAR) and in silico PH4-based screening of the hypothetical combinatorial library has resulted in proposed and predicted potent anticancer candidates with a suitable pharmacokinetic profile.                        Peer Review History: Received: 3 August 2023; Revised: 12 September; Accepted: 25 October, Available online: 15 November 2023 Academic Editor: Dr. Nuray Arı, Ankara University, Turkiye, [email protected] Received file:                             Reviewer's Comments: Average Peer review marks at initial stage: 7.0/10 Average Peer review marks at publication stage: 9.0/10 Reviewers: Prof. Hassan A.H. Al-Shamahy, Sana'a University, Yemen, [email protected] Prof. Dr. A. Hakan AKTAŞ, Süleyman Demirel University, Faculty of Science and Art, Department of Chemistry, Isparta-Turkey, [email protected]

Virtual design of novel Plasmodium falciparum cysteine protease falcipain-2 hybrid lactone–chalcone and isatin–chalcone inhibitors probing the S2 active site pocket

We report computer-aided design of new lactone–chalcone and isatin–chalcone (HLCIC) inhibitors of the falcipain-2 (PfFP-2). 3D models of 15 FP-2:HLCIC1-15 complexes with known observed activity (IC50exp) were prepared to establish a quantitative structure–activity (QSAR) model and linear correlation between relative Gibbs free energy of enzyme:inhibitor complex formation (ΔΔGcom) and IC50exp: pIC50exp = −0.0236 × ΔΔGcom+5.082(#); R2 = 0.93. A 3D pharmacophore model (PH4) derived from the QSAR directed our effort to design novel HLCIC analogues. During the design, an initial virtual library of 2621440 HLCIC was focused down to 18288 drug-like compounds and finally, PH4 screened to identify 81 promising compounds. Thirty-three others were added from an intuitive substitution approach intended to fill better the enzyme S2 pocket. One hundred and fourteen theoretical IC50 (IC50pre) values were predicted by means of (#) and their pharmacokinetics (ADME) profiles. More than 30 putative HLCICs display IC50pre 100 times superior to that of the published most active training set inhibitor HLCIC1